Recently, Wojciech Wisniewski and company found a deletion that eliminates an exon of the gene TM4SF20, a transmembrane protein expressed in the brain. The mutant protein is terminated prematurely and apparently accumulates inside the cell.
This mutation causes severe language delay, and also causes ominous-looking MRI brain scans, with white matter hypertensities (WMHs) scattered over the brain. Normally those spots are the result of brain aging, something you see in octogenarians. Incredibly rare in kids.
So far this is mildly interesting, in a depressing sort of way, but the genetics journals are full of new ways for your genes to screw you. Almost always, those newly discovered genetic syndromes are extremely rare, sometimes limited to a a single family. Mutation creates them, selection cuts them down.
But this one is common, at least in Southeast Asia. It’s a dominant – one copy causes trouble – and the gene frequency looks to be around 1% in Vietnam. It’s also been seen in people from Burma, Thailand, Indonesia, and the Philippines, although there’s no estimate of the frequency in those countries yet.
This is weird. Deleterious dominants should never be common, certainly not in a big population. It’s rather like those claims about a common dominant form of prosopagnosia – but the guy making that claim was probably just wrong. This one sounds real – they have found the gene, they seem to have good evidence of severe language delay in carriers, careful MRI studies, have done mouse genetic studies, etc. And the carrier parents report language delays in their own childhoods.
The kids seem to eventually catch up in language, at least to some extent. Some of the parents are smart, or at any rate have had academic success. Still, it’s hard to believe that all those funny-looking spots on the MRI brain scans are harmless – particularly with increasing age.
It’s a puzzle. Probably not to the authors, who come out of the medical world, but it is to me.
West Hunter 
A reference please. Can only find his name associated with fragile X.
http://www.sciencedirect.com/science/article/pii/S0002929713002693
Reference: http://www.ncbi.nlm.nih.gov/pubmed/23810381?dopt=AbstractPlus
This is a very interesting gene family, crucial for intercellular interactions. The deletion prevents protein from reaching the membrane and coordinating inter-neuronal interactions. Both alleles are active and so expression is cut in half, thus slowing the pace of creation of inter-neuronal connections in half, leading to development delays. But the level of intercellular connections is regulated, thus development continues until a fairly normal set of connections is achieved.
(This take is based on data from other genes in the same family; loss of both alleles is embryonically lethal, loss of one allele leads to developmental delays and an increased risk of miscarriage, but a nearly normal grown phenotype.)
As far as its effect on fitness, it is damaging, which is what limits the frequency to 1%, but not so much. The intracellular junk probably overstimulates certain nuclear pathways leading to minor health impairment; it is probably cleared through autophagy, and fasting was common in our ancestral environment, so ancestrally there would have been little impairment; failure to clear the intracellular mutated proteins sufficiently well leads to the buildup of lesions; this defect is probably akin to multiple sclerosis, which often only generates significant impairment after age 50. So plausibly we have developmental delays in infancy-toddlerhood; slight impairments in adulthood; and MS-like symptoms after age 50. This collection of problems might lead to only mild fitness impairment.
So: The homozygotes are embryonically lethal, but at a frequency of 1% only 1 in 10,000 pairings have a chance to produce homozygotes and even then only a quarter of the children are homozygotes. Heterozygotes have a 99% chance of breeding with someone lacking the mutation and their kids will be 50% heterozygotes, 50% normal; 1% of the time a heterozygote pairs with another heterozygote and 25% of their kids are homozygotes who die in the first 3 weeks after conception, so they end up having reduced fertility and 2/3 of their kids are heterozygotes, 1/3 normal.
So it’s not that deleterious to fitness. The question is whether it rose to 1% through some weird fitness advantage, or through genetic drift and inbreeding from a small founding population.
I don’t understand your reasoning. The mutant allele can’t be that damaging to fitness, because its frequency is not high enough to reduce fitness. Huh? How do you even know the selection coefficient for heterozygotes? This is what determines allele frequency, not the other way around.
This doesn’t look like one of those genes with a high mutation rate, like the genes for dystrophin or SMN protein.
Never mind, just read your first post.
Its not even that much a hit to fertility if it causes miscarriage before the mother has missed one period, and only if both parents are carriers of the gene. In most times and places, female fertility was limited by food supply and disease resistance, not opportunities for sex.
Seems like the only possible conclusion is that it’s just not that deleterious, fitness-wise. While the optimist in me would like to think that there is some as-yet-undocumented advantage that comes with this, thanks to pleiotropy or what have you, it seems that the simpler explanation would be that this gene came from some successful family of several centuries back. If the negative fitness impact is small enough, it could just be a human version of popular sire effect…
Sounds reasonable – although we’re probably talking a few millennia, rather than a few centuries, judging from the wide distribution. But that must mean that it is even closer to neutral.
Yeah, you might want to qualify this dangerous statement:
“Deleterious dominants should never be common, certainly not in a big population.”
Life is full of common, deleterious dominants, for reasonable values of “common” and “deleterious”. The words ‘never’ and ‘certainly’ are too strong, they need qualification.
*
I can’t find any sources on whether the white matter hyperintensities (WMHs) turn up in MRI only in the youthful specimens exhibiting the language delay phenotype, or whether they remain present in the adults whom have (apparently?) outgrown the retardation.
You’re wrong.
Shutting up never hurt anyone.
Good advice. Why don’t you take it?
Returning to the topic – I concur that either this trait wasn’t especially harmful, or it has some advantage that counters its deficiencies. Or both. Is it possible that it confers some benefit against a parasite or infectious disease endemic to the region where it’s common?
I’ll shoot from the hip. Perhaps it confers disease resistance. Southeast Asia is hot and wet; thus, lots of parasites. As for which disease or parasite it counters and the mechanism by which it counters it, well…
Hot and wet is a powerful catalyst for gene transfer between species, which is one of the primary reasons so many disease causing bacteria and viruses spring up in Southeast Asia and Africa. This makes your hypothesis is a possible explanation. I’m sure there are many other yet to be discovered deleterious mutations in one way that have not moved to extinction because they are counterbalanced by some resistance to disease or parasites.
This makes me wonder about homosexuality, yet again.
Especially when compared to what seems like the very low incidence of Gender Dysphoria.
Cochran may or may not be wrong about his gay germ hypothesis but he is completely right about homosexuality being a fascinating phenomenon that simply shouldn’t be, not for any nonsense ethical reasons but because Ma Nature does such a good job of disposing of any other trait that takes even a small hit on reproductive fitness. I think it is very much worth further scientific inquiry and discussion on this blog.
If a population’s average intelligence was above the minimum neccessary for group survival at various times in the past would it have been advantageous or deleterious to reduce it and don’t the calcs on the likelihood of spread of mutations within a population vary depending on whether it is advantageous or deleterious – or possibly both but at different times?
I guess it would depend on whether brain calorie usage varied with IQ?
If a population’s average intelligence was above the minimum neccessary for group survival at various times in the past would it have been advantageous or deleterious to reduce it and don’t the calcs on the likelihood of spread of mutations within a population vary depending on whether it is advantageous or deleterious – or possibly both but at different times?
Holy run on sentence, batman. Just what are you talking about?
You think its a quick and dirty way to reduce brain resource costs, when those cost are not providing utility (either giving the same or worse outcomes), but lowering fitness? That pretty seems hard to test.
“You think its..”
I wouldn’t put it as strongly as saying i think it. I just wonder if the assumption that evolution has *always* favored higher IQ *might* not have been true at all times. If so then at those moments in time “deleterious” and “advantageous” may have been flipped. For example you have a population that moves from an environment that requires a higher average IQ to survive to one that needs a lower average IQ to survive – would a “deleterious” allele be “deleterious” in that situation?
I wouldn’t put it as strongly as saying i think it. I just wonder if the assumption that evolution has *always* favored higher IQ *might* not have been true at all times.
Of course evolution does not always favor higher IQ. It will clearly be a balance between the benefits and the costs. Higher IQ requires either more brain matter, or more efficient brain matter. If you cannot find a pathway to greater efficiency, then more brain matter is the only pathway, and they already put a high cost on mothers during development and birth and on offspring during development and life.
If a group of humans does not need high IQs to get through life, then over time the average IQ of the group will shift such that large numbers have pretty much the optimum IQ for their lifestyles.
> Our data […] highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
Uh hello, pretty racist, man
I don’t have the fulltext, but I have to wonder whether the clinical and/or MRI phenotype are very marked. If they were, then with a frequency like 1%, how come this isn’t already a named syndrome? I realize MRI machines are very expensive and ‘Nam is, for now, very poor. Still.
If the phenotypes are not very marked, then as noted above, that opens the way for the allele’s existence to be ‘justified’ if it can confer some infectious disease protection effects or whatever. It might possibly be maintained primarily in a certain subniche, say a low-class one where infection exposure is rather higher and the marginal utility of IQ and executive function etc a little lower — it could leak from that subniche, but the rest of the pop might be a sink for it.
We are more used to thinking of such phenomena (sickle cell, cystic fibrosis) as involving recessive alleles . . . but a relatively dominant one that is homozygous-lethal (fairly early?) in gestation, as Jaminet is hypothesizing here, offers certain fitness advantages: you don’t end up burdened with sickly homozygous offspring.
If the disease is not so marked even now, and Jaminet right that it could have been still milder in the past due to greater autophagy, perhaps that would explain a lot.
Certain genes, and this is one of them, are involved specifically in cell migration, proliferation, and long-distance intercellular interactions. As such they are not expressed in mature tissues but are important during development and wound healing, and in diseases that involve growth such as cancer.
One minor fitness advantage of having mutations in growth-and-proliferation genes will be slightly reduced cancer mortality. Not that I think that was important historically in the case of this gene.
Because the development process is regulated and the genome generally has some redundancy and flexibility to cope with mutations, if one gene is underexpressed due to a monoallelic deletion or mutation, growth factors and transcription factors promoting expression of the mutated gene will generally be overexpressed to semi-normalize expression of the monoallelically mutated gene. Thus, heterozygotes might not manifest major negative effects apart from development delays and slow wound healing.
In mice, knockout mice with monoallelic deletions of such genes can generate embryonically lethality in homozygotes and developmental delays in heterozygotes, but though the heterozygote mice are smaller at birth (say 30% smaller), they typically continue their rapid early growth for a longer period of time and eventually catch up and are indistinguishable from wild-type mice by about age 3 months.
It’s possible these mutations might be quite common. Thomas Sowell wrote a book about late-talking children (http://www.amazon.com/Late-Talking-Children-Thomas-Sowell/dp/0465038352) in which he noted he was a late talker, his son is a later talker (suggesting inheritance), but both are quite bright as adults. Perhaps they have a monoallelic mutation or deletion in a gene related to development of speech, and it took a few extra years for their brains to complete development of the speech regions. Yet the final endpoint may be quite similar to those with a wild-type phenotype, and there has been no obvious fitness decrement for Sowell.
The Vietnamese Kinh people (http://en.wikipedia.org/wiki/Vietnamese_people) are an Austroasiatic people, seem to have developed agriculture rather late (so could have had a quite small population until rapid demographic growth in the last 4000 years), were largely isolated before the Holocene and gene flow from other populations was probably unimportant compared to demographic growth, thus the high Denisovan heritage still seen today. Though the population is 77 million now, making around 700,000 with the mutation we’re discussing, it would have been much smaller not long ago; compare England’s population growth from about 2.5 million in 1500 AD to 53 million today. The contemporary Kinh population of 77 million probably grew from a 2000 BC population of 500,000 or less and a hunter-gatherer population in 5000 BC of 20,000 or less. Presence of the mutation in a single extended family circa 5,000 BC could have represented 2% of the population at that time. So the major frequency growth of the mutated allele could have occurred within a single extended family at a time of low population density and pre-literacy, when delayed language development wouldn’t have been a big deal; then it was just carried along with the demographic expansion of the larger ethnic group because it did little to impair fitness.
Uh hello, pretty racist, man
Why, and why would you bother uttering that worthless epithet when we are discussing genetics and the effects of gene expression?
It seemed like he was joking.
If the allele arose in a much less populous Asia 300 generations ago, and had a 1%-ish frequency at that time, it would have to be mighty near neutral to still be preserved at so high a frequency as 1%. For instance, 0.998 ^ 300 ~= 0.55. It could be that there are no good effects at all but the total bad effect is only 0.002 . . . more likely though, I would think, is a mix of good and bad effects.
But you say Vietnam was probably rather isolated long ago. What of the allele showing up in “Burma, Thailand, Indonesia, and the Philippines”? The island peoples mentioned don’t even look much like the mainlanders, though I’m sure there’s been some flow. As Cochran says we don’t know what the frequency is in those places. In principle it could be far below the 1% seen in Vietnam: but given that someone could spot the allele at all in those places despite having too little data to be able to estimate the frequency, the frequency is pretty high more likely than not. Is the allele, then, more likely rather older than 300 generations?
“Deleterious dominants should never be common, certainly not in a big population. ”
Do small isolated groups of humans have a high incidence of deletrious dominants? It would seem to me that this could be difficult to assess for kind of trait this post is about. Imagine a small hunter gatherer group where 40% of the population has this type of trait because dominant traits proliferate throughout the tribe quickly in a group that small. In that case, we wouldn’t say that X group has a deletrious mutation, right? Wouldn’t we instead say that these hunter gatherers learn language much later on average? A dominant trait should be become prevalent in a small interbreeding group quickly (if it is not so deletrious that it impacts survival), and once a trait is prevalent it becomes considered a standard feature of the group, rather than a deletrious mutation.
A neutral dominant trait – one that does not increase or decrease fitness – does not have a tendency to increase or decrease in frequency , regardless of the population size. Hardy-Weinberg. It drifts: frequency changes randomly. It drifts more in a small population. A slightly deleterious dominant allele will on average decrease in frequency, but there is a nonzero chance that it will become common – and that is more likely in a small population.
Is it possible that this deletrious dominant was once more common in some proto southeast asian group that is now split across southeast asia and that this trait has actually decreased in frequency to 1% as the population became larger?
It almost seems like larger populations have greater inertia.
At 1%? Dubious.