Neural compensation and autism

So, a study just published in the Proceedings of the National Academy of Sciences uses fMRI to compare the neural response to biological motion in three groups of subjects: people with autism, unaffected siblings of people with autism, and a control group, who have neither autism nor family members with autism. This is a fairly standard sort of thing to do when people study disorders that, like autism, have high heritability, and therefore presumably a significant genetic component. There were some interesting findings in this paper, though, that make it stand out. In particular, the authors identify a set of brain regions that show elevated activity specifically in the group of unaffected siblings, and call these "compensatory" regions.

The idea is this. People with autism have a set of genetic variants that give them a predisposition for developing autism. Straightforward, right? Presumably, the siblings of people with autism carry many of these same genetic variants, but there is some reason why they don't develop the disorder. Of course, one possibility is that they do not, in fact, carry the autism-causing genetic variants. Another possibility, raised by this paper, is that they do have genes that predispose them to autism, but that some compensatory mechanism has maintained normal neural development in the face of this genetic predisposition. This compensation could be developmental – in that some sort of canalization mechanism sets in when it somehow senses that brain development is going off track. Or, it could be genetic, in that the unaffected siblings also possess genetic variants (presumably at other genetic loci) that shift them back towards normal development.

Here's Figure 3 from the paper. The top panel shows the "state" regions. Those are brain regions that show differential activation in the autism group (reduced activity in response to viewing biological motion). The middle panel shows the "trait" regions, which are the regions with reduced activity in both the autism group and the group of unaffected siblings. The bottom panel shows the "compensatory" regions, which show elevated activity specifically in the group of unaffected siblings.

The brain regions identified as "state" regions are those that are typically identified as regions of reduced activity in autism – a nice validation. The two "compensatory" regions are the right posterior superior temporal sulcus (pSTS) and ventromedial prefrontal cortex (vmPFC). Both of these regions have been associated with social perception and cognition. Note that both of these regions also appear in the "state" category.

So what does that mean? Well, that means that there are certain regions within these two structures that show reduced activity in cases of autism. There are other regions within the same two structures that are not impaired in autism, but show enhanced activity in unaffected siblings.

Like much of the most interesting science, this paper raises more questions than it answers, and there are many conceivable explanations of these patterns. The results suggest a number of interesting avenues for future research, however.

The paper can be found here. It is an open-access article, so you don't need a subscription to PNAS to get it.

Update: Full citation

Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, & Pelphrey KA (2010). Neural signatures of autism. Proceedings of the National Academy of Sciences of the United States of America PMID: 21078973

Snake parthenogenesis III: The final chapter

So, I really had no intention of doing three separate posts on virgin birth in snakes, and I sincerely hope – for your sake as well as mine – that this finishes off the topic for the time being. In the first installment, we talked about this Boa constrictor that had given parthenogenetic birth to 22 babies, and some of the interesting genetics raised by that observation. In the second installment, we noted some species that undergo paternal genome exclusion, which seems like a similar phenomenon.

I was then pointed toward the case of the whip-tail lizard in a note from John Wilkins, who not only has an AWESOME name, but also runs possibly the best blog out there on philosophy and evolution. If you're not already reading his blog, I highly recommend it.

The phenomenon of non-virgin virgin birth may not be all that rare or unexpected among herps (amphibians and reptiles). For example, in the case of the whip-tail lizards, some species consist only of females, all of whom reproduce parthenogenetically. The interesting thing is that mating is required in order to trigger this parthenogenetic developmental process. So, how does that work, if there are no males? What happens is that these females will mate with males of another species, and it is likely that the diploid, parthenogenetic egg starts developing only when it receives a biochemical signal that depends on physical contact with the sperm.

I spoke about this with Andrew Singson, who studies cell-cell interactions, particularly between gametes. He noted that the requirement for physical stimulation of the egg by sperm is actually quite widespread. In many birds, for example, polyspermy, where more than one sperm interacts with the egg, is required. Only one of these sperm fuses with the egg and contributes genetic material to the offspring. However, that single sperm may not provide enough of a signal to flip the egg's developmental switch. Before the process of embryonic development can start, many other sperm have to physically interact with the egg in a sort of wing-man role. Opportunities for analogy abound, but fortunately – for your sake as well as mine – other demands prohibit me from plumbing their depths at the moment.

Snake parthenogenesis II: Non-virgin virgin birth

So, in the last post, we went through some of the strange and interesting things associated with the Boa constrictor that gave parthenogenetic birth to 22 baby Boas. It turns out there's yet another crazy thing going on here. Etymologically speaking, parthenogenesis means "virgin birth." It is a combination of parthenos (παρθένος), meaning "virgin," like the parthenon, and genesis (γένεσις), meaning, well, genesis.

The thing is, though, while it seems clear that the baby Boas' genetic material comes entirely from the mother, she's likely not really a virgin. I don't mean that she's a born-again virgin who had some had some wild times back in snake college, repented, then ran for Senate. Instead, it appears that she only gave birth after being housed with a male snake. Of course, it's only two litters, so it could well be a coincidence. On the other hand, it could be that fertilization was required to initiate development of the diploid eggs produced by the female.

There is a somewhat related phenomenon of paternal genome loss that has been identified in several different species of creepy crawlies, including at least some species of Phytoseiid mites (click here for non-English text, but drawings of them preying on other mite species), scale insects, and sciarid flies. Typically, paternal genome exclusion is limited to males, which start of diploid, but then lose their paternally inherited genome at some point during development, often living much of their lives in a haploid state. These and related phenomena are nicely covered in chapter 10 of Genes in Conflict by Austin Burt and Robert Trivers. Of course, the difference here is that the snakes have two full maternal genomes. Also, we don't really know if they received, and then jettisoned paternal genes, or never got them in the first place.

It also bears some similarities to one of the mechanisms by which uniparental disomies arise in humans (among others). Normally, meiosis results in one copy of each chromosome going into each gamete. With some frequency, though, they don't sort out correctly, and two aneuploid gametes wind up being produced, one with an extra copy of one chromosome, and one that is missing that chromosome altogether. If one of these gametes winds up contributing to the offspring, that offspring may wind up missing one copy of a chromosome (e.g., the X chromosome in Turner's syndrome), or with an extra copy of a chromosome (e.g., the X chromosome in Kleinfelter's syndrome, or chromosome 21 in Down syndrome). Another possible outcome for the extra chromosome case is "trisomy rescue," where the zygote somehow recognizes the presence of the extra chromosome and kicks out one of the three copies.

There are a couple of different ways that this trisomy rescue can happen. Let's say the extra chromosome came in with the egg. If one of the two maternal copies is kicked out, you wind up back at the standard diploid genome. On the other hand, if the paternal copy gets kicked out, you have the standard number of chromosomes, but a uniparental disomy. If the chromosome contains one or more imprinted genes, this can have various developmental consequences.

So, one possibility is that this female snake, for whatever reason, produces diploid eggs. Fertilization triggers development, but then a triploid rescue mechanism kicks in. The key thing is that it would need to be kicking in before fusion of the maternal and paternal pronuclei, since it seems to be the paternal genome that goes missing in every case.

Or this could all be related to the fact that the males snakes housed with this female in 2009 and 2010 were all huge General Ripper fans.

Update: One more follow-up post here.

Parthenogenesis: now in snakes!

So, as if my friends on the religious right needed more reasons to be afraid of snakes, now they are threatening to undermine the nuclear family, which is clearly defined in the Bible as a mommy, a daddy, and two overachieving children. A recent paper in Biology Letters has studied two litters of offspring from a female Boa constrictor, totaling 22 baby snakes. All of the babies are female, and all of them have a rare, recessive color trait that is exhibited by the mother, but by none of the possible fathers.

What the researchers were able to demonstrate was that these baby snakes do not have a father at all. Rather, they are all parthenogenetic products of the mother. The researchers typed the offspring at eight microsatellite loci, and all the daughters were homozygous at all of the loci, matching in each case one of the two maternal alleles.

Note to self: No Boa constrictors on the island!

Several interesting things here. First, the implication is that these daughters are genome-wide homozygotes. This suggests a complete absence of lethal recessive mutations in the mother's genome. This seems surprising, but let's do a quick back of the envelope calculation. Let's assume there are about 10,000 genes in the snake where a loss-of-function mutation is lethal. Say the coding region for each gene is about 1000 nucleotides long, and that, say 1/10 of those nucleotides are fixed, in the sense that a mutation obliterates the gene's function. That would be a lethal mutational target of 100 nucleotides for each gene. Assuming a mutation rate of 10^-9, mutation-selection balance at each locus would have loss-of-function mutations circulating at a frequency of about 1 in 3000. So, we would expect each maternal half-genome to contain, on average, about 3 lethal recessive mutations. Assuming that those mutations are Poisson distributed, there is about a 5% chance that it would contain no such mutations. So, not super likely, but not out of the question either. And, that probability would be higher if the mutational target is smaller, or if the Boa population has undergone significant inbreeding, which would have driven the frequency down.

Second, there's a weirdness with the sex chromosomes. Now, in mammals, sex is determined by whether you have two X chromosomes, in which case you are a female, or an X chromosome and a Y chromosome, in which case you are a male. Everyone inherits an X chromosome from their mother, and you inherit either an X or a Y from your father. So, if you don't have any sons, it's not your wife's fault. Snakes also have chromosomal sex determination, but use a ZW system. Males have two Z chromosomes, while females have a W and a Z. It turns out that every one of the parthenogenetic daughter snakes is actually WW. That's some serious weirdness on which I have little insight. The one thing we can say is that you would never see a YY male. The Y chromosome is a shriveled little thing that does not do much other than tell you to be male, while the X does all the work. The snake W chromosome, on the other hand, is a real chromosome, that is, in fact, impossible to distinguish from the Z under the microscope.

Finally – and this is the reason I'm writing about this here – this tells us something about genomic imprinting. In mammals, there appear to be at least 50-100, possibly as many as 1000 imprinted genes, which are expressed from only one of the two copies. So, if there are 200 imprinted genes, there will be, say, 100 of them that are expressed only from the paternally inherited copy. If you produce parthenogenetic offspring, they will inherit two maternally derived alleles at each of these loci, which will be like having 100 of your genes knocked out, and is almost guaranteed to be lethal. In fact there are a number of genetic disorders in humans that result from uniparental inheritance of just a small subset of imprinted genes, and these produce fairly severe phenotypes. So, the fact that these parthenogenetic snakes appear to be perfectly viable implies that there are few – or quite possibly no – imprinted genes in this species.

Booth, W., Johnson, D., Moore, S., Schal, C., & Vargo, E. (2010). Evidence for viable, non-clonal but fatherless Boa constrictors Biology Letters DOI: 10.1098/rsbl.2010.0793

Update: Two follow-up posts here and here.

The flux capacitor in your brain

So, you already know that Friday was the 55th anniversary of Doc Emmett Brown's falling off his toilet, hitting his head, falling unconscious, and coming up with the flux capacitor, which not only allowed Teen Wolf to make out with Caroline in the City, but is singlehandedly responsible for the fact that anyone still remembers what a DeLorean is. How do I know you know? Because you spent all week baking this cake.

It took the good doctor thirty more years to get his idea working, so that time travel first became practical in 1985. However, it turns out that, as usual, natural selection got there first. There is an article in press in the Journal of Personality and Social Psychology that presents experimental evidence for precognition or time-reversed instances of causation. The preprint is available here, from the website of the author, Daryl Bem.

Bem is fairly well known, particularly for his early work in social psychology on the "self-perception theory of attitude change," which is basically that we learn about ourselves in much the same way that someone else might. For instance, say I hate peanut butter sandwiches. But then I eat a peanut butter sandwich every day for a month. I then look at myself, and say, "Hey, that handsome fellow really seems to like peanut butter sandwiches." This is the academic basis of that damn Stuart Smalley sketch. He is also responsible for the "Exotic becomes erotic" theory of the formation of sexual orientation.

The paper presents the results of nine experiments, each of which tested for awareness of future events. In the first experiment, subjects were told that there was a picture behind one of two (virtual) curtains, and they were supposed to guess which one. When the picture was just a picture, they picked the right curtain 49.8% of the time, which was not significantly different from the expected 1/2. But, when it was an EROTIC picture, they picked the right picture 53.1% of the time, which, while not particularly overwhelming, is apparently statistically significant at the p=0.011 level. There are eight more experiments on retroactive priming, precognitive avoidance of negative stimuli, and retroactive habituation and induction of boredom. The article also includes discussions of random number generators, pseudorandom number generators, quantum mechanics, and Alice in Wonderland.

So, if you read to the end of this blog post in the hopes that I would tell you what the hell is going on here, I'm afraid I'm going to leave you disappointed. Although, to be fair, your precognitive boredom should have known that I would have nothing intelligent to say sometime around the slash-fic link, in which case you've long since moved on. I'll just lay out the obvious candidates. First, it's pure chance, although getting consistent results across nine experiments makes this seem not terribly likely. Second, these are nine of a much larger number of experiments, most of which did not conform with the experimenter's expectations, and were therefore viewed as flawed and discarded. Third, there is actual manipulation of the experiments and/or data, either consciously or unconsciously. Fourth, there is some small possibility of some crazy-cool, Dune-esque, Jedi stuff going on here that is someday going to completely revolutionize how we understand cognition, causation, and time.

Personally, my money is on some combination of options two and three. Even without any type of fraud going on, I think it is incredibly easy for us as scientists to be so convinced that we know what the outcome of an experiment is going to be, that we can massage things around the margins. Keep in mind that these effects are only a couple of percent. On the other hand, even the smallest possibility of number for justifies, to me, the entire institution of tenure. This is exactly the sort of nut-bag research program that you can only pursue if you have absolute job security. I wish that more tenured faculty pursued research like this.

What's the Swedish internet made of?

So, if you've never played with Google Analytics, I highly recommend it. It is awesome. You can see who came to your website, where they came from, and what they were actually trying to find when they fell victim to your amateurish attempts at search engine optimization ("Sexy Megan Fox bikini pix!! Sexy Megan Fox bikini pix!!"). You can sort them by operating system, web browser, social security number, or alphabetically by password. It's the second best way to waste huge amounts of time on your computer – the best if you work at a place with content filtering.

For example, last week, I got a hit from Georgia. Not the Coca Cola and Peaches one; the Stalin and fighting-with-Chechens one. This person got to the site by searching for "ჯონ ვილკინს" on Google, which I can only assume is Kartuli for "People's 2010 rankings of the top 100 sexiest evolutionary biologists." It's an incredibly efficient language.

A couple of days ago, I got a hit from Sweden. Yes, the ABBA and Volvo one. In this case, the interesting thing was the service provider: "handelshogskolan." Now, we know that the American internet is a series of tubes. Well, apparently so is the Swedish internet, but their tubes are made out of pig intestines. Sadly, that means that from now on, when I hand my e-mails to my hamster, Hedwig, and send her off, I'm going to have to mentally revisit that whole Richard Gere thing.

Democrats investing in kleenex, socks in wake of midterm elections

So, yesterday's election turned out rather poorly for Democrats.

On a completely unrelated note, I wanted to draw attention to a paper published in Biology Letters that investigates the ejaculatory strategies of male flour beetles of the species Gnatocerus cornutus. As in many species, G. cornutus males engage in pre-copulatory sexual selection, where males fight, and the winners get privileged access to mates. The researchers, at Okayama University, find that the losers of these fights appear to shift to a strategy that focuses more on sperm competition, through increased "ejaculatory investment." Winning a fight has no effect on the number of sperm "transferred" during a copulatory event. However, losers show two effects that indicate a strategic shift: they are less aggressive towards other males, and they increase their sperm transfer by nearly two-fold.

By the fifth day after losing the fight, both aggressiveness and sperm-transfer levels return to normal, so we can expect a return to Republican levels of "transfer" sometime this weekend.