#jacquemont

I got into playing around with the Arctium local server for Wildstar and just revisiting some old places has really put a zip back in my step.

Naturally there are bugs abound and you can’t play, but that’s to be expected. At least now we can still see all this work Carbine did :’) and it won’t ever go to waste. I do miss Roger and everyone a whole ton.

As I mentioned in my earlier post, among the many papers that I bookmarked for “reading later”, this preprint was in the top of my list, and I managed to read it today. There are two reasons why I had a special interest in this preprint.

First, it addresses a question that I—and probably many others—were thinking about more and more recently: why some individuals carrying a large effect mutation(s) for a particular disease do not develop the disease; what factors make them resilient to the disease?

Second, I learnt about this preprint through Dr. Sébastien Jacquemont (a co-author in this paper,) a scientist whose work I’ve started admiring a lot recently. For e.g. I found two of his papers on the associations between copy number variants and intelligence highly insightful, which I have also summarized as twitter threads (thread1, thread2.)

In this paper, the authors have analyzed the exomes of around 10,000 ASD cases and 100,000 non-ASD individuals (who were mainly from the UK Biobank) with one particular aim: what makes non-ASD individuals who carry loss of function (LOF) mutations in known ASD genes resilient to ASD?

The authors have looked into a list of 156 genes what seem to be “robustly associated with ASD.” For each gene, the authors calculated the ASD penetrance (in terms of relative risk, which is “the risk of being diagnosed with ASD when carrying such variants,”) and compared the penetrance estimates with the LOF intolerance measures, and found them to be highly concordant. This reinforces the notion that genes linked to ASD are simply genes linked to brain in general. The most robust metric of a gene’s specificity to brain is its mutation constraint. And we see it for the ASD genes as well, also intellectual disability (ID) genes. Note that there is no clear distinction across ASD specific genes, ID specific genes and brain specific genes. And this has been the basis of a paper titled ‘Insufficient Evidence for “Autism-Specific” Genes,’ that came out last year, and stirred some tension among the ASD researchers.

Despite the high concordance between ASD penetrance and mutation constraints, there seem to be some interesting exceptions, e.g. PTEN, SHANK2, which are highly penetrant for ASD, yet less intolerant to LOF mutations. That is, despite mutations in these genes often leading  to ASD or ID, they seem to evade natural selection. How? Such outlier genes, perhaps, hold the key to opening the ASD mystery? The authors also report a list of 25 genes that are fully penetrant for ASD. That is, among the 100k non-ASD individuals, the authors found not even one person who carried a LOF mutation in any of these 25 genes and did not develop ASD. I find this list extremely intriguing, and I plan to dive deep into this list later.

The authors found that the cognitive functions of non-ASD LOF carriers in the UK biobank are significantly lower compared to non-ASD non-carriers.  More penetrant the genes are for ASD, higher the differences in cognitive functions between carriers and non-carriers. My immediate thought on reading this finding is if the authors repeated the same analysis in some brain-specific highly constrained genes (irrespective of their association with ASD), they would have seen the same. In fact, that’s what exactly was shown in Dr. Jacquemont’s previous paper. My point is all these analyses are reflecting brain specificity, rather than ASD specificity.

Importantly, the authors found that the liability threshold model holds true for ASD; non-ASD LOF carriers had lower burden of common ASD risk variants than ASD LOF carriers, which seems to indicate that the decreased common variant burden might have contributed to the resiliency of the non-ASD LOF carriers.

Finally, the authors searched for clues that might support the “female protective effect” hypothesis. The authors expected (or may be they didn’t) that female sex might be one of the contributing factors for ASD resiliency in non-ASD LOF carriers. Unfortunately, that wasn’t the case. The non-ASD LOF carriers were equally distributed among males and females.

“One more game Roger then we'll stop! Pretty please?” Mara bobbed back and forth in her seat and clapped her hands together.

Roger grunted and looked down at the table. He was sick of playing card games. Mara seemed to like those however, and she was always really nice and brought snacks and those juice boxes...so he let it go without throwing a fit.

I have every reason to believe there is in fact a show called The Roan Ranger on Protostar networks for television.

Walker's weird, weird, weird little family spanning over ...well probably a good century and a half or so

A doodle that got out of hand. It was for this initially, then it just got away from me.

“Ugh- where's my tablet-” Walker pat around himself, turned around several times before slapping a palm onto his face and running it down. “Roger go look in that aisle right there, I probably put my datacron down for a moment when I heard you screaming. Jacque go check, hurry up.”

Jacque buzzed loudly and floated over towards the designated aisle, leading a grumpy Roger over to it.

The man scowled and stood on his toes, leaning to one side to look down said aisle. A datacron was sitting on a shelf not so far away; he ran over to it, picked it up and looked at it.

As he was about to return, however, he paused. Glancing over at the book-area. Quickly he looked back to Walker. The Mordesh had his back turned to him and was fighting with the scanning machine.

Good...

Quickly he pulled off his coat and snuck back towards the books. Jacquemont watched him go, confused.

“ROGER? GET OVER HERE!”

“OK! COMING! Coming...”

_______________________________

Walker was far too occupied with getting the 'groceries' back home in one piece to notice Roger lingering behind him. “Where are you? For gods' sakes, get over here before you get left behind again.” He grumbled, pressing a series of buttons on the teleporter's keypad in order to send them back to their home lot.

Roger caught up with him and almost crashed into him, his coat bundled in a big wad in his arms.

Walker eyed him suspiciously. “What's that? Why're you holding your coat like that?”

“N-nothing!” Roger chirped, hugging it closer to himself. Before the botanist could question it any further, there was a flash of bright blue light. They were home now.

Immediately the human darted out into the yard and turned back to make sure Walker was still there. He was.

Jacque made a strange noise before turning to Walker, startled to see he was being stared at. The Grismaran narrowed his eyes. “What did he do.”

The yellow bot hovered up and down, 'wing-flaps' moving up and down, antenna perking up and blinking rapidly. He looked nervous somehow (as much as a piece of A.I. could be.) And that wasn't a good sign.

What on Nexus did Roger do now??

After frowning extra hard, the Mordesh grumbled to himself some more, bringing the bags of cereal and cup noodles over and into the house. There they would sit in the cabinets until they were consumed. What a cruel fate.

Roger on the other hand was nowhere to be seen. But he did hear the man's footsteps running back and forth upstairs.

“...Roger? What are you doing up there??”

The noises stopped. “...UHM...”

That wasn't helping his case. Walker waited for a response, but none came. Did he forget again? Maybe so. “...Roger...”

“NOTHING!”

Like hell was it nothing.

Scowling, the botanist moved up the stairs, glancing around the kitchen. No, Roger was probably in the other room. “Roger, I'm not going to ask you again, WHAT did you do, WHY are you acting so strangely?”

As he turned the corner into the living-slash-bedroom, he saw why.

Roger stood with his back turned to him, looking over his shoulder with his coat still bunched up in his arms. Amongst it though was something green and soft-looking with blue button eyes.

It was that hoogle doll.

Roger must have stolen it from the store when he brought back Walker's datacron.

The botanist didn't know what to feel about it. It wasn't often that Roger did something like this (if at all,) but at the same time, not surprising either.

“...Roger did you steal that from the store earlier?”

The man's eyes darted to and fro, unable to settle on Walker's face. In fact, Walker was amazed he remembered about it this long in the first place. Roger must've been really focused on this.

“Answer me.”

Ashamed, Roger held his hands behind his back and looked down at the floor, or at his feet in particular. He didn't answer right away. “...I ...I just-” He sounded upset.

Walker tapped his foot impatiently, waiting for an answer.

“...I just wanted it I-” Sheepishly he looked back at the stuffed green lump sitting on his bed, 'nestled' in his coat. All the other animals were around is as if they were 'greeting' the thing. “I'm sorry- I'm sorry-” He whimpered afterwards, rubbing at his eyes.

Great, just the thing Walker didn't want. “...Roger- no- no stop- don't cry. Look, you can't go taking things from stores without PAYING for them. That's called STEALING. And I'm not housing any THIEVES either. Do you understand?” It was hard to be angry with him, even if he just committed a crime (petty as it was.)

Roger nodded several times too many before returning to the doll and squeezing it tightly. “Don't take it back- Don't take it back-” He shook his head after that. “Please-”

Walker stared at him for a while, mentally debating on what he should do. If he took the thing back, they were likely going to give him more trouble than the object was even worth. And if he didn't...Well, it wasn't like he wanted to reinforce the idea of stealing.

“Gimme it. I'm putting it away for now. You can work to get it back and pay for it like you should have done.” He held out a hand in his typical 'give me' fashion.

Roger swallowed and looked from the Mordesh's face to his open hand. He really didn't want to fork it over, but it was probably the best thing to do. “...You promise?” He asked, or squeaked.

The botanist nodded once. “Yes.”

Reluctantly, the human gave him the hoogle, very unhappy about it all. It just looked and felt so soft; he didn't want to leave it at the store. Big globby tears came shortly after that.

Walker sighed loudly. “...Don't cry anymore...You'll get it back soon.” If Roger didn't forget about it, and if he could save his money. Usually he never could hang onto it, so this was going to be particularly difficult for him.

Still, he could be determined when he wanted to be. He did remember the movie marathon on television after all.

“Look, go pull some of the weeds outside ok? Before it gets dark...take your mind off it.”

Roger sniffed loudly, wiping at his eyes and dragging his feet all the way downstairs and out the door.

Walker groaned loudly and looked up at the ceiling. Jacquemont floated next to him, bleeping questioningly and looking at the hoogle. The bot opened up, revealing what had happened at the store. Jacque had seen the whole thing (which Walker had expected anyway.)

“Right then... I'm going to have to keep a closer eye on him in that case.”

“You used to steal, too. But, not because you were bad.” The narration-app's voice said suddenly and clearly.

Walker froze and looked right at the scanbot, before shivering and swallowing the lump that was rapidly forming in his throat. “...Deactivate that program. Now.”

Jacquemont did so quickly and closed up again, taking on his usual spherical shape. Walker hated that voice and he didn't know why. Didn't he miss it?

The Mordesh closed his eyes, inhaled slowly and shook his head before returning downstairs to his workspace. The yellow scanbot hovered there, tilting his entire body to the side (a gesture of confusion if anything.)