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 TeasersGcochran@GNXP Blogview

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In Table S48, on page 135 of the supplement to the big Neandertal paper in Science, fourth line from the bottom, the text says ‘San closer to Han+French than to Yoruba (!)” – but that is a typo.

I trust you all see the implications.

(Republished from GNXP.com by permission of author or representative)
 
• Category: Science 
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With the detection of Neanderthal admixture in Eurasians (Green et al), evidence for two admixture events in an upcoming paper from Jeffrey Long’s group (probably Neanderthals and erectus), and analysis from Jeffrey Wall and Vincent Plagnol suggesting that some African populations (Pygmies and Bushmen) admixed with other archaic populations, it seems that we are on the verge of a new paradigm.* In the picture, anatomically modern humans arose in East Africa and then spread globally – but mixed (to a degree) with the archaic humans that already already occupied most of the Old World.
Of course this is the surprise-free prediction, much more plausible than total replacement, which would have required an unlikely biological incompatibility.

Admixture at the few-percent level would have given most favorable archaic alleles a good chance of reaching high frequency in modern human populations, and some must have done so – alleles that conferred regional adaptations, and perhaps some that had general advantages. Svante Paabo thinks, or any rate says, that this Neanderthal admixture probably didn’t have any biological significance, but he’s almost certainly wrong.
This pattern has been seen in some other invasive species: the cosmopolitan species assimilates favorable alleles from local sister species. Resistance is futile.

There may be more in the pipeline: The Max Planck people have that strange finger bone from the Altai, and if it’s a good-enough sample, they could run the same general analysis and check for admixture from that archaic population, whoever they were. And there’s a possibly-significant line in their Science paper, concerning Wall and Plagnol’s high estimate (14%) of archaic admixture in Europeans:
“almost an order of magnitude greater than our estimates, suggesting that their observations may
not be entirely explained by gene flow from Neandertals. ” Maybe from somebody else?

*Mike Hammer and others have also been saying this.

(Republished from GNXP.com by permission of author or representative)
 
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So says David Reich, and he was hardly alone. Why? It was always likely, in fact almost inevitable. I can’t think of a human expansion where there wasn’t some admixture with the locals. I’m serious: why? I’ve certainly heard arguments to that effect, but they were all silly. Intersterility was quite unlikely, if you look at mammalian hybridization. Lack of Neanderthal mtDNA in moderns meant nothing much, since it could easily have been lost due to selective disadvantage or by chance. The argument that humans were simply too picky to have ever mated with Neanderthals is plain ridiculous: at worst, they were a lot more human than sheep. Even a small amount of admixture would have allowed introgression of alleles with an advantage: we’re seeing a higher level of admixture than that bare minimum but nothing particularly surprising.

So, why?

(Republished from GNXP.com by permission of author or representative)
 
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David Reich says “There are populations that have lived in the same town and same village for thousands of years without exchanging genes.” Sounds familiar.

If this was indeed the case, and if fitness payoffs differed significantly between castes – then there has almost certainly been genetic adaptation. Those whose ancestors lived a particular kind of life for a long time, with very low inward gene flow, should on average have traits that better fit them to that (past) way of life. This doesn’t necessarily mean that they would better at the supposed formal role or purpose of that caste, more that they would be more successful (in a reproductive sense) in that niche . For example, depending on the reward structure, the soldier with greatest fitness might well be one who avoided combat.

Reich said that average inward gene flow in castes appears to have been less than than 1 in 30 per generation: that’s low enough to allow this.

(Republished from GNXP.com by permission of author or representative)
 
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I ran into an interesting comment on the net the other day.. “for some, it is hard to determine what productive and ethical use society can make of genetic knowledge that certain individuals are predisposed to higher than average intelligence”

Perhaps others can think of some productive and ethical uses. Any suggestions?

Some people may already have a certain amount of such knowledge. For example, my high school geometry teacher thought I would probably do well – he had some strange rationale based on remembering how my mother had done in his class. I did do well, but maybe he was just a lucky guesser.

(Republished from GNXP.com by permission of author or representative)
 
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Someone has suggested that the cover of our new book (the 10,000 year explosion) symbolizes the splitting of the human race into different species. I will award a metaphorical cigar to the first person who figures out what it _really_ means.

(Daddy’s Skeleton Army is the alternate title suggested by my son Ben)

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In yesterday’s New York Times article, David Goldstein makes sense: he says “We’ve looked for common variants in schizophrenia and get almost nothing. This means natural selection has done a really good job of purging them away, and we’re left with rare variants, a constant flow of them, as the principal driver of the disease.”

Which is what any reasonable person thought a long time ago: the common disease-common variant notion never made much sense for a syndrome with a large impact on fitness. That genetic heterogeneity does not make drug development easier: even if the mutations cluster in certain pathways, reactivating a broken pathway may still require mutation-specific methods, which would sure take the profit out of drug development.

But the most interesting point in the article is Stefansson’s statement – “I would have thought the brain was a luxury organ when it comes to reproductive success.” That’s a weird thing to say. For one thing we known damn well that schiz strongly impacts fitness, even in contemporary society: the affected families dwindle away, which interferes with genetic studies.

More than that, does he really believe that being insane had no effect on reproductive success back in the Malthusian past? It’s hard to find a place more Malthusian than Iceland: does he think that crazy hardscrabble farmers did just as well as sane ones? Does he think that lunatics were just as likely to become godir and hornswoggle the neighbors out of their land?

The brain burns out 20% of our calories: does he think that could continue long under natural selection if there wasn’t a big payoff?

The answer is that he _does_ think all those absurd things: he doesn’t believe in ongoing natural selection in humans, particularly above the neck. I wonder why – but once we sequence him, maybe we’ll know.

(Republished from GNXP.com by permission of author or representative)
 
• Category: Science • Tags: Genetics 
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There was an interesting paper in BMC Genetics back in in February: “Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping. ” They ran 500K Affy chips on 100 Ashkenazi women and on 60 CEPH-derived HapMap (CEU) individuals. They hoped to find greater levels of linkage disequilibrium and lower haplotype complexity among the Ashkenazim, as a putatively bottlenecked population. This would simply some forms of genetic mapping. Some earlier work had suggested that this might be the case – but that earlier work had either looked at a single chromosome or at a small samples from a number of chromosomes.

The expected pattern is not there. Average LD is very similar in the two populations, although it varies from chromosome to chromosome. It’s slightly smaller among the Ashkenazi at short distances, slighter greater for longer distances, but overall very similar, as you can see.

There were somewhat _more_ haplotype blocks among the Ashkenazi sample, not fewer.
You would expect a bottlenecked population to have more monomorphic sites, but the Ashkenazi sample had noticeably fewer, 9.1 % versus 12.4 %.

Altogether, the paper concludes that “These data are more consistent with the AJ as an older, larger population than CEU. ” Which means that there is no sign of any bottleneck in this data. The paper, obviously written by several people, _refers_ to several bottlenecks that have been discussed in earlier studies, but this measurement set contains thousands of times more data than those earlier studies. If there had been a bottleneck, they would have seen it, and if they don’t see it, there must not have been one.

They see very significant gene frequency differences in a couple of fair-sized regions: LCT and and HLA. Those differences were of course generated by selection. There are differences in smaller regions at a number of other positions, and long homozygous regions in the Ashkenazi sample average about 20% longer – so at least some of their long haplotypes are younger.

Fact: we find long haplotypes around the mutations causing common Ashkenazi diseases, on the order of one to ten Mb.

Bottlenecks affect the whole genome, but selection only affects a small fraction. Selection would not change genome-wide LD much, would not much increase the number of monomorphic sites, but it could generate long haplotypes around selected mutations.

The authors think that these differences “reflect the impact of both selection as well as genetic drift.” – but there is, as far as I can tell, no evidence of drift in this data at all. Perhaps I’m missing something.

This SNP study (and others) also shows that Ashkenazim are genetically distinct from other Europeans, which allows fairly accurate identification of group membership. Almost perfectly distinct, if you look at Ashkenazim whose grandparents are all Ashkenazi (the violet dots). Obviously, there was low inward gene flow for a long time, but that has increased a lot in the last century. Distinct local selection pressures could have caused noticeable change when gene flow was that low.

Check out this figure, from a recent paper in PLOS Genetics ( Tian et al, Analysis and Application of European Genetic Substructure Using 300 K SNP Information):

Heny Harpending and I came to these same conclusions several years ago, using a far smaller data set: the evidence indicated low gene flow that would allow local selection, and we found no evidence for – indeed, solid evidence against – the kind of bottleneck that would explain the observed spectrum of genetic disease among the Ashkenazim. Which leaves selection as the only explanation – but selection for what?

(Republished from GNXP.com by permission of author or representative)
 
• Category: Science • Tags: Genetics 
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It’s hard to have a recessive lethal hang around for a long time without some kind of heterozygote advantage: selection reduces its frequency. If the population is even moderately large, more than a few thousand, changes in allele frequency over time are very predictable: deterministic.

That also means that one can calculate past frequencies, as long as as these assumptions hold (i.e. as long as there was no tight bottleneck & selection coefficients were the same).

Going forward in time , the frequency of a recessive lethal with no het advantage declines more and more slowly, since the ratio of homozygotes to heterozygotes declines as the allele frequency declines. But if you go backward in time, the frequency grows, and it grows more and more rapidly as you go further and further back in time. This doesn’t continue indefinitely: the frequency can’t go above 100%. Project the frequency of such a recessive lethal back in time and you hit a singularity.

Today, lethal cystic fibrosis alleles have a frequency of 2% in northern Europeans. Unless I’m wrong, it takes 50 generations for a recessive lethal to go from almost 100% to 2%, and another 50 to go from 2% to 1%, assuming no reproductive compensation. ‘Reproductive compensation’ means that parents have another kid when one dies young and thus end up with the same number of children raised to adulthood. This effect weakens, but does not eliminate, selection against lethal recessives. With full reproductive compensation, it takes 80 generations for a recessive lethal to go from 99.5% to 2%, and another 75 to go from 2% to 1%.

If the frequency of lethal CF alleles is 2% today, there must have either been a selective advantage in heterogygotes over most the of the past two thousand years, or the population of northern Europe must have crashed down to a few hundred or less sometime during that period.

There was no such crash, which would have been worse than a nuclear war. Indeed, there was no bottleneck of any kind in that time period: we know this from the historical record. Events like the Black Death do not a bottleneck make: you need to get the population down into the low thousands or less. The Black Death left tens of millions.

So lethal CF mutants had some kind of selective advantage, or were closely linked to some allele that did.

(Republished from GNXP.com by permission of author or representative)
 
• Category: Science • Tags: Disease, Evolution 
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John and I have an article out now on Neanderthal introgression: Dynamics of Adaptive Introgression from Archaic to Modern Humans. It’s in Paleoanthropology
The major point is that Neanderthals and modern humans were probably interfertile and most likely interbred – and that we would then have picked up most favorable Neanderthal alleles. Which may have something to do with the cultural ‘ big bang’ that happened not long after.

The argument relies on a simple result of population genetics, due to Haldane – that the probability of success of one copy of a new favorable allele is 2s, when s is the selective advantage, much higher than that of a neutral allele.

As far as I know, this conclusion has not been published before.

You have to wonder why.

(Republished from GNXP.com by permission of author or representative)
 
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A few years ago, I was thinking about Out-of-Africa, and it occurred to me that we probably picked up a lot of favorable alleles from Neanderthals, the logic being that such alleles would have probability 2s per copy (Haldane) of reaching high frequency (maybe even going to fixation). The chances of acquisition of a neutral allele (from a single introduced copy) was 1/2Ne; so, for s = 5% and an effective population of 10,000, that allele with the 5% advantage was 2000 times more likely to make the interspecies jump. Therefore mtDNA stats really told you nothing.

So as we spread out into Neanderthal territory, even a few tens of interspecies matings would have let us scarf up most of their good genes. Individuals from every pair of mammalian sister species with comparably recent common ancestry are interfertile, so it was a good bet that this actually happened. This seems to happen frequently in invasive weed species, by the way. They arrive, they hang around the docks for a few years, stealing the good alleles from related local species – then they go forth and conquer.

Looking at the new article in PNAS, I’d say that Bruce Lahn and company have probably found one. Read it.

Now if the Neanderthals were really effectively isolated before we expanded into their territory, they’d have a lot of significantly different alleles. Some would have involved various kinds of regional adaptations, which might be a good thing to have in Eurasia. (MC1R?) But it’s entirely possible that some alleles solved adaptive problems that had existed in Africa as well – but solved them better.

Brains had expanded over the last half-million years in both Africans and Neanderthals, but it seems likely that those changes in size and structure were driven by different mutations, just as light skin in Europe and East Asia was. The Neanderthals had slightly bigger brains than Africans: obviously those brains were useful for _something_. Anyhow, in this kind of convergent evolution of sister species, there can be lots of alleles worth stealing. When we select for the same trait in multiple lines, sometimes we get higher values of that trait by hybridizing a couple of the best-performing lines. Also, since the Neanderthals were ecologically different (cold weather, high risk hunters & pure carnivores), they might have been able to evolve some adaptations that just couldn’t happen in Africa (different constraints, different topography of the fitness surface).

Maybe Africans and Neanderthals ‘nicked’. Any farm boy, looking at the timeline of African expansion, encounter with Neanderthals, and the subsequent ‘great leap forward’, should have suspected hybrid vigor. It’s corny but it makes sense.

So when you think about the cultural explosion that occurred shortly after we overwhelmed the Neanderthals (cave paintings, sculptures, new tools and weapons, all that jazz) – well, you have to wonder if assimilating a passel of adaptive alleles in a few thousand years, way more than the typical number that would arise and become established over such a short time span, didn’t give us a hell of a boost. There are signs of behavioral modernity a bit earlier in Africa – but those ostrich eggshells are dull as hell compared to Gravettian cave paintings. Expansion out of Africa must itself be a sign of new capabilities (I’d bet on sophisticated language) but you only see full-fledged behavioral modernity in the European Upper Paleolithic… Judging from neutral genes, it can’t have happened often, but those few furtive human-Neanderthal couplings may well played a crucial role in the future development of the human race. I’m sure that this notion will suggest new pick-up lines to some readers.

If this pans out the way we think it will, introgression from Neanderthals (and maybe with other archaics) may have been one of the two fundamental patterns underlying recent human evolution.

Update by Darth Quixote: John Hawks has more here and here.

(Republished from GNXP.com by permission of author or representative)
 
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A lot of people seem to have the idea that significant human biological evolution stopped when we became behaviorally modern. I’m wondering just how they got that idea. Can anyone give me some examples of influential instances of this claim? Influential papers, texts, popular books, bubble gum wrappers, etc etc

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I need an estimate of the fraction of selected variants that involve an amino acid change, as opposed to noncoding changes in promoters and enhancers and such. Something for mammals would do. Can anyone find one?

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There’s an interesting article (by Eric Wang, Bob Moyzis and company, using HapMap data) coming out in the next day or so in PNAS. It’s covered by Science: http://sciencenow.sciencemag.org/cgi/content/full/2005/1220/2

Seems that they’ve found some 1800 human genes currently undergoing selective sweeps: most are regional. The gene functions ae highly concentrated in host-pathogen interactions, reproduction, DNA metabolism/cell cycle, protein metabolism, and neuronal function.

Update from Razib: Here is the link to the abstract, it is “open access” so you can read the full PDF.

Update from Razib II: More from John Hawks & Steve. Also, check out Civilization has left its mark on genes.

Update from Razib III: Related item from Dienekes on a specific locus that suggests selection on early farmers….

Update from Razib IV: Agnostic has an interesting article.

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Genes such as G6PD, ASPM, and hemochromatosis are known to be undergoing strong positive selection in humans. You see a high-frequency variant with next-to-no variety and lots of linkage disequilibrium.

If you had to guess, what fraction of human genes would you expect to be currently experiencing such strong positive selection?

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” “There’s just no correlation,” said Duke’s Wray, calling education and other environmental factors more important for intelligence than DNA anyway.”

Rikurzhen: Source

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There is a new BRCA1 haplotype with a geographical distribution reminiscent of that seen in microcephalin and ASPM: the new variant is about 30k years old and considerably more common outside of sub-Saharan Africa (~55%) than inside (~20%) . BRCA1 has also been evolving unusually rapidly in the hominid lineage (like ASPM and microcephalin). It is suspected of having something to do with brain development, since it is highly expressed in neural stem cells and is functionally linked with microcephalin. Also, the high incident of BRCA1 mutations among the Ashkenazi Jews – as part of a complex of DNA-repair mutations – suggests that tweaking BRCA1 can affect cognition.

(Republished from GNXP.com by permission of author or representative)
 
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