Procrastinating Polymath

TEMPLE GRANDIN AND MARK J. DEESING

Genetics and the Behavior of Domestic Animals (Chapter One) Acedemic Press 1998 San Diego, California ISBN # 0-12295130-1

Department of Animal Science Colorado State University Fort Collins, Colorado

A bright orange sun is setting on a prehistoric horizon. A lone hunter is on his way home from a bad day at hunting. As he crosses the last ridge before home. a quick movement in the rocks off to his right catches his attention. Investigating, he discovers some wolf pups hiding in a shallow den. He exclaims, "Wow ... cool! The predator... in infant form."

After a quick scan of the area for adult wolves, he cautiously approaches. The pups are all clearly frightened and huddle close together as he kneels in front of the den . . . all except one. The darkest colored pup shows no fear of the man's approach. "Come here you little predator! Let me take a look at you, he says. After a mutual bout of petting by the man and licking by the wolf, the man suddenly has an idea. "If I take you home with me tonight, maybe mom and the kids will forgive me for not catching dinner . . . again."

INTRODUCTION

The opening paragraphs depict a hypothetical scenario of man first taming the wolf. Although we have tried to make light of this event, the fact is that no one knows exactly how or why this first encounter took place. The earliest archeological estimate indicates that it occurred in the late Glacial period, approximately 14,000 years BC (Boessneck, 1985). Another scenario is that wolves domesticated themselves. The presumption is that calm wolves with low levels of fear were likely to scavenge near human settlements. Both Coppinger and Smith (1983) and Zeuner (1963) suggest that wild species which later became domesticants started out as camp followers. Some wolves were believed to have scavenged near human settlements or followed hunting parties; wild cattle supposedly invaded grain fields, and wild cats may have invaded grainaries while hunting for mice. However, the most recent evidence obtained by sequencing mitochondrial DNA of 67 dog breeds and wolves from 27 localities indicates that dogs may have diverged from wolves over 100,000 years ago (Vita et al., 1997).

In any event, wolves kept for companions had to be easy to handle and socialize to humans. Within a few generations, early humans may have turned wolves into dogs by selecting and breeding the tamest ones. Thousands of years ago, humans were not aware that behavior in animals was heritable. However, even today people who raise dogs, horses, pigs, cattle, or chickens notice differences in the behavior of the offspring. Some animals are friendly and readily approach people, while others may be shy and nervous.

GENETIC EFFECTS OF DOMESTICATION

Price (1984) defined domestication as a process by which a population of animals becomes adapted to man and the captive environment by some combination of genetic changes occurring over generations and environmentally induced developmental events recurring during each generation:' In long-term selection experiments designed to study the consequences of selection for the tame" domesticated type of behavior, Belyaev (1979) and Belyaev et al. (1981) studied foxes reared for their fur. The red fox (Vulpes fulva) has been raised on seminatural fur farms for over 100 years and was selected for fur traits and not behavioral traits. However, they demonstrate three distinctly different characteristic responses to man. Thirty percent were extremely aggressive toward man, 60% were either fearful or fearfully aggressive, and 10% displayed a quiet exploratory reaction without either fear or aggression. The objective of this experiment was to breed animals similar in behavior to the domestic dog. By selecting and breeding the tamest individuals, 20 years later the experiment succeeded in turning wild foxes into tame, border collie-like fox-dogs. The highly selected "tame" population of (fox-dog) foxes actively sought human contact and would whine and wag their tails when people approached (Belyaev 1979). This behavior was in sharp contrast to wild foxes which showed extremely aggressive and fearful behavior toward man. Keeler et al.(1970) described this behavior:

Vulpes fulva (the wild fox) is a bundle of jangled nerves. We had observed that when first brought into captivity as an adult, the red fox displays a number of symptoms that are in many ways similar to those observed in psychosis. They resemble a wide variety of phobias, especially fear of open spaces, movement, white objects, sounds, eyes or lenses, large objects, and man, and they exhibit panic, anxiety, fear, apprehension and a deep trust of the environment~ They are 1) catalepsy-like frozen positions, accompanied by blank stares; 2) fear of sitting down; 3) withdrawal; 4) runaway flight reactions; and 5) aggressiveness. Sometimes the strain of captivity makes them deeply disturbed and confused, or may produce a depression- like state. Extreme excitation and restlessness may also be observed in some individuals in response to many changes in the physical environment. Most adult red foxes soon after capture break off their canine teeth on the mesh of our expanded metal cage in their attempts to escape. A newly captured fox is known to have torn at the wooden door of his cage in a frenzy until he dropped dead from exhaustion.

Although the stress of domestication is great, Belyaev (1979) and Belyaev et al. (1981) concluded that selection for tameness was effective in spite of the many undesirable characteristics associated with tameness. For example, the tame foxes shed during the wrong season and developed black and white patterned fur, and changes were found in their hormone profiles. This means that the monoestrus (once a year) cycle of reproduction was disturbed and the animals would breed at any time of the year. Furthermore, changes in behavior occurred simultaneously with changes in tail position and ear shape, and the appearance of a white muzzle, forehead blaze, and white shoulder hair. The white color pattern on the head is similar to many domestic animals (Belyaev 1979) (Figs. 1.1 and 1.2). The most dog-like foxes had white spots and patterns on their heads, drooping ears, and curled tails and looked more like dogs than the foxes that avoided people. The behavioral and morphological (appearance) changes were also correlated with corresponding changes in the levels of gender hormones. The tame foxes had higher levels of the neurotransmitter serotonin (Popova et al., 1975). Serotonin is known to inhibit some kinds of aggression (Belyaev, 1979), and serotonin ~levels are increased in the brains of people who take Prozac (fluoxetine).

The study of behavioral genetics can help explain why selection for calm temperament was linked to physical and neurochemical changes in Belyaev's foxes. Behavior geneticists and animal scientists are interested in understanding effects on behavior due to genetic influences or those which are due to environment and learning.

A BRIEF HISTORICAL REVIEW OF ANIMAL BEHAVIOR STUDY

This historical review is not intended to he comprehensive; our objective is to discuss some of the early discoveries that are important for our current understanding of animal behavior, with particular emphasis on genetic influence on behavior in domestic animals.

Early in the 17th century, Descartes came to the conclusion "that the bodies of animals and men act wholly like machines and move in accordance with purely mechanical laws" (in Huxley 1874). After Descartes, others undertook the task of explaining behavior as reactions to purely physical, chemical, or mechanical events. For the next three centuries scientific thought on behavior oscillated between a mechanistic view that animals are '~automatons" moving through life without consciousness or self-awareness and an opposing view that animals had thoughts and feelings similar to those of humans.

In "On the Origin of the Species" (1859), Darwin's ideas about evolution began to raise serious doubts about the mechanistic view of animal behavior. He noticed that animals share many physical characteristics and was one of the first to discuss variation within a species, both in their behavior and in their physical appearance. Darwin believed that artificial selection and natural selection were intimately associated (Darwin, 1868) and cleverly outlined the theory of evolution without any knowledge of genetics. In "The Descent of Man" (1871) Darwin concluded that temperament traits in domestic animals are inherited. He also believed, as did many other scientists of his tune, that animals have subjective sensations and could think. Darwin wrote: "The differences in mind between man and the higher animals, great as it is, is certainly one of degree and not of kind."

Other scientists realized the implications of Darwin's theory on animal behavior and conducted experiments investigating instinct. Herrick (1908) observed the behavior of wild birds in order to determine, first, how their instincts are modified by their ability' to learn, and second, the degree of intelligence they attain. On the issue of thinking in animals, Schroeder (1914) concluded: ~The solution, if it ever comes, can scarcely fail to illuminate, if not the animal mind, at least that of man." It is evident that by the end of the 19th century, scientists who studied animal behavior in natural environments learned that the mechanical approach could not explain all behavior.

Behaviorism

During the middle of the 20th century', scientific thought again reverted to the mechanical approach and behaviorism reigned throughout America. The behaviorists ignored both genetic effects on behavior and the ability of animals to engage in flexible problem solving. The founder of behaviorism, J. B. Watson (1930), stated that differences in the environment can explain all differences in behavior." He did not believe that genetics had any effect on behavior. In The Behavior of Organisms]' the psychologist B. F Skinner (1958) wrote that all behavior could be explained by the principles of stimulus-response and operant conditioning.

The first author visited with Dr. Skinner at Harvard University in 1968. Skinner responded to a question from her about the need for brain research by saying, '~We don't need to know about the brain because we have operant conditioning" (T. Grandin, personal communication, 1968). Operant conditioning uses food rewards and punishments to train animals and shape their behavior. In a simple Skinner box experiment, a rat can be trained to push a lever to obtain food when a green light turns on, or to push a lever very quickly to avoid a shock when a red light appears. The signal light is the '~conditioned stimulus." Rats and other animals can be trained to perform a complex sequence of behaviors by chaining together a series of simple operant responses. Skinner believed that even the most complex behaviors can be explained as a series of conditioned responses.

However, a rat's behavior is very limited in a Skinner box. It's a world with very little variation, and the rat has little opportunity to use its natural behaviors. It simply learns to push a lever to obtain food or prevent a shock. Skinnerian principles explain why a rat behaves a certain way in the sterile confines of a 30 x 30-cm Plexiglas box, but they don't reveal much about the behavior of a rat in the local dump. Outside of the laboratory, a rat's behavior is more complex.

Instincts versus Learning

Skinner's influence on scientific thinking slowed a bit in 1961 following the publication of ~The Misbehavior of Organisms" by Brelands and Brelands. This paper described how Skinnerian behavioral principles collided with instincts. The Brelands were trained Skinnerian behaviorists who attempted to apply the strict principles of operant conditioning to animals trained at fairs and carnivals. Ten years before this classic paper, the Brelands (1951) wrote, we are wholly affirmative and optimistic that principles derived from the laboratory can be applied to the extensive control of animal behavior under non laboratory condition]' However, by 1961, after training more than 6000 animals as diverse as reindeer, cockatoos, raccoons, porpoises, and whales for exhibition in zoos, natural history museums, department store displays, fair and trade convention exhibits, and television, the Brelands wrote a second article featured in the American Psychologist (1961), which stated, our backgrounds in behaviorism had not prepared us for the shock of some of our failures."

One of the failures occurred when the Brelands tried to teach chickens to stand quietly on a platform for 10 to 12 seconds before they received a food reward. The chickens would stand quietly on a platform in the beginning of training; however, once they learned to associate the platform with a food reward, half (50%) started scratching the platform, and another 25% developed other behaviors, such as pecking the platform. The Brelands salvaged this disaster by developing a wholly unplanned exhibit involving a chicken that turned on a juke box and danced. They first trained the chickens to pull a rubber loop which turned on some music. When the music started, the chickens would jump on the platform and start scratching and pecking until the food reward was delivered. This exhibit made use of the chicken's instinctive food-getting behavior. The first author remembers as a teenager seeing a similar exhibit, at the Arizona State Fair, of a piano-playing chicken in a little red barn. The hen would peck the keys of a toy piano when a quarter was put in the slot and would stop when the food came down the chute. This exhibit also worked because it was similar to a Skinner box in the laboratory.

The Brelands experienced another classic failure when they tried to teach raccoons to put coins in a piggy bank. Because raccoons are adept at manipulating objects with their hands, this task was initially easy. As training progressed, however, the raccoons began to rub the coins before depositing them in the bank. This behavior was similar to the washing behavior raccoons do as instinctive food-getting behavior. The raccoons at first had difficulty letting go of the coin and would hold and rub it. However, when the Brelands introduced a second coin, the raccoons became almost impossible to train. Rubbing the coins together 'in a most miserly fashion]' the raccoons got worse and worse as time went on. The Brelands concluded that the innate behaviors were suppressed during the early stages of training and sometimes long into the training, but as training progressed, instinctive food-getting behaviors gradually replaced the conditioned behavior. The animals were unable to override their instincts and thus a conflict between conditioned and instinctive behaviors occurred.

Ethology

While Skinner and his fellow Americans were refining the principles of operant conditioning on thousands of rats and mice, ethology was being developed in Europe. Ethology is the study of animal behavior in natural environments and the primary concern of the ethologists is instinctive or innate behavior (Eibl-Eibesfeldt and Kramer, 1958). Essentially, ethologists believe that the secrets to behavior are found in the animals genes and in the way the genes have been modified during evolution to deal with particular environments. The ethological trend originated with Whitman (1898), who regarded instincts as congenital reactions which are so constant and characteristic for each species that, like morphological structures, they may he of taxonomic significance. A similar opinion was held by Heinroth (1918). He trained newly hatched fledglings in isolation from adult birds of their own species and found that instinctive movements such as preening, shaking, and scratching were performed by young birds without observing other birds.

Understanding the mechanisms and programming that result in innate behavioral patterns and the motivations behind why animals behave the way they do is the primary focus of ethologists. Konrad Lorenz (1939, 1965, 1981) and Niko Tinbergen (1948, 1951) cataloged the behavior of many animals in their natural environments. Together they developed the ethogram. An ethogram is a complete listing of all the behaviors that an animal performs in its natural environment. The ethogram includes both innate and learned behaviors.

An interesting contribution to ethology came from studies on egg-rolling behavior in the greylag goose (Lorenz, 1965, 1981). He observed that when a brooding goose notices an egg outside her nest, an innate instinctive program is triggered to retrieve it. The goose fixates on the egg, rises to extend her neck and bill out over it, then gently rolls it back to the nest. This behavior is performed in a highly mechanical way If the egg is removed as the goose begins to extend her neck, she still completes the pattern of rolling the nonexistent egg back to the nest. Lorenz (1939) and Tinbergen (1948) termed this a 'fixed action pattern." Remarkably, Tinbergen also discovered that brooding geese can be stimulated to perform egg rolling on such items as beer cans and baseballs. The fixed action pattern of rolling the egg back to the nest can be triggered by anything outside the nest that even marginally resembles an egg. Tinbergen realized that geese possess a genetic-releasing mechanism for this fixed action pattern. Lorenz and Tinbergen called the object that triggers the release of a fixed action pattern "sign stimuli." When a mother bird sees the gaping mouth of her young, it triggers the maternal feeding behavior and the mother feeds her young. The gaping mouth is another example of sign stimuli that acts as a switch and turns on the genetically determined program (Herrick, 1908; Tinbergen, 1951).

Ethologists also explained the innate escape response of newly hatched goslings. When goslings are tested with a cardboard silhouette in the shape of a hawk moving overhead, it triggers a characteristic escape response. The goslings will crouch or run. However, when the silhouette is reversed to look like a goose, there is no effect (Tinbergen, 1951). Several members of the research community doubted the existence of such a hard-wired instinct because other scientists failed to repeat these experiments (Hirsh et al., 1955). Recently Canty and Gould (1995) repeated the classic experiments and explained why the other experiments failed. In the first place, goslings only respond to the silhouette when they are under 7 days old. Second, a large silhouette which casts a shadow must be used; third, goslings respond to the perceived predator differently depending on the circumstances. For example, birds tested alone try to run away from the hawk silhouette and birds reared and tested in groups tend to crouch (Canty and Gould, 1995). Nevertheless, fear is likely to be the basis of the response. Ducklings were shown to have higher heart rate variability when they saw the hawk silhouette (Mueller and Parker, 1980). Research by Balaban (1997) indicates that species-specific vocalizations and head movements in chickens and quail are controlled by distinct cell groups in the brain. To prove this, Balaban transplanted neural tube cells from developing quail embryos into chicken embryos. Chickens hatched from the transplanted eggs exhibited species-specific quail songs and bobbing head movements.

Do similar fixed action patterns occur in mammals? Fentress (1973) conducted an experiment on mice which clearly showed that animals have instinctive species-specific behavior patterns which do not require learning. Day-old baby mice were anesthetized and had a portion of their front legs amputated. Enough of the leg remained that the mice could easily walk. The operations were performed before the baby mice had fully coordinated movements so there was no opportunity for learning. When the mice became adults, they still performed the species-specific face-washing behavior; normal mice close their eye just prior to the foreleg passing over the face, and in the amputees the eye still closed before the nonexistent paw hit it. The amputees performed the face- washing routine as if they still had their paws. Fentress (1973) concluded that the experiment proved the existence of instincts in mammals.

The Science of Behavior Today

Two years after the Brelands article, Jerry Hirsh (1963) at the University of Illinois wrote a paper emphasizing the importance of studying individual differences. He wrote, "Individual differences are no accident. They are generated by properties of organisms as fundamental to behavior science as thermodynamic properties are to physical science." Today, scientists recognize the contributions of both the Skinnerian and the ethologists approach to understanding behavior Modern neuroscience supports Darwin's view on behavior. Bird and mammal brains are constructed with the same basic design. They all have a brain stem, limbic system, cerebellum, and cerebral cortex. The cerebral cortex is the part of the brain used for thinking and flexible problem solving. The major difference between the brains of people and animals is in the size and complexity of the cortex. Primates have a larger and more complex cortex than a dog or a pig; pigs have a more complex cortex than a rat or a mouse. Furthermore, all animals possess innate species-specific motor patterns which interact with experience and learning in the formation of behavior. Certain behaviors in both wild and domestic animals are governed largely by innate (hard-wired) programs; however, experiencing and learning are the most important factors in other behaviors.

A basic principle to remember is that animals with large, complex brains are less governed by innate behavior patterns. For example, bird behavior is governed more by instinct than that of a dog, whereas an insect would have more hard-wired behavior patterns than that of a bird. This principle was clear to Yerkes (1905) who wrote:

Certain animals are markedly plastic or voluntary in their behavior, others are as markedly fixed or instinctive. In the primates plasticity has reached its highest known stage of development; in the insects fixity has triumphed, instinctive action is predominant. The ant has apparently sacrificed adapt-ability to the development of ability to react quickly, accurately and uniformly in a certain way Roughly, animals might he separated into two classes: those which are in high degree capable of immediate adaptation to their conditions, and those that are apparently automatic since they depend upon instinct tendencies to action instead of upon rapid adaptation.

INTERACTIONS BETWEEN GENETICS AND EXPERIENCE

Some behavior patterns are similar between different species, and some are found only in a particular species. For example, the neural programs that enable animals to walk are similar in most mammals (Melton, 1991). On the other hand, courtship rituals in birds are very species-specific (Nottebohm, 1977). Some innate behavior patterns are very rigid and experience has little effect on them; other instinctive behaviors can be modified by learning and experience. The flehmann, or lip curl response of a bull when he smells a cow in estrus, and the kneel-down (lordois) posture of a rat in estrus are examples of behaviors that are rigid. Suckling of the mother by newborn mammals is another example of a hard-wired behavioral system. Suckling behavior does not vary Newborn mammals suckle almost anything put in their mouth.

An example of an innate behavior that is affected by learning is burrowing behavior in rats. Boice (1977) found that wild Norway rats and albino laboratory rats both dig elaborate burrows. Learning has some effect on the efficiency of burrowing, but the configuration of the burrows was the same for both the wild and domestic rats. The albino laboratory rats dug excellent burrows the first time they were exposed to an outdoor pen. Nest building in sows is another example of the interaction between instinct and learning. When a sow is having her first litter, she has an uncontrollable urge to build a nest. Nest building is hard-wired and hormonally driven because prostaglandin F2a injections will induce it in sows (Widowski and Curtis, 1989). However, sows earn from experience how to build a better nest with each successful litter.

Other behaviors are almost entirely learned. Some seagulls learn to drop shellfish on rocks to break them open, while others drop them on the road and let cars break them open (Grandin, 1995). Many animals ranging from apes to birds use tools to obtain food. Griffin (1994) and Dawkins (1993) provide many examples of complex learned behaviors and flexible problem solving in animals.

Innate behaviors used for finding food, such as grazing, scavenging, or hunting, are more dependent on learning than behaviors used to consume food. Mating behavior, nesting, eating, and prey-killing behaviors tend to be governed more by instinct (Gould, 1977). The greater dependence on learning to find food makes animals in the wild more flexible and able to adapt to a variety of environments. Behaviors used to kill or consume food can be the same in any environment. Mayr (1974) called these different behavioral systems "open" or "closed" to the effects of experience. A lion hunting her prey is an example of an open system. The hunting female lion recognizes her prey from a distance and carefully stalks her approach. Herrick (1910) wrote, "the details of the hunt vary every time she hunts; therefore, no combination of simple reflex arcs laid down in the nervous system will be adequate to meet the infinite variations of the requirements for obtaining food:'

Complex Interactions

Some of the interactions between genetics and experience have very complex effects on behavior. In birds, the chaffinch learns to sing its species-specific song even when reared in a sound-proof box where it is unable to hear other birds (Nottebohm, 1970, 1979). However, when chaffinches are allowed to hear other birds sing, they develop a more complex song. The basic pattern of canary song emerges even in the absence of conspecific (flock-mate) auditory models (Metfessel, 1935; Poulsen, 1959). Young canaries imitate the song of adult canaries they can hear, and when reared in groups they develop song patterns that they all share (Nottebohm, 1977). Many birds, such as the white crowned sparrow chaffinch, and parrot, can develop local song dialects (Nottebohm et al., 1976). Sparrows are able to learn songs by listening to recordings of songs with either pure tones or harmonic overtones. Birds trained with harmonic overtones learned to sing songs with harmonic overtones, but 1 year later, 85% of their songs reverted back to innate pure tone patterns (Nowicki and Marler, 1988). Further experiments by Mundinger (1995) attempted to determine the relative contribution of genetics and learning in bird song. Inbred lines of roller and border canaries were used in this study along with a hybrid cross of the two. The rollers were cross fostered to border hens and vice versa to control for effects of maternal behavior. The roller and border males preferred to sing innate song patterns instead of copying their tutors. The hybrids preferred to learn some of both songs. Furthermore, canaries are capable of learning parts of an alien song but have a definite preference for their own songs. Comparing these animals to those in Brelands and Brelands (1961) exhibits, birds can be trained to sing a different song, but genetically determined patterns have a strong tendency to override learning. In reviewing all this literature, it became clear that innate patterns in mammals can be overridden. Unfortunately the animals tend to revert back to innate behavior patterns.

THE PARADOX OF NOVELTY

Novelty is anything new or strange in an animal's environment. Novelty is a paradox because it is both fear-provoking and attractive. Paradoxically it is most fear-provoking and attractive to animals with a nervous, excitable temperament. Skinner (1922) wrote that a flighty animal such as the pronghorn antelope will approach a person lying on the ground waving a red flag. Einarsen (1948) further observed that some wild animals will approach various large, dangerous objects such as a power steam shovel. In more recent studies, Kruuk (1972) also observed attraction and reaction to novelty in Thompson's gazelles in Africa. In small groups, Thompson's gazelles are most watchful for predators (Elgar, 1989). Animals that survive in the wild by flight are more attentive to novelty than more placid animals. Gazelles can also distinguish between a dangerous hunting predator and one that is not hunting. The most dangerous predators attract the highest degrees of attraction in the Thompson's gazelle. They often move close to a cheetah when the cheetah is not hunting. Furthermore, when predators walk through a herd of Thompson's gazelles, the size of the flight zone varies depending on the species of predator.

Reaction to Novelty

Confronted with sudden novelty, highly reactive animals are more likely to have a major fear reaction. Examples of sudden novelty include being placed in a new cage, transport in a strange vehicle, an unexpected loud noise, or being placed in an open field. Using various experimental environments, Hennessy and Levine (1978) found that rats show varying degrees of stress and stress hormone levels proportional to the degree of novelty of the environment they are placed in; a glass jar is totally novel in appearance compared to the lab cage to which the animal was accustomed. Being placed in a glass jar was more stressful for rats than a clean lab cage with no bedding.

Livestock and Poultry Reaction to Novelty

Studies of the reaction to novelty in farm animals have been conducted by Moberg and Wood (1982), Stephens and Toner (1975), and Dantzer and Mormede (1983). When calves are placed in an open field test arena that is very dissimilar from their home pen, they show the highest degrees of stress (Dantzer and Mormede, 1983). Calves raised indoors were more stressed by an outdoor arena and calves raised outdoors were more stressed by an indoor arena. The second author is painfully familiar with similar responses in horses. When horses are taken to the mountains for the first time, a well-trained riding horse that is accustomed to many different show rings may panic when it sees a butterfly or hears a twig snapping on a mountain trail.

Genetic Factors and the Need for Novelty

In mammals and birds, normal development of the brain and sense organs requires novelty and varied sensory input. Nobel prize winning research of Hubel and Wiesel (1970) showed that the visual system is permanently damaged if kittens do not receive varied visual input during development. When dogs are raised in barren and nonstimulating environments they are also more excitable (Walsh and Cummins, 1975; Melzak and Burns, 1965). Schultz (1965) stated, "when stimulus variation is restricted central regulation of threshold sensitivities will function to lower sensory thresholds." Krushinski (1960) studied the influence of isolated conditions of rearing on the development of passive defense reactions (fearful aggression) in dogs and found that the expression of a well-marked fear reaction depends on the genotype of the animal. Airedales and German shepherds were reared under conditions of freedom (in homes) and in isolation (in kennels). Krushinski (1960) found that the passive defense reaction developed more acutely and reached a greater degree in the German shepherds kept in isolation compared to the Airedales. In general, animals reared in isolation become more sensitive to sensory stimulation because the nervous system attempts to readjust for the previous lack of stimulation.

In an experiment with chickens, Murphy (1977) found that chicks from a flighty genetic line were more likely to panic when a novel ball was placed in their pen, but they were also more attracted to a novel food than birds from a calm line. Cooper and Zubeck (1958), and Henderson (1968) found that rats bred to be dull greatly improved in maze learning when housed in a cage with many different objects; however, enriched environments had little effect on the rats bred for high intelligence. Greenough and Juraska (1979) found that rearing rats in an environment with many novel objects improves learning and resulted in increased growth of dendrites, which are nerve endings in the brain.

Pigs raised in barren concrete pens also seek stimulation (Grandin, 1989a,b; Wood-Gush and Vestergaard, 1991; Wood-Gush and Beilharz, 1983). Piglets allowed to choose between a familiar object and a novel object prefer the novel object (Wood-Gush and Vestergaard, 1991). Pigs raised on concrete are strongly attracted to novel objects to chew on and manipulate. The first author has observed that nervous, excitable hybrid pigs often chew and bit vigorously on boots or coveralls. This behavior is less common in placid genetic lines of pigs.

Although hybrid pigs are highly attracted to novelty, tossing a novel object into their pen will initially cause a strong flight response. Compared to calm genetic lines, nervous-hybrid pigs pile up and squeal more when startled. Pork producers report that nervous, fast-growing, lean hybrid pigs also tail-bite other pigs more often than calmer genetic lines Of pigs. jail biting occurs more often when pigs are housed on a concrete slatted floor which provides no opportunity for rooting.

Strong attraction or strong reaction to novelty has also been observed by the first author in cattle. Cattle will approach and lick a piece of paper laying on the ground when they can approach it voluntarily (Fig. 1.3). However, the same piece of paper blowing in the wind may trigger a massive flight response. Practical experience by both authors suggests that highly reactive horses are more likely to engage in vices such as cribbing or stall weaving when housed in stalls or runs where they receive little exercise. Denied variety and novelty in their environments, highly reactive animals adapt poorly compared to animals from calmer genetic lines (Price, 1984).

In summary, in both wild and domestic animals novelty is both highly feared and necessary Novelty is most desirable when animals can approach it slowly. Unfortunately, novelty is also fear-provoking when animals are suddenly confronted with it.

TEMPERAMENT

In animals as diverse as rats, chickens, cattle, pigs, and humans, genetic factors influence differences in temperament (Murphey et al., 1980b Kagan et al., 1988; Grandin, 1993b; Fordyce et al., 1988; Fujita et al., 1994; Hemsworth et al., 1990; Broadhurst, 1975; Reese et al., 1983; Murphy, 1977; Tulloh, 1961; Blizard, 1971). Some individuals are wary and fearful and others are calm and placid. Boissy (1995) stated, fearfulness is a basic psychological characteristic of the individual that predisposes it to perceive and react in a similar manner to a wide range of potentially frightening events]' In all animals, genetic factors influence reactions to situations which cause fear (Davis, 1992; Murphey et al., 1980b; Kagan et al, 1988; Boissy and Bouissou, 1995); therefore, temperament is partially determined by an individual animal's fear response. Rogan and LeDoux (1996) suggest that fear is the product of a neural system that evolved to detect danger and that it causes an animal to make a response to protect itself. Plomin and Daniels (1987) found a substantial genetic influence on shyness (fearfulness) in human children. Shy behavior in novel situations is considered a stable psychological characteristic of certain individuals. Shyness is also suggested to be among the most heritable dimensions of human temperament throughout the life span.

In an experiment designed to control for maternal effects on temperament and emotionality, Broadhurst (1960) conducted cross-fostering experiments on Maudsley Reactive (MR) and Non Reactive (MNR) rats. These lines of rats are genetically selected for high or low levels of emotional reactivity The results showed that maternal effects were not great enough to completely mask the temperament differences between the two lines (Broadhurst, 1960). Maternal effects can affect temperament, but they are not great enough to completely change the temperament of a cross-fostered animal which has a temperament that is very different from that of the foster mother. In extensive review of the literature, Broadhurst (1975) examined the role of heredity in the formation of behavior and found that differences in temperament between rats persist when the animals are all raised in the same environment.

Measuring Fear-Based Behaviors

One method of testing fearfulness is the open field test (Hall, 1934). Sudden placement of an animal in an open field test arena is used to measure differences in fearfulness. Open field testing has shown differences in fearfulness between different genetic lines of animals. The test arena floor is usually marked in a grid to measure how much the animals walk around and explore. Huck and Price (1975) showed that domestic rats are less fearful and will walk round the open held more than wild rats. Price and Loomis (1973) explained that some genetic strains of rats are less fearful and explore an open field arena more than others. Eysenck and Broadhurst (1964) found that rodents with high emotional reactivity are more fearful and explore the open field less compared to placid genetic lines.

In their study of genetic effects on behavior, Fuller and Thompson (1978) found that "simply providing the same defined controlled environment for each genetic group is not enough. Conditions must not only be uniform for all groups, but also favorable to the development of the behavior of interest." For example, in wartime Russia, Krushinski (1960) investigated the ability of dogs to be trained for the antitank service or as trail dogs trained to track human scent. The dogs were tied to a spike driven into the ground, and the person who regularly looked after them would let them lick from a bowl of food and then summon the dog to follow the man as he retreated 10 to 15 meters. The dog's activity was measured with a pedometer for the next 2 minutes. The most active dogs were found to be the best antitank dogs. They were also fearless. In the antitank service, dogs were trained to run up to a tank and either run along side of it or penetrate under the caterpillars of the tank. In order to do this, the dogs had to overcome their natural fear of a tank moving toward them at high speed. The less active dogs (as measured by the pedometer) were found to make the best trailer dogs. They slowly followed a trail and kept their noses carefully to the scent while negotiating the corners and turns on the trail. The more active dogs trailed at too high a speed and often jumped the corners and turns in the trail, which sometimes resulted in switching to another trail.

Mahut (1958) demonstrated an example of differences in fear responses between beagles and terriers. When frightened, beagles freeze and terriers run around frantically In domestic livestock, measuring fear reactions during restraint or in an open field test has revealed differences in temperament both between breeds and between individuals within a breed (Grandin, 1993a; Tulloh, 1961; Dantzer and Mormede, 1983; Murphey et al., 1980b, 1981). The fearful, flighty animals become more agitated and struggle more violently when restrained for vaccinations and other procedures (Fordyce et al., 1988; Grandin, 1993a). Fear is likely to be the main cause of agitation during restraint in cattle, horses, pigs, and chickens. Genetic effects on behavior during transport, handling, and restraint of these animals are further discussed in Chapter 4.

Species Differences in Fear Reactions

In an open field test, frightened rodents often stay close to the arena walls, whereas frightened cattle may run around wildly and attempt to escape. Rodents stay close to the walls because they naturally fear open spaces, whereas cattle run around wildly because they fear separation from the herd. This is an example of differences between species in their response to a similar fear- provoking situation. Fear can be manifested in many different ways. For example, a frightened animal may run around frantically and try to escape in one situation, while in another situation the same animal may freeze or limit its movement. Chickens often freeze when handled by humans. Jones (1984) called this "tonic immobility." The chickens become so frightened that they cannot move. Forceful capture of wild animals can sometimes inflict fatal heart damage. Wildlife biologists call this capture myopathy In summary, much is known about the complex phenomenon of fear, but many questions still remain.

BIOLOGICAL BASIS OF FEAR

Genetics influences the intensity of fear reactions. Genetic factors can also greatly reduce or increase fear reaction in domestic animals (Price, 1984; Parsons, 1988; Flint et al., 1995). Research in humans has clearly revealed some of the genetic mechanisms which govern the inheritance of anxiety (Lesch et al., 1996). LeDoux (1992) and Rogan and LeDoux (1996) state that all vertebrates can be fear-conditioned. Davis (1992) recently reviewed studies on the biological basis of fear. Overwhelming evidence points to the amygdala as the fear center in the brain. A small bilateral structure located in the limbic system, the amygdala is where the triggers for flight or fight" are located. Electrical stimulation of the amygdala is known to increase stress hormones in rats and cats (Matheson et al., 1971; Setckleiv et al., 1961); destroying the amygdala can make a wild rat tame and reduce its emotionality (Kemble et al., 1984). Destroying the amygdala also makes it impossible to provoke a fear response in animals (Davis, 1992). Blanchard and Blanchard (1972) showed that rats lose all of their fear of cats when the amygdala is lesioned. Furthermore, when a rat learns that a signal light means an impending electric shock, a normal response is to freeze. Destroying the amygdala will eliminate this response (Blanchard and Blanchard, 1972; LeDoux et al., 1988, 1990). Finally, electrical stimulation of the amygdala makes humans feel fearful (Gloor et al., 1981). Animal studies also show that stimulation of the amygdala triggers a pattern of responses from the autonomic nervous system similar to that found in humans when they feel fear (Davis, 1992).

Heart rate, blood pressure, and respiration also change in animals when the flight or fight response is activated (Manuck and Schaefer, 1978). All these autonomic functions have neural circuits to the amygdala. Fear can be measured in animals by recording changes in autonomic activity In humans, Manuck and Schaefer (1978) found tremendous differences in cardiovascular reactivity in response to stress, reflecting a stable genetic characteristic of individuals.

Fearfulness and Instinct

Fearfulness and instinct can conflict. This principle was observed firsthand by the second author during his experience raising Queensland Blue Heeler dogs. Annie's first litter was a completely novel experience because she had never observed another dog giving birth or nursing pups. She was clearly frightened when the first pup was born and it was obvious that she did not know what the pup was; however, as soon as she smelled it her maternal instinct took over and a constant uncontrollable licking began. Two years later, Annie's daughter Kay had her first litter. Kay was more fearful than her mother and her highly nervous temperament overrode her innate licking program. When each pup was born Kay ran wildly around the room and would not go near them. The second author had to intervene and place the pups under Kay's nose; otherwise, they may have died. Kay's nervous temperament and fearfulness were a stronger motivation than her motherly instinct.

NERVOUS SYSTEM REACTIVITY CHANGED BY THE ENVIRONMENT

Raising young animals in barren environments devoid of variety and sensory stimulation will have an effect on development of the nervous system. It can cause an animal to be more reactive and excitable when it becomes an adult. This is a long-lasting, environmentally induced change in how the nervous system reacts to various stimuli. Effects of deprivation during early development are also relatively permanent. Melzak and Burns (1965) found that puppies raised in barren kennels developed into hyperexcitable adults. In one experiment the deprived dogs reacted with ~diffuse excitement" and ran around a room more than control dogs raised in homes by people. Presenting novel objects to the deprived dogs also resulted in diffuse excitement." Furthermore, the EEGs of the kennel-raised dogs remained abnormal even after they were removed from the kennel (Melzak and Burns, 1965). Simons and Land (1987) showed that the somatosensory cortex in the brains of baby rats will not develop normally if sensory input was eliminated by trimming their whiskers. A lack of sensory input made the brain hypersensitive to stimulation. The effects persisted even after the whiskers had grown back.

Development of emotional reactivity of the nervous system begins during early gestation. Denenberg and Whimbey (1968) showed that handling a pregnant rat can cause her offspring to be more emotional and explore less in an Open field compared to control animals. This experiment is significant because it shows that handling the pregnant mother had the opposite effect on the behavior of the infant pups. Handling and possibly stressing the pregnant mothers changed the hormonal environment of the fetus which resulted in nervous offspring. However, handling newborn rats by briefly picking them up and setting them in a container reduced emotional reactivity when the rats became adults (Denenberg and Whimbey 1968). The handled rats developed a calmer temperament.

The adrenal glands are known to have an effect on behavior (Fuller and Thompson, 1978). The inner portions of the adrenals secrete the hormones adrenaline and noradrenaline, while the outer cortex secretes the gender hormones androgens and oestrogens (reproductive hormones), and various corticosteroids (stress hormones). Yeakel and Rhoades (1941) found that Hall's (1938) emotional rats had larger adrenals and thyroids compared to the nonemotional rats. Richter (1952, 1954) found a decrease in the size of the adrenal glands in Norway rats accompanied by domestication. Several line and strain differences have been found since these early reports. Furthermore, Levine (1968) and Levine et al. (1967) showed that brief handling of baby rats reduces the response of the adrenal gland to stress. Denenberg et al. (1967) concluded that early handling may lead to major changes in the neuroendocrine system.

Changing Reactivity versus Taming

Adult wild rats can be tamed and become accustomed to handling by people (Galef, 1970). This is strictly learned behavior. Taming full-grown wild animals to become accustomed to handling by people will not diminish their response to a sudden novel stimulus. This principle was demonstrated by Grandin et al. (1994) in training wild antelope at the Denver Zoo for low- stress blood testing. Nyala are African antelope with a hair-trigger flight response used to escape from predators. During handling in zoos for veterinary treatments, nyala are often highly stressed and sometimes panic and injure themselves. Over a period of 3 months, Grandin et al.(1995) trained nyala to enter a box and stand quietly for blood tests while being fed treats. Each new step in the training had to be done slowly and carefully Ten days were required to habituate the nyala to the sound of the doors on the box being closed.

All the training and petting by zoo keepers did not change the nyala's response to a sudden, novel stimulus. When the nyala saw repairman on the barn roof they suddenly reacted with a powerful fear response and crashed into a fence. They had become accustomed to seeing people standing at the perimeter of the exhibit, but people on the roof was novel and very frightening. Sudden movements such as raising a camera up for a picture also caused the nyala to flee.

Domestic versus Wild

Wild herding species show much stronger fear responses to sudden novelty compared to domestic ruminants such as cattle and sheep. Domestic ruminants have attenuated flight responses due to years of selective breeding (Price, 1984). Wild ruminants will learn to adapt in captivity and associate people with food, but when frightened by some novel stimulus they are more likely to panic and injure themselves (Grandin, 1993b, 1997).This is especially likely if they are prevented from fleeing by a fence or other barrier. Principles for training and handling all herding animals are basically similar. Training procedures used on flighty antelope or placid domestic sheep are the same. The only difference is the amount of time required. Grandin (1989c) demonstrated this by training placid Suffolk sheep to voluntarily enter a tilting restraining device in one afternoon, but it took 3 months to train the nyala.

In summary, experience can affect behavior in two basic ways: by conventional learning or by changing nervous system reactivity Most importantly, environmental conditions (enriched versus barren) have the greatest effect on the nervous systems of young animals.

NEOTENY

Neoteny is the retention of the juvenile features in an adult animal. Genetic factors influence the degree of neoteny in individuals. Neoteny is manifested both behaviorally and physically In the forward to "The Wild Canids" (Fox, 1975), Conrad Lorenz adds a few of his observations on neoteny and the problems of domestication:

The problems of domestication have been an obsession with me for many years. On the one hand I am convinced that man owes the life-long persistence of his constitutive curiosity and explorative playfulness to a partial neoteny which is indubitably a consequence of domestication In a curiously analogous manner does the domestic dog owe its permanent attachment to its master to a behavioral neoteny that prevents it from ever wanting to be a pack leader On the other hand, domestication is apt to cause an equally alarming disintegration of valuable behavioral traits and an equally alarming exaggeration of less desirable ones.

Infantile characteristics in domestic animals are discussed by Price (1984), Lambooij and van Putten (1993), Coppinger and Coppinger (1993), Coppinger and Scheider (1993), and Coppinger et al.(1987). The shortened muzzle in dogs and pigs is an example. Domestic animals have been selected for a juvenile head shape, shortened muzzles, and other features (Coppinger and Smith, 1983). Furthermore, retaining juvenile traits makes animals more tractable and easy to handle. The physical changes are also related to changes in behavior.

Genetic studies point to the wolf as the ancestor of domestic dogs (Isaac, 1970). During domestication, domestic dogs have retained many of the infant wolf behaviors. For example, wolf pups bark and yap a lot but adult wolves rarely bark; domestic dogs bark a lot (Fox, 1975; Scott and Fuller, 1965). Wolves have hard-wired instinctive behavior patterns that determine dominance or submission in social relationships. In domestic dogs, the ancestral social behavior patterns of the wolf are fragmented and incomplete. Frank and Frank (1982) observed that the rigid social behavior of the wolf has disintegrated into "an assortment of independent behavioral fragments." Malamutes raised with wolf pups fail to read the social behavior signals of the wolf pups. Further comparisons found that the physical development of motor skills is slower in the malamute. Goodwin et al. (1997) studied 10 different dog breeds which ranged from German shepherds and Siberian huskies to bulldogs, cocker spaniels, and terriers. They found that the breeds which retained the greatest repertoire of wolf-like social behaviors were the breeds that physically resembled wolves, such as German shepherds and huskies. Barnett et al. (1979) and Price (1985) both conclude that experience can also cause an animal to retain juvenile traits. Gould (1977) also considered the effects of neoteny and stated that neoteny is determined by changes in a few genes that determine the timing of different developmental stages.

OVERSELECTION FOR SPECIFIC TRAITS

Countless examples of serious problems caused by continuous selection for a single trait can be found in the medical literature (Steinberg et al., 1994; Dykman et al., 1969). People with experience in animal husbandry know that overselection for single traits can ruin animals. Good dog breeders know this. Sometimes traits that appear to be unrelated are in fact linked. Wright (1922, 1978) demonstrated this clearly by continuous selection for hair color and hair patterns in inbred strains of guinea pigs. Depressed reproduction resulted in all the strains. Furthermore, differences in temperament, body conformation, and the size and shape of internal organs were found. Belyaev (1979) further showed that continuous selection for a calm temperament in foxes resulted in negative effects on maternal behavior and neurological problems. The fox experiments also found graded changes in many traits over several years of continuous selection for tame behavior. Physiological and behavioral problems increased with each successive generation. In fact, some of the tamest foxes developed abnormal maternal behavior and cannibalized their pups. Belyaev et al.(1981) called this "destabilizing selection," in contrast to "stabilizing selection" found in nature (Dobzhansky 1970; Gould, 1977).

There are also countless examples in the veterinary medical literature of abnormal bone structure and other physiological defects caused by overselecting for appearance traits in dog breeds (Ott, 1996). The abnormalities range from bulldogs with breathing problems to German shepherds with hip problems. Scott and Fuller (1965) reported the negative effects of continuous selection for a certain head shape in cocker spaniels:

In our experiments we began with what were considered good breeding stocks, with a fair number of champions in their ancestry. When we bred these animals to their close relatives for even one or two generations, we uncovered serious defects in every breed. . .Cocker spaniels are selected for a broad forehead with prominent eyes and a pronounced "stop," or angle, between the nose and forehead. When we examined the brains of some of these animals during autopsy, we found that they showed a mild degree of hydroencephaly; that is, in selecting for skull shape, the breeders accidentally selected for a brain defect in some individuals. Besides all this, in most of our strains only about 50 percent of the females were capable of rearing normal, healthy litters, even under nearly ideal conditions of care.

Overselection in Livestock

Single-minded selection for production traits such as rapid gain and leanness resulted in pigs and cattle with more excitable temperaments (Grandin, 1994). Compared to the older genetic lines with more hack fat, observations by the first author on thousands of pigs indicate that lean hybrids are more excitable and difficult to drive through races. Lean hybrid pigs also have a greater startle response. Separating a single animal from the group is more difficult. Recent research conducted in our laboratory has shown that cattle with an excitable temperament have lower weight gains and more meat quality problems (Voisinet et al., 1997a,b). This research illustrates that selection away from a very excitable temperament would be beneficial. However, overselection for an excessively calm temperament could possibly result in some unknown detrimental trait.

Links between Different Traits

Casual observations by the first author also indicate that the most excitable, flighty pigs and cattle have a long, slender body with fine bones. Some of the lean hybrid pigs have weak legs and a few of the normally brown-eyed pigs now have blue eyes. Blue eyes are often associated with neurological problems (Bergsma and Brown, 1971; Schaible, 1963). Furthermore, pigs and cattle with large, bulging muscles often have a calmer temperament than lean animals with less muscle definition. However, animals with the muscle hypertrophy trait (double muscling) have a more excitable temperament (Holmes et al., 1972). Double muscling is extreme abnormal muscling and it might have the opposite effect on temperament compared to normal muscling.

Another example of apparently unrelated traits being linked is deafness in dogs of the pointer breed selected for nervousness (Kllen et al., 1987, 1988). There appears to be a relationship between thermoregulation and aggressiveness. Wild mice selected for aggressiveness used larger amounts of cotton to build their nests than mice selected for low aggression (Sinyter et al., 1995). This effect occurred in both laboratory and wild Strains of mice.

Researchers using high-tech "knockout" gene procedures have been frustrated by the complexity of genetic interactions. In this procedure, genes are knocked out in a gene-targeting procedure whereby a gene is prevented from performing its normal function. The knockout experiments have shown that blocking different genes can have unexpected effects on behavior. In one experiment, superaggressive mice were created when genes involved with learning were inactivated (Chen et al., 1994). The mutant mice had little or no fear and fought until they broke their backs. In another experiment the knockout mutants demonstrated normal behavior until they had pups, and failed to care for them (Brown et al., 1996). In still another experiment, Konig et al. (1996) disabled the gene that produces enkephalin (a brain opioid substance) and found unexpected results. Enkephalin is a substance normally involved in pain perception; however, the mice that were deficient in this substance were very nervous and anxious. They ran frantically around their cages in response to noise. The bottom line conclusion from several different knockout experiments is that changing one gene has unexpected effects on other systems. Traits are linked, and it may be impossible to completely isolate single gene effects. Researchers warn that one must be careful not to jump to a conclusion that they have found an '~aggression gene" or a "maternal gene" or an "anxiety gene." To use an engineering analogy, one would not conclude that they had found the "picture center" in a television set after they cut one circuit inside the set that ruined the picture. Gerlai (1996) and Crawley (1996) also warn that knocking out the same gene in two different species may have different effects on behavior. This is due to the complex interactions between many different genes.

Twenty years ago behavioral geneticists concluded that the inheritance of behavior is complex. Fuller and Thompson (1978) concluded, "It has been found repeatedly that no one genetic mechanism accounts exclusively for a particular kind of behavtor.

Random Factors

Behavioral geneticists have discovered that it is impossible to completely control variation in some traits. Gartner (1990) found that breeding genetically similar inbred lines of rats failed to stop weight fluctuations. Even under highly standardized laboratory conditions, body weights continued to fiuctuate between animals. Pig breeders have also observed that commercially bred hybrid lines of pigs do not gain weight at the same rate. Random unknown factors affect variability even in genetically identical animals. Factors in utero may be one cause; the other causes are unknown. Darrel Tatum and his students at Colorado State University found both body conformation and meat quality variation in cattle which were 50% English (Bos taurus) and 50% Brabman (Bos indicus). Some animals had more Brahman characteristics, with larger humps and longer ears than others; the body conformation of many of the animals was not half English and half Brahmatn. The characteristics of the meat varied as well; animals that looked more Brahman had tougher meat. The animals had about 10% variation from the body shape and meat characteristics of Brahman half-bloods.

Gartner (1990) concluded that up to 90% of the cause of random variability cannot be explained by differences in the animals' physical environment. In both mice and cattle, random factors affected body weights. Gartner (1990) believes that the random factors may have their influence either before or shortly after fertilization.

The interactions between environmental and genetic factors are complex. Both an animals' genetic makeup and its environment determine how it will behave. In subsequent chapters in this book the interactions of genetics and environment will be discussed in greater detail. Genetics has profound effects on an animal's behavior.

CONCLUSIONS

There is a complex interaction between genetic and environmental factors which determines how an animal will behave. The animal's temperament is influenced by both genetics and learning. Another principle is that changes in one trait, such as temperament, can have unexpected effects on other apparently unrelated traits. Overselection for a single trait may result in undesirable changes in other behavioral and physical traits.

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Irving Isadore Gottesman (born December 29, 1930) is a psychiatric geneticist who has devoted most of his career to the study of the genetics of schizophrenia.

Studies on schizophrenia and psychopathology

Gottesman first studied the genetics of schizophrenia on a large scale using the Maudsley–Bethlem register of twin admissions for 16 years. Later he worked on psychiatric genetics and genomics. In his Twin Cities MMPI study, part of his Ph.D. thesis, Gottesman found high levels of inheritance in the scales related to schizophrenia, depression, anti-social personality disorder, and social introversion.[2] Genes strongly influenced social introversion and aggressive tendencies. This led to further studies on personality traits of identical twins such as the Minnesota Study of Identical Twins Reared Apart.[3]

Analyzing the results of the Maudsley–Bethlem study, Gottesman and Shields devised the multi-element, polygenic causation model for schizophrenia. The book that summarized and expanded on the study, Schizophrenia and Genetics: A Twin Study Vantage Point, argued that schizophrenia is a product of several genes acting together, and introduced the techniques of precise analysis in the field of behavioral genetics.[3]Gottesman and Shields introduced terms such as "reaction ranges/surface", "endophenotype" and "epigenetic puzzle" into the behavioral sciences.[2] The threshold model hypothesized that both genetic and environmental risks combined to produce schizophrenia, and pushed an individual into a diagnosable condition when their influence grew strong enough. The reaction range concept is the idea that the genes and the environment control behavior, but with separate upper and lower limits on the strength of that control in each case, a concept now part of basic psychology.[8] Before the study, the prevailing opinion was that schizophrenia originated from bad parental relationships.[3] The researchers showed identical twins were more likely to either have or not have schizophrenia together, concluding the disorder was the "outcome of a genetically determined developmental predisposition".[10]

The Maudsley–Bethlem study also hypothesized that schizophrenia was caused by a mixture of many small traits working together. These endophenotypes could be used for diagnosis.[3] Endophenotypes have been interpreted as a link between genes and the final behavior, acted on by the environment and chance elements, with biochemical and epigenetic influences changing the genome but not being passed on to children. Molecular-biological studies in genetics have referred to endophenotypes to explain genetic causes of psychopathology.[11] The researchers also examined how schizoids, those with mild, schizophrenia-like personality disorders, were linked to schizophrenics. Gottesman and Shields extended the term to classes of mild psychological disorders in twins and relatives of schizophrenics.[12] The researchers had hypothesized that schizoida in a twin was how a schizophrenia carrier gene, one in a non-schizophrenic still passing on a genetic risk, expressed itself. The twin study did not confirm this.[13]

In the Denmark study, the researchers evaluated the extent to which genes underpin psychopathology.[2] Their twin studies of criminality found that a genetic disposition to poor self-control caused both identical twins to become felons, or to not become felons. They also studied identical twins who were discordant for schizophrenia, where one twin was schizophrenic and the other not, and found children of such twins had equal genetic vulnerability to the disease.[3] A later study in the mid-1980s, resulting in a paper awarded the Kurt Schneider Prize, concluded that children of identical twins were at higher risk than those of fraternal twins, indicating the non-schizophrenic identical twin passed on a latent genetic disposition, even if it had not been expressed through schizoida.[11] The Denmark study introduced the concepts of "unexpressed genotypes"—the latent genetic risk, and "epigenetic control"—the biochemical regulation of how genes work, into the new field of behavioral genetics.[2]

Studies on delinquency and violence

Gottesman's multifactorial model applied to alcoholism

In a 1989 review of the research on juvenile delinquency and violence, Lisabeth DiLalla and Gottesman found delinquency could be transitory or continuous, and genes contributed more to the continuous type.[14] In 1991 the same authors published a critique of the then-prevalent idea of antisocialism being transmitted through generations by child abuse alone in antisocial families. They stated that a review by Cathy Spatz Widom and the studies she cited had missed an element: children maltreated in families might have been targets because their genes might have influenced them into committing antisocial acts and attracting such treatment from parents.[15]

Wim E. Crusio is a Dutch behavioral neurogeneticist and a directeur de recherche (research director) with the French National Centre for Scientific Research in Talence, France.

Exploratory behavior

When confronted with a novel environment, animals from non-sessile non-predatory animal species will often engage in exploratory behavior. Together with his mentor Hans van Abeelen, Crusio hypothesized that, on the one hand, this would be advantageous (as it would enable animals to find resources, such as water, food, etc.), but on the other hand disadvantageous (because moving around in unfamiliar territory will render an animal vulnerable to predation).[15] Such stabilizing selection would be expected to lead to a genetic architecture characterized by ambidirectional dominance.[16] This was indeed found both for mice[15][17][18] and for Paradise fish.[19]

Hippocampal mossy fibers

During his postdoc, Crusio became interested in the inheritance of neuroanatomical variations in the mouse hippocampus, showing that about 50% of the variation found between different inbred mouse strains in the sizes of their intra- and infrapyramidal mossy fiber (IIPMF) projections could be attributed to heredity. It had previous been shown by Herbert Schwegler and Hans-Peter Lipp that these variations are correlated with the capacity of mice to master a two-way active avoidance task, animals with smaller projections learning much faster than animals with larger IIPMF.[20][21] Together with Schwegler and Lipp, Crusio showed that an inverse correlation, that is, animals with larger IIPMF learning better, could be found for spatial learning in a radial arm maze task.[22][23] This correlation was amenable to experimental manipulation by inducing early postnatal hyperthyroidy by injecting pups with thyroxine, which results in an enlargement of the IIPMF projection.[24] As expected, when mice from a strain with scant IIPMF projections were rendered hyperthyroid, they showed enlarged IIPMF and improved learning ability on the radial maze.[25][26] Taken together, Crusio and collaborators think that it is highly likely that this correlation is causal,[27] although this is not universally accepted.[28]

Mouse model of depression

When mice are exposed to unpredictable chronic mild stress (UCMS), they start exhibiting symptoms reminiscent of major depressive disorder in humans.[29] As it had been suggested that deficits in hippocampal neurogenesis might underlie depression,[30] Crusio and collaborators undertook a series of experiments investigating changes in behavior and neurogenesis in mice that had undergone UCMS. They showed dramatic changes in levels of aggression,[31] anxiety,[32] depressive-like behaviors,[32] and learning,[33] with a concomitant drop in neurogenesis.[33] However, the results were strain- and sex-specific and there did not appear to be a clear-cut correlation between the different changes, so that they finally concluded that although their data do not disprove the idea that deficits in hippocampal neurogenesis solely underlie the behavioral impairments observed in human psychiatric disorders such as depression, they do not provide support for this hypothesis either.[33]

Mouse model of autism

Dorret I. Boomsma (b. November 18, 1957, Huizen, The Netherlands) is a Dutch biological psychologist specializing in the study of twins.

Boomsma has built a database of over 75,000 twins and family members in The Netherlands,[1] which has been used for dozens of twin studies. The twins and their families have undergone periodic testing over a period of decades, providing a mass of longitudinal data for statistical analysis. A large number of participants have also provided DNA, blood, and urine samples for testing. Her research has primarily focused on better understanding the influence of heredity on various physical and mental diseases, including cardiovascular diseases, pediatric bipolar disorder, and depression. This work has been reported in over 450 published papers and one book and has led to many awards for Boomsma.

Twin studies[2] provide a way to understand how genotype affects an observable characteristic (called a phenotype). In short, identical (monozygotic) twins carry the same alleles for 100% of their genes whereas fraternal (dizygotic) twins will carry different alleles at 50% of the genes for which their parents had different genotypes. So if some characteristic (say, depression) that is observed in one identical twin is always observed in the other one, but this does not hold for fraternal twins, then one can conclude that heredity plays an important role in causing the condition.

Boomsma has been a pioneer in collecting a broad spectrum of data (e.g., medical histories, IQ tests, MRI scans) and biological material (e.g., DNA and RNA samples, blood and urine samples) from thousands of twins and analyzing them to determine the role of genetics in characteristics as varied as adult height, brain volume, intelligence, migraine headaches, anxiety, drug addiction, and love of coffee.

Sir Francis Galton, FRS (/ˈfrɑːnsɪs ˈɡɔːltən/; 16 February 1822 – 17 January 1911), cousin of Douglas Strutt Galton, cousin of Charles Darwin, was an English Victorian polymath: anthropologist, eugenicist, tropical explorer, geographer, inventor, meteorologist, proto-geneticist, psychometrician, and statistician. He was knighted in 1909.

Galton produced over 340 papers and books. He also created the statistical concept of correlation and widely promoted regression toward the mean. He was the first to apply statistical methods to the study of human differences and inheritance of intelligence, and introduced the use of questionnaires and surveys for collecting data on human communities, which he needed for genealogical and biographical works and for his anthropometric studies.

He was a pioneer in eugenics, coining the term itself and the phrase "nature versus nurture". His book Hereditary Genius (1869) was the first social scientific attempt to study genius and greatness.[1]

As an investigator of the human mind, he founded psychometrics (the science of measuring mental faculties) and differential psychology and the lexical hypothesis of personality. He devised a method for classifying fingerprints that proved useful in forensic science. He also conducted research on the power of prayer, concluding it had none by its null effects on the longevity of those prayed for.[2]

As the initiator of scientific meteorology, he devised the first weather map, proposed a theory of anticyclones, and was the first to establish a complete record of short-term climatic phenomena on a European scale.[3] He also invented the Galton Whistle for testing differential hearing ability. [4]

What is behavioral genetics? [text provided by Joseph McInerney]

Sir Francis Galton (1822-1911) was the first scientist to study heredity and human behavior systematically. The term "genetics" did not even appear until 1909, only 2 years before Galton's death. With or without a formal name, the study of heredity always has been, at its core, the study of biological variation. Human behavioral genetics, a relatively new field, seeks to understand both the genetic and environmental contributions to individual variations in human behavior. This is not an easy task, for the following reasons.

It often is difficult to define the behavior in question. Intelligence is a classic example. Is intelligence the ability to solve a certain type of problem? The ability to make one's way successfully in the world? The ability to score well on an IQ test? During the late summer of 1999, a Princeton molecular biologist published the results of impressive research in which he enhanced the ability of mice to learn by inserting a gene that codes for a protein in brain cells known to be associated with memory. Because the experimental animals performed better than controls on a series of traditional tests of learning, the press dubbed this gene "the smart gene" and the "IQ gene," as if improved memory were the central, or even sole, criterion for defining intelligence. In reality, there is no universal agreement on the definition of intelligence, even among those who study it for a living.

Having established a definition for research purposes, the investigator still must measure the behavior with acceptable degrees of validity and reliability. That is especially difficult for basic personality traits such as shyness or assertiveness, which are the subject of much current research. Sometimes there is an interesting conflation of definition and measurement, as in the case of IQ tests, where the test score itself has come to define the trait it measures. This is a bit like using batting averages to define hitting prowess in baseball. A high average may indicate ability, but it does not define the essence of the trait.

Behaviors, like all complex traits, involve multiple genes, a reality that complicates the search for genetic contributions.

As with much other research in genetics, studies of genes and behavior require analysis of families and populations for comparison of those who have the trait in question with those who do not. The result often is a statement of "heritability," a statistical construct that estimates the amount of variation in a population that is attributable to genetic factors. The explanatory power of heritability figures is limited, however, applying only to the population studied and only to the environment in place at the time the study was conducted. If the population or the environment changes, the heritability most likely will change as well. Most important, heritability statements provide no basis for predictions about the expression of the trait in question in any given individual.

What indications are there that behavior has a biological basis? [text provided by Joseph McInerney]

Behavior often is species specific. A chickadee, for example, carries one sunflower seed at a time from a feeder to a nearby branch, secures the seed to the branch between its feet, pecks it open, eats the contents, and repeats the process. Finches, in contrast, stay at the feeder for long periods, opening large numbers of seeds with their thick beaks. Some mating behaviors also are species specific. Prairie chickens, native to the upper Midwest, conduct an elaborate mating ritual, a sort of line dance for birds, with spread wings and synchronized group movements. Some behaviors are so characteristic that biologists use them to help differentiate between closely related species.

Behaviors often breed true. We can reproduce behaviors in successive generations of organisms. Consider the instinctive retrieval behavior of a yellow Labrador or the herding posture of a border collie.

Behaviors change in response to alterations in biological structures or processes. For example, a brain injury can turn a polite, mild-mannered person into a foul-mouthed, aggressive boor, and we routinely modify the behavioral manifestations of mental illnesses with drugs that alter brain chemistry. More recently, geneticists have created or extinguished specific mouse behaviors—ranging from nurturing of pups to continuous circling in a strain called "twirler"— by inserting or disabling specific genes.

In humans, some behaviors run in families. For example, there is a clear familial aggregation of mental illness.

Behavior has an evolutionary history that persists across related species. Chimpanzees are our closest relatives, separated from us by a mere 2 percent difference in DNA sequence. We and they share behaviors that are characteristic of highly social primates, including nurturing, cooperation, altruism, and even some facial expressions. Genes are evolutionary glue, binding all of life in a single history that dates back some 3.5 billion years. Conserved behaviors are part of that history, which is written in the language of nature's universal information molecule—DNA.

How is behavioral genetics studied? [text provided by Joseph McInerney]

Traditional research strategies in behavioral genetics include studies of twins and adoptees, techniques designed to sort biological from environmental influences. More recently, investigators have added the search for pieces of DNA associated with particular behaviors, an approach that has been most productive to date in identifying potential locations for genes associated with major mental illnesses such as schizophrenia and bipolar disorder. Yet even here there have been no major breakthroughs, no clearly identified genes that geneticists can tie to disease. The search for genes associated with characteristics such as sexual preference and basic personality traits has been even more frustrating.

Genetics and molecular biology have provided some significant insights into behaviors associated with inherited disorders. For example, we know that an extra chromosome 21 is associated with the mental retardation that accompanies Down's syndrome, although the processes that disrupt brain function are not yet clear. We also know the steps from gene to effect for a number of single-gene disorders that result in mental retardation, including phenylketonuria (PKU), a treatable metabolic disorder for which all newborns in the United States are tested.

In general, it is easier to discern the relationship between biology and behavior for chromosomal and single-gene disorders than for common, complex behaviors that are of considerable interest to specialist and nonspecialist alike. So the former are at the more informative end of a sliding scale of certainty with respect to our understanding of human behavior. At the other end of the scale are the hard-to-define personality traits, while somewhere in between are traits such as schizophrenia and bipolar disorder—organic diseases whose biological roots are undeniable yet unknown and whose unpredictable onset teaches us about the importance of environmental contributions, even as it reminds us of our ignorance.

What implications does behavioral genetics research have for society? [text provided by Joseph McInerney and Mark Rothstein]

Researchers in the field of behavioral genetics have asserted claims for a genetic basis of numerous physical behaviors, including homosexuality, aggression, impulsivity, and nurturing. A growing scientific and popular focus on genes and behavior has contributed to a resurgence of behavioral genetic determinism—the belief that genetics is the major factor in determining behavior.

Are behaviors inbred, written indelibly in our genes as immutable biological imperatives, or is the environment more important in shaping our thoughts and actions? Such questions cycle through society repeatedly, forming the public nexus of the "nature vs. nurture controversy," a strange locution to biologists, who recognize that behaviors exist only in the context of environmental influence. Nonetheless, the debate flares anew every few years, reigniting in response to genetic analyses of traits such as intelligence, criminality, or homosexuality, characteristics freighted with social, political, and legal meaning.

What social consequences would genetic diagnoses of such traits as intelligence, criminality, or homosexuality have on society? What effect would the discovery of a behavioral trait associated with increased criminal activity have on our legal system? If we find a "gay gene," will it mean greater or lesser tolerance? Will it lead to proposals that those affected by the "disorder" should undergo treatment to be "cured" and that measures should be taken to prevent the birth of other individuals so afflicted?

There are several scientific obstacles to correlating genotype (an individual's genetic endowment) and behavior. One problem is in defining a specific endpoint that characterizes a condition, be it schizophrenia or intelligence. Another problem is in identifying and excluding other possible causes of the condition, thereby permitting a determination of the significance of a supposed correlation. Much current research on genes and behavior also engenders very strong feelings because of the potential social and political consequences of accepting these supposed truths. Thus, more than any other aspect of genetics, discoveries in behavioral genetics should not be viewed as irrefutable until there has been substantial scientific corroboration.

How do genes influence behavior?

No single gene determines a particular behavior. Behaviors are complex traits involving multiple genes that are affected by a variety of other factors. This fact often gets overlooked in media reports hyping scientific breakthroughs on gene function, and, unfortunately, this can be very misleading to the public.

For example, a study published in 1999 claimed that overexpression of a particular gene in mice led to enhanced learning capacity. The popular press referred to this gene as "the learning gene" or the "smart gene." What the press didn't mention was that the learning enhancements observed in this study were short-term, lasting only a few hours to a few days in some cases.

Dubbing a gene as a "smart gene" gives the public a false impression of how much scientists really know about the genetics of a complex trait like intelligence. Once news of the "smart gene" reaches the public, suddenly there is talk about designer babies and the potential of genetically engineering embryos to have intelligence and other desirable traits, when in reality the path from genes to proteins to development of a particular trait is still a mystery.

With disorders, behaviors, or any physical trait, genes are just a part of the story, because a variety of genetic and environmental factors are involved in the development of any trait. Having a genetic variant doesn't necessarily mean that a particular trait will develop. The presence of certain genetic factors can enhance or repress other genetic factors. Genes are turned on and off, and other factors may be keeping a gene from being turned "on." In addition, the protein encoded by a gene can be modified in ways that can affect its ability to carry out its normal cellular function.

Genetic factors also can influence the role of certain environmental factors in the development of a particular trait. For example, a person may have a genetic variant that is know to increase his or her risk for developing emphysema from smoking, an environmental factor. If that person never smokes, then emphysema will not develop.

Where can I learn more about the genetics of different behavioral traits?

Online Mendelian Inheritance in Man (OMIM) is a large, searchable, up-to-date database of human genes, genetic traits, and disorders. Each OMIM record contains bibliographic references and a summary of the scientific literature describing what is known about a particular gene, trait, or disorder. The following behavioral traits are included in OMIM. The six-digit number MIM number is used to uniquely identify each record.

Hand skill, relative (handedness): (139900)

Hand clasping pattern: (139800)

Arm folding preference: (107850)

Ears, ability to move: (129100)

Tongue curling, folding, or rolling: (189300)

Musical perfect pitch: (159300)

Novelty seeking personality trait: (601696)

Stuttering: (184450)

Tobacco addiction: (188890)

Alcoholism: (103780)

Homosexuality: (306995)

You also may want to search OMIM for behavioral traits not included in the list above. For step-by-step instructions, see our OMIM Search Tutorial. For more detailed information, review the Help and FAQs pages. For information on other databases of human genes, see the Gene and Protein Database Guide available through Gene Gateway.

Behavioral Genetics Links

General Information

University of Pennsylvania Behavioral Genetics Laboratory

Virginia Institute for Psychiatric and Behavioral Genetics

Behavioral Genetics A downloadable book and special supplement from AAAS and the Hastings Center

Genetics and Human Behaviour - Health feature from the BBC in the U.K.

DNA & Behavior: Is Our Fate in Our Genes? - An overview of the science and social implications of research in behavior genetics. From The DNA Files, last updated October 2001.

Personality Traits: Nature and Nurture - Audio file of a radio program from SoundVision Productions. From The DNA Files.

Genes, Environment, and Human Behavior -- Educational module targeted to teachers includes five student activities and extensive background information on the methods and assumptions of behavioral genetics (2000).

Articles

Toward Behavioral Genomics - Article from Science (February 2001).

Learning About Addiction From the Genome - Article from Nature (February 2001).

Caution urged for brain research on violence--from CNN (July 28, 2000)

Judging Molecular Biology of Murder, Addictive Disorders, and Dementia - Meeting proceedings, Human Genome News 11(1-2)

Genes and Behavior: A Complex Relationship - Article by Joseph D. McInerney, Judicature 83, 112 (November-December 1999).

The Impact of Behavioral Genetics on the Law and the Courts - Article by Mark A. Rothstein, Judicature 83, 116 (November-December 1999).

Recent Developments in Human Behavioral Genetics: Past Accomplishments and Future Directions - Am. J. Hum. Genet. 60, 1265 (1997 ASHG Statement).

Associations

Behavior Genetics Association

Society of Behavioral Medicine

International Society of Behavioral Medicine

International Society for the Study of Behavioural Development

Books

Behavioral Genetics in the Postgenomic Era, by Robert Plomin, John C. Defries, Ian Craig, and Peter McGuffin, eds., and Jerome Kagan. 2002, 608 pp.

Behavioral Genetics: The Clash of Culture and Biologyby Ronald A. Carson and Mark A. Rothstein. 1999, 224 pp.

Behavioral Geneticsby Robert Plomin (Editor), John C. Defries, Gerald E. McClearn, Peter McGuffin. 2000, 4th edition, 449 pp.

Living With Our Genes: Why They Matter More Than You Thinkby Dean H. Hamer and Peter Copeland. 1999, 368 pp.

Behavioral genetics

Behavioral genetics is the field of study that examines the role of genetics in animal (including human) behavior. Often associated with the "nature versus nurture" debate, behavioral genetics is highly interdisciplinary, involving contributions from biology, genetics, epigenetics, ethology, psychology, and statistics. Behavioral geneticists study the inheritance of behavioral traits. In humans, this information is often gathered through the use of the twin study or adoption study. In animal studies, breeding, transgenesis, and gene knockout techniques are common. Psychiatric genetics is a closely related field.

History

Sir Francis Galton, a nineteenth-century intellectual, is recognized as one of the first behavioral geneticists. Galton, a cousin of Charles Darwin, studied the heritability of human ability, focusing on mental characteristics as well as eminence among close relatives in the English upper class. In 1869, Galton published his results in Hereditary Genius.[1] In his work, Galton "introduced multivariate analysis and paved the way towards modern Bayesian statistics" that are used throughout the sciences—launching what has been dubbed the "Statistical Enlightenment".[2] Galton is often credited as the pioneer of eugenics. Subsequently, Adolf Hitler is believed to have been motivated by Galton's work in enacting the Final Solution during World War II.[3]

In 1951, Calvin S. Hall in his seminal book chapter on behavioral genetics introduced the term "psychogenetic",[4] which enjoyed some limited popularity in the 1960s and 1970s.[5][6] However, it eventually disappeared from usage in favor of "behavior genetics".

Behavior genetics, per-se, gained recognition as a research discipline with the publication in 1960 of the textbook Behavior Genetics by J.L. Fuller and W.R. Thompson.[7] Nowadays, it is widely accepted that most behaviors in animals and humans are under some degree of genetic influence.[8]

Underscoring the role of evolution in behavioral genetics, Theodosius Dobzhansky was elected the first president of the Behavior Genetics Association in 1972; the BGA bestows the Dobzhansky Award on researchers for their outstanding contributions to the field. In the early 1970s, Lee Ehrman, a doctoral student of Dobzhansky, wrote seminal papers describing the relationship between genotype frequency and mating success in Drosophila,[9][10][11] lending impetus to the pursuit of genetic studies of behaviour in other animals. Studies on hygienic behavior in honeybees were also carried out early in the history of the field.[12][13] The social behavior of honey bees has also been studied and recent work has focused on the gene involved in the foraging behavior of Drosophila; this essentially allowed for deriving a relationship between gene expression and behavior, where the gene regulating foraging behavior in Drosophila also regulated social behavior in bees.[14]

Methods

The primary goal of behavioral genetics is to establish causal relationships between genes and behavior.[3] One common approach is the reductionist approach. Under this approach, scientists first observe a psychological or behavioral function (e.g., schizophrenia). Next, using known functions of brain systems and neurotransmitter systems, scientists correlate behavior to these brain areas (e.g., excess glutamate release may stimulate excess dopamine in the limbic system leading to schizophrenic symptoms). Once scientists are able to map behavior to biological systems, they can then turn to genetics to understand the development of these biological systems (e.g., an abnormal glutamate gene could be a candidate gene for schizophrenia). Quantitative trait loci (QTL) are the attempt to map genes to behavior. Other methods involve twin studies and adoption studies. These two methods attempt to separate environmental contributions to behavior from genetic contributions.

The Human Genome Project has allowed scientists to understand the coding sequence of human DNA nucleotides. Once candidate genes for behaviors are discovered scientists may be able to genetically screen individuals to determine their likelihood of developing certain pathologies.

Notable behavioral geneticists

Notable behavioral geneticists include Dorret Boomsma, Wim Crusio (the founding editor of the journal Genes, Brain and Behavior), John DeFries, Lindon Eaves, David Fulker, John Hewitt, Kenneth Kendler, John Loehlin, Nick Martin, Gerald McClearn, Robert Plomin, Theodore Reich (a pioneer in psychiatric genetics), Hans van Abeelen, Avshalom Caspi, Steven G. Vandenberg (the founding editor of the journal Behavior Genetics), and Irving Gottesman.

Journals

Field of Study

Genetics (from Ancient Greek γενετικός genetikos, "genitive" and that from γένεσις genesis, "origin"), a discipline of biology, is the science of genes, heredity, and variation in living organisms.

Genetics deals with the molecular structure and function of genes, gene behavior in context of a cell or organism (e.g. dominance and epigenetics), patterns of inheritance from parent to offspring, and gene distribution, variation and change in populations, such as through Genome-Wide Association Studies. Given that genes are universal to living organisms, genetics can be applied to the study of all living systems, from viruses and bacteria, through plants and domestic animals, to humans (as in medical genetics).

The fact that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding. However, the modern science of genetics, which attempts to understand the process of inheritance, only began with the work of Gregor Mendel in the mid-19th century. Although he did not know the physical basis for heredity, Mendel observed that organisms inherit traits by way of discrete units of inheritance, which are now called genes.

Genes correspond to regions within DNA, a molecule composed of a chain of four different types of nucleotides—the sequence of these nucleotides is the genetic information organisms inherit. DNA naturally occurs in a double stranded form, with nucleotides on each strand complementary to each other. Each strand can act as a template for creating a new partner strand. This is the physical method for making copies of genes that can be inherited.

The sequence of nucleotides in a gene is translated by cells to produce a chain of amino acids, creating proteins—the order of amino acids in a protein corresponds to the order of nucleotides in the gene. This relationship between nucleotide sequence and amino acid sequence is known as the genetic code. The amino acids in a protein determine how it folds into a three-dimensional shape; this structure is, in turn, responsible for the protein's function. Proteins carry out almost all the functions needed for cells to live. A change to the DNA in a gene can change a protein's amino acids, changing its shape and function: this can have a dramatic effect in the cell and on the organism as a whole.

Although genetics plays a large role in the appearance and behavior of organisms, it is the combination of genetics with what an organism experiences that determines the ultimate outcome. For example, while genes play a role in determining an organism's size, the nutrition and health it experiences after inception also have a large effect.

History

Main article: History of genetics

DNA, the molecular basis for inheritance. Each strand of DNA is a chain of nucleotides, matching each other in the center to form what look like rungs on a twisted ladder.

Although the science of genetics began with the applied and theoretical work of Gregor Mendel in the mid-19th century, other theories of inheritance preceded Mendel. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents. Mendel's work provided examples where traits were definitely not blended after hybridization, showing that traits are produced by combinations of distinct genes rather than a continuous blend. Blending of traits in the progeny is now explained by the action of multiple genes with quantitative effects. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrong—the experiences of individuals do not affect the genes they pass to their children. Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited.

Mendelian and classical genetics

Modern genetics started with Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who studied the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brünn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically. Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until the 1890s, after his death, when other scientists working on similar problems re-discovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905. (The adjective genetic, derived from the Greek word genesis—γένεσις, "origin", predates the noun and was first used in a biological sense in 1860.) Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1911, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies. In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.

Morgan's observation of sex-linked inheritance of a mutation causing white eyes in Drosophila led him to the hypothesis that genes are located upon chromosomes.

Molecular genetics

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA, and scientists did not know which of these is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty identified the molecule responsible for transformation as DNA. The role of the nucleus as the respository of genetic information in eukaryotes had been established by Hämmerling in 1943 in his work on the single celled alga Acetabularia. The Hershey-Chase experiment in 1952 confirmed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance.

James D. Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA had a helical structure (i.e., shaped like a corkscrew). Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what looks like rungs on a twisted ladder. This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for duplication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand.

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production. It was discovered that the cell uses DNA as a template to create matching messenger RNA (a molecule with nucleotides, very similar to DNA). The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide and amino acid sequences is known as the genetic code.

With this molecular understanding of inheritance, an explosion of research became possible. One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger. This technology allows scientists to read the nucleotide sequence of a DNA molecule. In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of a DNA from a mixture. Through the pooled efforts of the Human Genome Project and the parallel private effort by Celera Genomics, these and other methods culminated in the sequencing of the human genome in 2003.

Features of inheritance

Discrete inheritance and Mendel's laws

Main article: Mendelian inheritance

A Punnett square depicting a cross between two pea plants heterozygous for purple (B) and white (b) blossoms

At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called genes. This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants. In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white—but never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of pea, which is a diploid species, each individual plant has two copies of each gene, one copy inherited from each parent. Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Notation and diagrams

Genetic pedigree charts help track the inheritance patterns of traits.

Geneticists use diagrams and symbols to describe inheritance. A gene is represented by one or a few letters. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.

In fertilization and breeding experiments (and especially when discussing Mendel's laws) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.

When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits. These charts map the inheritance of a trait in a family tree.

Interactions of multiple genes

Human height is a trait with complex genetic causes. Francis Galton's data from 1889 shows the relationship between offspring height as a function of mean parent height. While correlated, remaining variation in offspring heights indicates environment is also an important factor in this trait.

Organisms have thousands of genes, and in sexually reproducing organisms these genes generally assort independently of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all or are white. When a plant has two copies of this white allele, its flowers are white—regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.

Many traits are not discrete features (e.g. purple or white flowers) but are instead continuous features (e.g. human height and skin color). These complex traits are products of many genes. The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability. Measurement of the heritability of a trait is relative—in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a trait with complex causes. It has a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.

Molecular basis for inheritance

DNA and chromosomes

Main articles: DNA and Chromosome

The molecular structure of DNA. Bases pair through the arrangement of hydrogen bonding between the strands.

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.Viruses are the only exception to this rule—sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double-helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.

Genes are arranged linearly along long chains of DNA base-pair sequences. In bacteria, each cell usually contains a single circular genophore, while eukaryotic organisms (including plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length. The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes, chromatin is usually composed of nucleosomes, segments of DNA wound around cores of histone proteins. The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene. The two alleles for a gene are located on identical loci of the two homologous chromosomes, each allele inherited from a different parent.

Walther Flemming's 1882 diagram of eukaryotic cell division. Chromosomes are copied, condensed, and organized. Then, as the cell divides, chromosome copies separate into the daughter cells.

Many species have so called sex chromosomes. They are special in that they determine the sex of the organism. In humans and many other animals, the Y-chromosome contains the gene that triggers the development of the specifically male characteristics. In evolution, this chromosome has lost most of its content and also most of its genes, while the X chromosome is similar to the other chromosomes and contains many genes. The X and Y chromosomes form a very heterogeneous pair.

Reproduction

Main articles: Asexual reproduction and Sexual reproduction

When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid). Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes such as sperm or eggs.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium. Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genomes, a phenomenon known as transformation. These processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would be otherwise unrelated.

Recombination and linkage

Main articles: Chromosomal crossover and Genetic linkage

Thomas Hunt Morgan's 1916 illustration of a double crossover between chromosomes

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently during sexual reproduction, recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine, however, were it not for the process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid cells.

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between the points. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage—alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.

Gene expression

Genetic code

Main article: Genetic code

The genetic code: DNA, through a messenger RNA intermediate, codes for protein with a triplet code.

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are made up of one or more polypeptide chains, each of which is composed of a sequence of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific amino acid sequence. This process begins with the production of an RNA molecule with a sequence matching the gene's DNA sequence, a process called transcription.

This messenger RNA molecule is then used to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds either to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence; this correspondence is called the genetic code. The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but it never transfers from protein back into the sequence of DNA—a phenomenon Francis Crick called the central dogma of molecular biology.

A single amino acid change causes hemoglobin to form fibers.

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of proteins are related to their functions. Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the β-globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties. Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clog or degrade, causing the medical problems associated with this disease.

Some genes are transcribed into RNA but are not translated into protein products—such RNA molecules are called non-coding RNA. In some cases, these products fold into structures which are involved in critical cell functions (e.g. ribosomal RNA and transfer RNA). RNA can also have regulatory effect through hybridization interactions with other RNA molecules (e.g. microRNA).

Nature versus nurture

Main article: Nature vs. nurture

Siamese cats have a temperature-sensitive mutation in pigment production.

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotype—a phenomenon often referred to as "nature vs. nurture". The phenotype of an organism depends on the interaction of genetics with the environment. One example of this is the case of temperature-sensitive mutations. Often, a single amino acid change within the sequence of a protein does not change its behavior and interactions with other molecules, but it does destabilize the structure. In a high temperature environment, where molecules are moving more quickly and hitting each other, this results in the protein losing its structure and failing to function. In a low temperature environment, however, the protein's structure is stable and it functions normally. This type of mutation is visible in the coat coloration of Siamese cats, where a mutation in an enzyme responsible for pigment production causes it to destabilize and lose function at high temperatures. The protein remains functional in areas of skin that are colder—legs, ears, tail, and face—and so the cat has dark fur at its extremities.

Environment also plays a dramatic role in effects of the human genetic disease phenylketonuria. The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. If someone with the phenylketonuria mutation follows a strict diet that avoids this amino acid, however, they remain normal and healthy.

A popular method to determine how much role nature and nurture play is to study identical and fraternal twins or siblings of multiple birth. Because identical siblings come from the same zygote they are genetically the same. Fraternal siblings however are as different genetically from one another as normal siblings. By comparing how often the twin of a set has the same disorder between fraternal and identical twins, scientists can see whether there is more of a nature or nurture effect. One famous example of a multiple birth study includes the Genain quadruplets, who were identical quadruplets all diagnosed with schizophrenia.

Gene regulation

Main article: Regulation of gene expression

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA (and translated into protein), and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to the start of genes, either promoting or inhibiting the transcription of the gene. Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genes—tryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.

Transcription factors bind to DNA, influencing the transcription of associated genes.

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells. These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.

Genetic change

Mutations

Main article: Mutation

Gene duplication allows diversification by providing redundancy: one gene can mutate and lose its original function without harming the organism.

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low—1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases. (Without proofreading error rates are a thousandfold higher; because many viruses rely on DNA and RNA polymerases that lack proofreading ability, they experience higher mutation rates.) Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure. Chemical damage to DNA occurs naturally as well, and cells use DNA repair mechanisms to repair mismatches and breaks in DNA—nevertheless, the repair sometimes fails to return the DNA to its original sequence.

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations. Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence—duplications, inversions or deletions of entire regions, or the accidental exchanging of whole parts between different chromosomes (called translocation).

Natural selection and evolution

Main article: Evolution

Further information: Natural selection

Mutations alter an organisms genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive fitness. Mutations that do have an effect are usually deleterious, but occasionally some can be beneficial. Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations will be harmful with the remainder being either neutral or weakly beneficial.

An evolutionary tree of eukaryotic organisms, constructed by comparison of several orthologous gene sequences

Population genetics studies the distribution of genetic differences within populations and how these distributions change over time. Changes in the frequency of an allele in a population are mainly influenced by natural selection, where a given allele provides a selective or reproductive advantage to the organism, as well as other factors such as mutation, genetic drift, genetic draft,artificial selection and migration.

Over many generations, the genomes of organisms can change significantly, resulting in the phenomenon of evolution. Selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment, a process called adaptation. New species are formed through the process of speciation, often caused by geographical separations that prevent populations from exchanging genes with each other. The application of genetic principles to the study of population biology and evolution is referred to as the modern synthesis.

By comparing the homology between different species' genomes it is possible to calculate the evolutionary distance between them and when they may have diverged (called a molecular clock). Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form evolutionary trees; these trees represent the common descent and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).

Research and technology

Model organisms

The common fruit fly (Drosophila melanogaster) is a popular model organism in genetics research.

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research. Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenience—short generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medicine

Medical genetics seeks to understand how genetic variation relates to human health and disease. When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a method especially useful for multigenic traits not clearly defined by a single gene. Once a candidate gene is found, further research is often done on the corresponding gene (called an orthologous gene) in model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of pharmacogenetics—studying how genotype can affect drug responses.

Individuals differ in their inherited tendency to develop cancer, and cancer is a genetic disease. The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process; signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Normally, a cell divides only in response to signals: "growth factors", it stops growing when making contact with surrounding cells (contact inhibition), and in response to growth inhibitory signals, it divides a limited number of times and dies (apoptosis), it stays inside the epithelium and is not able to migrate to invade other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (3-7) that allow it to bypass all these regulations: it no longer needs growth factors to divide, it continues growing when making contact to neighbor cells, and ignores inhibitory signals, it will keep growing indefinitely and is immortal, it will escape from the epithelium and ultimately may be able to escape from the primary tumor, cross the endothelium of a blood vessel, be transported by the bloodstream and will colonize a new organ, forming deadly metastasis. Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny (somatic mutations). The most frequent mutations are a loss of function of p53 protein, a tumor suppressor, or in the p53 pathway, and gain of function mutations in the ras proteins, or in other oncogenes.

Research methods

DNA can be manipulated in the laboratory. Restriction enzymes are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA. DNA fragments can be visualized through use of gel electrophoresis, which separates fragments according to their length.

The use of ligation enzymes allows DNA fragments to be connected, and by ligating fragments of DNA together from different sources, researchers can create recombinant DNA. Often associated with genetically modified organisms, recombinant DNA is commonly used in the context of plasmids—short circular DNA fragments with a few genes on them. By inserting plasmids into bacteria and growing those bacteria on plates of agar (to isolate clones of bacteria cells), researchers can clonally amplify the inserted fragment of DNA (a process known as molecular cloning). (Cloning can also refer to creating clonal organisms, by various means.)

Colonies of E. coli on a plate of agar, an example of cellular cloning and often used in molecular cloning.

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR). By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing and genomics

One of the most fundamental technologies developed to study genetics, DNA sequencing allows researchers to determine the sequence of nucleotides in DNA fragments. Developed in 1977 by Frederick Sanger and coworkers, chain-termination sequencing is now routinely used to sequence DNA fragments. With this technology researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive, researchers have sequenced the genomes of many organisms, using computational tools to stitch together the sequences of many different fragments (a process called genome assembly). These technologies were used to sequence the human genome, leading to the completion of the Human Genome Project in 2003. New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars.

The large amount of sequence data available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data.

See also

Genetic disorder

Index of genetics articles

Modern Evolution of Genetics Timeline

Outline of genetics

Bacterial genome size

Notes

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pol·y·math

pol y·math, pol y·math ic adj.

po·lym a·thy  n.

pro·cras·ti·nate  

v. pro·cras·ti·nat·ed, pro·cras·ti·nat·ing, pro·cras·ti·nates

v.intr. To put off doing something, especially out of habitual carelessness or laziness.