SLC24A5 is very important, but we don’t know why

The golden of pigmentation genetics started in 2005 with SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Prior to that pigmentation genetics was really to a great extent coat color genetics, done in mice and other organisms which have a lot of pelage variation.

Of course there was work on humans, mostly related to melanocortin 1. But more interesting were classical pedigree studies which indicated that the number of loci controlling variation in pigmentation was not that high. This, it was a mildly polygenic trait insofar as some large effect quantitative trait loci could be discerned in the inheritance patterns.

From The Genetics of Human Populations, written in the 1960s, but still useful today because of its comprehensive survey of the classical period:

Depending on what study samples you use variance on a locus of SLC24A5 explains less than 10% or more than 30% of the total variance. But it is probably the biggest effect locus on the whole in human populations when you pool them altogether (obviously it explains little variance in Africans or eastern non-Africans since it is homozygous ancestral by and large in both groups).

One aspect of the derived SNP in this locus is that it seems to be under strong selection. In a European 1000 Genomes sample there are 1003 SNPs of the derived variant, and 3 of the ancestral. Curiously this allele was absent in Western European Mesolithic European hunter-gatherers, though it was present in hunter-gatherers on the northern and eastern fringes of the continent. It was also present in Caucasian hunter-gatherers and farmers from the Middle East who migrated to Europe. It seems very likely that these sorts of high frequencies are due to selection in Europe.

The variant is also present in appreciably frequencies in many South Asian populations, and there seems to have been in situ selection there too, as well as the Near East. In Ethiopia it also seems to be under selection.

It could be something due to radiation…but the Near East and South Asia are quite high intensity in that regard. As are the highlands of Ethiopia. About seven years ago I suggested that rather that UV radiation as such the depigmentation that has occurred across the Holocene might be due to agriculture and changes in diet.

But a new result from southern Africa presented at the SMBE meeting this year suggests that this can not be a comprehensive answer. Meng Lin in Brenna Henn’s lab uses a broad panel of KhoeSan populations to find that the derived allele on SLC24A5 reaches ~40% frequency. Probably a high fraction of West Eurasian admixture in these groups is around ~10% being generous. Where did this allele come from? The results from Joe Pickrell a few years back are sufficient to explain: there was a movement of pastoralists with distant West Eurasian ancestry who brought cattle to southern Africa, and so resulted in the ethnogenesis of groups such as the Nama people (there is also Y chromosomal work by Henn on this).

Sad human with two derived alleles of SNP of interest

Lin reports that the haplotype around SLC24A5 is the same one as in Western Eurasia. Iain Mathieson (who is now at Penn if anyone is looking for something to do in grad school or a post-doc) has told me that the haplotype in the Motala Mesolithic hunter-gatherers and in the hunter-gatherers from the Caucasus are the same. It seems that this haplotype was widespread early in the Holocene. Curiously, the Motala hunter-gatherers also carry the East Asian haplotype around their derived EDAR variant.

I don’t know what to make of this. My intuition is that if a haplotype like this is so widespread nearly ~10,000 years ago recombination would have broken it apart into smaller pieces so that haplotype structure would be easier to discern. As it is that doesn’t seem to be the case.

And we also don’t know what’s going on withSLC24A5. Obviously it impacts skin color. It has been shown to do so in admixed populations. But it is hard to believe that that is the sole target of natural selection here.

Rome fell fast, and so did we

The fall of Rome has obviously been a topic of much interest and discussion. It is, after all, a conversation about the fall of civilization as we knew it.

If you read my blog you are probably aware that I lean toward a thesis of genuine and rapid fall. One of the most revelatory books I’ve read in the past 20 years is Bryan Ward-Perkins’ The Fall of Rome: And the End of Civilization. Ward-Perkins’ tale is an apocalyptic one. The material basis of Roman civilization the West collapsed. Perhaps the most relevant and evocative fact for me is that pollution due to manufacturing production in England did not match that of the Roman period until the industrial revolution. Though the Roman economy never achieved the industrial revolution’s gains in productivity, it did attain a level of Smithian efficiency and interdependence on the margins of the factors of production.

From a totally different perspective Peter Heather in The Fall of the Roman Empire broadly agrees with Ward-Perkins’ contention. The Roman Empire fell, and it fell fast, and the imperial elites didn’t see it coming. Remember, the Roman Empire was dismembered and disordered during the “crisis of the third century”. Under Diocletian and his successors in the 4th century it came back to health and strength before the distress of the 5th century in the West. But at the time contemporaries did not view the shocks and exigencies of these decades as any more distressing then the events of the 3rd century, and the Eastern Empire around Constantinople was reasonably robust.

Ultimately though 476 was a coup de grace to the Western Empire. The Gothic wars tore apart the fabric of the Italian peninsula in the 6th century, and the substantive reality of the old empire faded away. There was no going back. Of course I’m well aware of the argument that the Roman world evolved, that it did not collapse. And Late Antiquity and its continuities with the Classical world, and how it bridged itself to the Medieval world, are fascinating. But I do not accept that the preservation of Roman motifs and ideals in the courts of barbarian German warlords is evidence that substantively nothing changed.

Much of it depends on how you weight material vs. ideological parameters. The idea of Rome cast a shadow centuries beyond its substantive material integrity. After, the Byzantines called themselves Romans until the conquest of their city-stateless in 1453. But no matter the name, they were not Romans as the Romans were in 400 A.D.

The theoretical context of all this is that it strikes me cultures can go through rapid nonlinear shocks which induce very quick and unexpected changes. In the human past this would often entail collapses and regressions. The “Dark Age” after the chaos of the late Bronze Age is a case in point. In one generation the citadel society of Mycenanean Greece disappeared across much its extant range. The gap between 1966 and 1969 in much of the West was arguably greater than between 1956 and 1966.

The United States today is the most powerful nation in the world. And our cultural centrality and ascendency is such that we don’t challenge our implicit position as the premier power in the world. But I believe that we’ve become a inward looking involuted culture. There’s no point in litigating this, and obviously I may be wrong. But too often we confuse our own petty internecine squabbles with the concerns of the world. The world is passing us by….

Open Thread, 7/3/2017

Reading The Enigma of Reason. Pretty good so far. Not incredibly surprising to me so far. To be clear, their argument is somewhat orthogonal to the whole ‘rationality’ debate you may be familiar with from Daniel Kahneman and Amos Tversky’s work (e.g., see Heuristics and Biases).

One of the major problems in analysis is that rationality, reflection and ratiocination, are slow and error prone. To get a sense of that, just read ancient Greek science. Eratosthenes may have calculated to within 1% of the true circumference of the world, but Aristotle’s speculations on the nature of reproduction were rather off.

You may be as clever as Eratosthenes, but most people are not. But you probably accept that the world is round and 24,901 miles around. If you are not American you probably are vague on miles anyway. But you know what the social consensus is, and you accept it because it seems reasonable.

One of the points in cultural evolution work is that a lot of the time rather than relying on your own intuition and or reason, it is far more effective and cognitively cheaper to follow social norms of your ingroup. I only bring this up because unfortunately many pathologies of our political and intellectual world today are not really pathologies. That is, they’re not bugs, but features.

But I do suspect that the human bias toward trusting social wisdom is less useful in a world as fast changing and protean as ours. The math is pretty clear that in a stable environment there is no gain to reinventing wheels, as opposed to learning and believing what always works. Where individual learning and cognition are useful is in a situation where parameters are changing constantly, and folk wisdom leads you astray.

The Languages of Political Islam in India c.1200–1800 is only $5.99 on Kindle. I have no idea how Amazon figures out which academic books to discount highly, and which not to, but it’s always something I keep an eye out for.

RV dwellers in Palo Alto neighborhood forced to motor on and a reflection by a Stanford post-doc how difficult it is to make ends meet. One response is “we need affordable housing.” The reality is that you don’t need anything targeted, and special-built housing for the poor inevitably is subject to shortages. What is needed is more housing. But for various reasons incumbents between San Francisco and San Jose don’t want development.

Viral NRA ad sparks controversy. People are very freaked out on my Twitter timeline (I mostly follow liberals since I mostly follow scientists). Some people are saying that this is white supremacy in action. At this point it is useful to step outside of your socio-political bubble. For the past few years the dominant Left discourse has suffused all injustice with the term “white supremacy” and “systemic racism.” At some point you desensitize people who aren’t already fully on board with you

If 2011’s Rise Of The Planet of the Apes was filmed today I wonder if CRISPR/Cas9 would play a role?

I will be filling up the #SMBE17 hashtag tomorrow.

Bringing Neanderthals to Life: The Sculptures of Elisabeth Daynès. Neanderthals are depicted as having straight hair and African hominins with wooly hair. Is this justified? Is wooly hair the ancestral state?

Since wooly hair is found in many disparate human populations it probably is ancestral. But it would be nice to have more than a hunch or phylogenetic inference based on extant distributions of the trait.

How much bigger Americans are in two generations


Average American Size 2015
  Men Women
Height 69.2 inches (175.8 cm) 63.7 inches (161.8 cm)
Weight 195.7 lbs (88.8 kg) 168.5 lbs (76.4 kg)
Waist 40 inches (101.5 cm) 38.1 (96.9 cm)
Average American Size 1960
  Men Women
Height 68 inches (173 cm) 63 inches (160 cm)
Weight 166.3 lbs (75.3 kg) 140 lbs (63.5 kg)

The film WALL-E came out in 2008, and at this point it seems already quaint. Remember, when WALL-E was in theaters smartphones were not ubiquitous. Today it is not abnormal for people in social situations to always have one eye on their phone, or for people to text each other in close proximity.

Another aspect of WALL-E is that it depicted future humans as obese unitard wearing consumers. If such a film came out in 2017 I do wonder if it would be accused of being fatphobic and fat-shaming. WALL-E‘s general critique of post-industrial gluttony seems to be spot on.

Some of this is on my mind because I’ve gained 5-10 pounds over the past year due to new jobs and a move. As some of you know I’ve been trying out the ketogenic diet. In just a few weeks I’ve shed enough water weight to make a difference.

I would recommend it to someone trying to kickstart a change in their lifestyle for a simple reason: it does take care of the satiety aspect. If you work long hours it reduces the urge to snack on something. But if you are a social eater it will be difficult for it to be sustainable. I’m going to go off the diet for SMBE.

After joining a gym recently I got a full body analysis of my fitness level. At 5’8 and at 165 pounds I feel rather large for me. My body fat percentage was estimate at around 17%, which sounds right (I fluctuate between 14 and 18 depending on my fitness level). Recently my waist has gone up to 31 inches from 29 or 30. But I was surprised that my percentiles were not that bad.

That’s because the average American man is rather overweight.

Look at the statistics above. You probably know this, but let’s reiterate: the average American woman in 2015 is heavier than the average American man in 1960.

Does Tad Williams still have game?

Like many people I was quite taken with Tad Williams Memory, Sorry, and Throne, when they came out in the years around 1990. George R. R. Martin has admitted that Williams’ trilogy helped awaken him to the possibilities of the fantasy genre.

I tried to read his Shadowmarch series, but I didn’t find it as original so gave up after one and a half books. So I was excited for Williams to go back to a world where he seemed to shine. The first reviews for The Witchwood Crown make it seem like it’s actually pretty good, and perhaps even might be better then the original series. Not sure frankly I’ll ever get to reading it, but who knows.

Addendum: In the fall Brandon Sanderson is coming out with Oathbringer, and R. Scott Bakker’s Unholy Consult will be out at the end of July. I preordered the latter because I thought Bakker’s third book in the tetralogy was actually better than the first two so I have hopes the fourth will be best of all.

Basal humans in our evolutionary closet

The ancient genome from South Africa was of not because it confirmed what many had long suspected: the deep structure of modern humans in Africa goes back quite a bit further than we had been assuming. A few years ago I co-wrote an op-ed for USA Today where I initially wrote that the Khoisan divergence from other humans was around ~200,000 years ago. For various reasons I let a “fact-checker” change that to ~150,000 years ago. But as I told my co-author Alex Berezow people had access to whole genomes just leaning toward an older date than in the current literature.

Now we know that the date of divergence may be closer to ~300,000 years. Both because of the ancient DNA, and the Moroccan fossils which make it obvious that morphology associated with our own lineage was already beyond incipient before 300,000 years ago.

The past was more complicated than we think. Ancient DNA has made us toss many of our preconceptions out. For example, several years ago researchers concluded that the Out of Africa populations exhibited a different structure than we had thought. Populations of the Near East and Europe had ancestry from a group that was basal to all other non-Africans. That is, if you have a family tree then Oceanians, East Asians, Amerindians, Siberians, and European hunter-gatherers would be on one branch. On the other branch would be “Basal Eurasians” (BEu), named due to their basal position on the tree in comparison to all other non-Africans. Ancient DNA has not uncovered any population which is mostly BEu. Early Holocene Near Eastern populations, the various first farmers, invariably seem to show mixture between BEu and a West Eurasian element similar to what gave rise to the Mesolithic hunter-gatherers of Europe.

It seems possible we may never find “pure” BEu samples. We know that 10,000-15,000 years ago in Europe there was a massive expansion of a population of hunter-gatherers with stronger affinities to modern Middle Easterners than in the past. Perhaps this was part of a broader expansion of this group of hunter-gatherers across vast swaths of Western Eurasia, and in the process they absorbed the BEu populations until there were no pure populations left?

These questions were triggered by novel results which couldn’t be accommodated by current accepted models. This reminds me of a paper from over a year ago which presented some puzzling results which make much more sense now, Ancient gene flow from early modern humans into Eastern Neanderthals. The authors compared the Altai Neanderthal genome, the Denisovan genome, and those of modern humans (as well as a European Neanderthal). The stylized phylogenetic tree is one which the Neanderthal-Denisovan clade spits off from African proto-modern humans ~600,000 years ago. Then around ~400,000 years ago you see the divergence between Neanderthals and Denisovans. This gives us rough expectations as to the nature of the genetic variation in these populations, as they shared quite distinct periods of evolutionary history together and apart.

What the authors found is that a small minority of the Altai Neanderthal genome exhibited much stronger affinities to modern African populations than to the Denisovan. On the order of ~5%. Looking at the length of the haplotypes they estimated that the admixture occurred ~100,000 year ago. Curiously, at least at the time, this modern human population was basal to all modern humans. The authors estimate that the divergence from modern lineages occurred about ~200,000 year ago based on what was understood about modern human differentiation at the time.

At the time that was pushing it, though not unreasonably so. Now that number is probably comfortably defensible. One important point to note is that the modern human admixture was from a group equally related to all Africans. This implied that this group separated before the division of the Bantu and the Yoruba. So if you accept the most recent genomics then this group may date to closer to 260,000 years before the present. And in fact if the fossil record is correct they might have separated as early 350,000 years before the present. Additionally, the group which published the South African genome study posited another group, Basal Africans (BA), who diverged far earlier than the Khoisan from most African (and also non-African) groups.

Maximal Neanderthal range

The Neanderthals are a well studied group. We know what their range was. One can spit all sorts of speculative scenarios, from wide range proto-modern humans pushing deep in Eurasia during the Eemian interglacial 130,000 years ago. Or, it may have been through contact in the Near East and expansion of a somewhat admixed Neanderthal population north and east over time. Who knows? At least until there’s more ancient DNA….

Desperately seeking the secret of FOXP2

Since the early 2000s FOXP2 has shown up again and again in the press and scientific literature. Dubbed the “language gene” it exhibits evidence of accelerated evolution in the human lineage after it split from other apes. Additionally, a homolog of the same gene shows evidence of evolutionary change distinctive to songbirds and whales. Obviously this locus is involved in vocalization. Mutated mice on FOXP2 can even sing.

It isn’t difficult to connect the dots here. From 2002:

Dr. Paabo says this date fits with the theory advanced by Dr. Klein to account for the sudden appearance of novel behaviors 50,000 years ago, including art, ornamentation and long distance trade. Human remains from this period are physically indistinguishable from those of 100,000 years ago, leading Dr. Klein to propose that some genetically based cognitive change must have prompted the new behaviors. The only change of sufficient magnitude, in his view, is acquisition of language.

Klein’s thesis, advanced in The Dawn of Human Culture, is that a singular genetic change resulted in some sort of developmental cascade that allowed for the emergence of syntactically rich recursive language. And from language comes culture, and from culture comes world domination.

It was a clean and powerful hegemony while it lasted, but genomic and archaeological findings of the last decade have put such a elegant and simple model under a harsh light. With genomic technology even FOXP2 turns out to be much more complex and rich than the earlier reports had suggested. Neanderthals exhibited all the same mutations as modern humans to make them distinctive from chimpanzees. In other words, the changes on FOXP2 by and large predate the emergence of modern humanity, and go back closer to the root of the hominin lineage (Neanderthals and modern humans diverged ~600,000 years ago).

But FOXP2 keeps coming back. Why? It is an important gene. But another issue is that researchers still perceive in it the key to the holy grail of finding out what makes us distinctively human.

A new preprint (which is somewhat peculiarly formatted), takes another look at FOXP2, Human-specific changes in two functional enhancers of FOXP2:

Two functional enhancers of FOXP2, a gene important for language development and evolution, exhibit several human-specific changes compared to extinct hominins that are located within the binding site for different transcription factors. Specifically, Neanderthals and Denisovans bear the ancestral allele in one position within the binding site for SMARCC1, involved in brain development and vitamin D metabolism. This change might have resulted in a different pattern of FOXP2 expression in our species compared to extinct hominins.

The big picture is now the authors are focusing on gene expression levels as what might allow for modern human traits to be distinctive. Basically the DNA does not magically turn into protein. Biological machinery has to transcribe the sequence, and to transcribe it it has to bind to a particular region, a transcription factor binding site.

Most of the analysis involves comparing genomes of Neanderthals, Denisovans, and the human reference. I would be curious if they looked across lots of whole genomes to check if there was polymorphism in modern human populations. If modern humans with Neanderthal and Denisovan mutations had perfectly fine speech, that would be interesting.

Also, they spend a lot of time talking about how other genes interact and express with FOXP2, and all the other functions that are implicated. This is important, because of course selection may have nothing to do with speech, though perhaps speech changes are a side effect? Remember to that the Altai Neanderthal had some modern human admixture, and that one of the introgressed regions turns out to be FOXP2.

This sort of comparative genomic style research is interesting and suggestive. But we need more population wide analysis.

But, the authors do allude other work using genetic engineering where cell lines did show radically difference gene expression based on the mutation above. I do believe that CRISPR/Cas9 technology is cheap enough and going to be widespread enough that someone’s going to play around with splicing in “human” variants into primate models. Meanwhile, bioethicists will furrowing their brows about sequencing humans….

Why you should learn some population genetics

From reader surveys I know a substantial portion of the people who will see this post are financially well off (of those who aren’t, a large number are students). Therefore, you can invest in some books.

Often people ask me questions related to population genetics in the comments (sometimes I get emails). That is all well and good. But it is always better to be able to fish than have to ask for fish. Additionally, learning some population and quantitative genetics allows you to develop some tacit schemas through which you can process information coming at you, and through with you can develop some general intuition.

If you have a modest level of mathematical fluency and and the disposable income, here are three indispensable books which are like the keys to the kingdom:

* Elements of Evolutionary Genetics
* Principles of Population Genetics
* Introduction to Quantitative Genetics.

If you don’t have the cash to spare, there are online notes which are pretty good:

* Graham Coop’s Population Genetics notes
* Joe Felsenstein’s Theoretical Evolutionary Genetics

There are others online resources, but they are not as comprehensive. John Gillespie’s Population Genetics: A Concise Guide is good as very gentle introductions go, but if you are going to spend money, I think just plumping down for a more comprehensive textbook (which will have more genomics in it) is better over the long run.

The goal of getting these books isn’t to make you a population geneticist, but, if you are interested in evolutionary questions it gives you a powerful toolkit. Really nothing in evolutionary process makes sense except in the light of population genetics.

Genome sequencing for the people is near

When I first began writing on the internet genomics was an exciting field of science. Somewhat abstruse, but newly relevant and well known due to the completion of the draft of the human genome. Today it’s totally different. Genomics is ubiquitous. Instead of a novel field of science, it is transitioning into a personal technology.

But life comes at you fast. For all practical purposes the $1,000 genome is here.

And yet we haven’t seen a wholesale change in medicine. What happened? Obviously a major part of it is polygenicity of disease. Not to mention that a lot of illness will always have a random aspect. People who get back a “clean” genome and live a “healthy” life will still get cancer.

Another issue is a chicken & egg problem. When a large proportion of the population is sequenced and phenotyped we’ll probably discover actionable patterns. But until that moment the yield is going to not be too impressive.

Consider this piece in MIT Tech, DNA Testing Reveals the Chance of Bad News in Your Genes:

Out of 50 healthy adults [selected from a random 100] who had their genomes sequenced, 11—or 22 percent—discovered they had genetic variants in one of nearly 5,000 genes associated with rare inherited diseases. One surprise is that most of them had no symptoms at all. Two volunteers had genetic variants known to cause heart rhythm abnormalities, but their cardiology tests were normal.

There’s another possible consequence of people having their genome sequenced. For participants enrolled in the study, health-care costs rose an average of $350 per person compared with a control group in the six months after they received their test results. The authors don’t know whether those costs were directly related to the sequencing, but Vassy says it’s reasonable to think people might schedule follow-up appointments or get more testing on the basis of their results.

Researchers worry about this problem of increased costs. It’s not a trivial problem, and one that medicine doesn’t have a response to, as patients often find a way to follow up on likely false positives. But it seems that this is a phase we’ll have to go through. I see no chance that a substantial proportion of the American population in the 2020s will not be sequenced.

Over the long term civilization matters

In Peter Turchin’s work modeling human historical dynamics he introduces the idea of a “meta-ethnic” identity. Quite often this is synonymous with a world religion. These identities emerged in the last few years as human polities scaled so large as to expand beyond tribal-national boundaries.

These sorts of dynamics are clear when we think about the Crusades, the defense against the Ottomans in the 17th century, or the Iberian “division” of the world between Castile and Portugal. Common ties of civilization and identity allow for ingroup cohesion, as well as heightening hostilities against outgroups.

Of course there many exceptions. When reading The Great Sea: A Human History of the Mediterranean I recall being struck by how southern Italian city-states like Amalfi opportunistically allied with Muslim pirates against other Christian powers. Similarly, during the Battle of Vienna Protestant Hungarians marched with the Ottomans against the broader Christian alliance which came to the aid of the Habsburgs.

These are two instances which show short term self-interest or necessity driving choices of group coalitions. Amalfi, like later Italian city-states, found it in their interest to do business with Muslims, even if it was to the detriment of their co-religionists. This did not mean they were no longer Christians. But in many instances they put that identity aside for their own gains. In the case of the Protestant Hungarians there’s was an alliance of necessity.

As recounted in Divided by the Faith the decades leading up to the Battle of Vienna the Hungarians experienced a concerted campaign of conversion and persecution of the part of the Habsburg monarchy in concert withe Roman Catholic Church. The Habsburg’s Austrian lands were brought back fully into Catholicism, as was most of Imperial Hungary. It is no coincidence that Hungarian Reformed Protestantism was strong in the east, which had been under Ottoman influence. The arrival of an expansive Austrian monarchy was an existential threat for them.

The flip side are cases where groups with the same civilizational identity engage in wars over resources or boundaries. The conflict between Ethiopia and Eritrea would certainly fit into this mold, and to some extent the Great War in the Congo which has flared for two decades now.

This sort of dynamic has been used to argue that Samuel P. Huntington’s The Clash of Civilizations and the Remaking of World Order is not a useful framework. But on the contrary what Turchin and colleagues have shown is that over the long run civilizational fissures tend to result in the most vicious and dehumanizing wars.