To be a scientific intellectual today

George Busby has put up note about changes in his career path, Meditation on the Caltrain. I took offense to this section:

On top of this, there was the burgeoning realisation that no one actually reads the academic papers that I write. This is no moot point: writing papers is the main purview of a research scientist, and the central way we both communicate our results and measure success. However, compared to the proportion of the world’s population who can read, the number of people that had sat down to ingest my latest, dense, and fascinating (to me at least) treaty on the population genetics of Africa, three years in the making, was minuscule. The words of a colleague rang in my head: “99.9% of scientific papers just don’t get read”.

His most recent paper, Admixture into and within sub-Saharan Africa, was great. I meant to blog it, but got busy with other things. To be frank the fact that someone like George Busy is having trouble in the academic market is sobering. He has produced good and prominent work, and has been attached to groups which have some prominence. Of course grant approvals and job prospects have a stochastic element. But his experience shows that talent and good work is just a necessary, not sufficient, condition.

It looks like Busby will land in Silicon Valley with one of the two companies that do a lot of work on ancestry. Good for him. I think it does behoove those of us with intellectual pretensions to wonder what we’re doing out in the world. And, it also behooves academics to wonder what they’re doing with their job security. Sometimes it is important to tell the truth and explore topics even if people don’t care, or don’t want to listen. Otherwise, why fund anything that’s not practical with the public fisc?

The misrepresentation of genetic science in the Vox piece on race and IQ

I don’t have time or inclination to do a detailed analysis of this piece in Vox, Charles Murray is once again peddling junk science about race and IQ. Most people really don’t care about the details, so what’s the point?

But in a long piece one section jumped out to me in particular because it is false:

Murray talks about advances in population genetics as if they have validated modern racial groups. In reality, the racial groups used in the US — white, black, Hispanic, Asian — are such a poor proxy for underlying genetic ancestry that no self-respecting statistical geneticist would undertake a study based only on self-identified racial category as a proxy for genetic ancestry measured from DNA.

Obviously the Census categories are pretty bad and not optimal (e.g., the “Asian American” category pools South with East & Southeast Asians, and that has caused issues in biomedical research in the past). But the claim is false. In the first half of the 2000s the eminent statistical geneticist Neil Risch specifically addressed this issue. From 2002 in Genome Biology Categorization of humans in biomedical research: genes, race and disease:

A debate has arisen regarding the validity of racial/ethnic categories for biomedical and genetic research. Some claim ‘no biological basis for race’ while others advocate a ‘race-neutral’ approach, using genetic clustering rather than self-identified ethnicity for human genetic categorization. We provide an epidemiologic perspective on the issue of human categorization in biomedical and genetic research that strongly supports the continued use of self-identified race and ethnicity.

A major discussion has arisen recently regarding optimal strategies for categorizing humans, especially in the United States, for the purpose of biomedical research, both etiologic and pharmaceutical. Clearly it is important to know whether particular individuals within the population are more susceptible to particular diseases or most likely to benefit from certain therapeutic interventions. The focus of the dialogue has been the relative merit of the concept of ‘race’ or ‘ethnicity’, especially from the genetic perspective. For example, a recent editorial in the New England Journal of Medicine [1] claimed that “race is biologically meaningless” and warned that “instruction in medical genetics should emphasize the fallacy of race as a scientific concept and the dangers inherent in practicing race-based medicine.” In support of this perspective, a recent article in Nature Genetics [2] purported to find that “commonly used ethnic labels are both insufficient and inaccurate representations of inferred genetic clusters.” Furthermore, a supporting editorial in the same issue [3] concluded that “population clusters identified by genotype analysis seem to be more informative than those identified by skin color or self-declaration of ‘race’.” These conclusions seem consistent with the claim that “there is no biological basis for ‘race'” [3] and that “the myth of major genetic differences across ‘races’ is nonetheless worth dismissing with genetic evidence” [4]. Of course, the use of the term “major” leaves the door open for possible differences but a priori limits any potential significance of such differences.

In our view, much of this discussion does not derive from an objective scientific perspective. This is understandable, given both historic and current inequities based on perceived racial or ethnic identities, both in the US and around the world, and the resulting sensitivities in such debates. Nonetheless, we demonstrate here that from both an objective and scientific (genetic and epidemiologic) perspective there is great validity in racial/ethnic self-categorizations, both from the research and public policy points of view.

From a 2005 interview:

Gitschier: Let’s talk about the former, the genetic basis of race. As you know, I went to a session for the press at the ASHG [American Society for Human Genetics] meeting in Toronto, and the first words out of the mouth of the first speaker were “Genome variation research does not support the existence of human races.”

Risch: What is your definition of races? If you define it a certain way, maybe that’s a valid statement. There is obviously still disagreement.

Gitschier: But how can there still be disagreement?

Risch: Scientists always disagree! A lot of the problem is terminology. I’m not even sure what race means, people use it in many different ways.

In our own studies, to avoid coming up with our own definition of race, we tend to use the definition others have employed, for example, the US census definition of race. There is also the concept of the major geographical structuring that exists in human populations—continental divisions—which has led to genetic differentiation. But if you expect absolute precision in any of these definitions, you can undermine any definitional system. Any category you come up with is going to be imperfect, but that doesn’t preclude you from using it or the fact that it has utility.

We talk about the prejudicial aspect of this. If you demand that kind of accuracy, then one could make the same arguments about sex and age!

You’ll like this. In a recent study, when we looked at the correlation between genetic structure [based on microsatellite markers] versus self-description, we found 99.9% concordance between the two. We actually had a higher discordance rate between self-reported sex and markers on the X chromosome! So you could argue that sex is also a problematic category. And there are differences between sex and gender; self-identification may not be correlated with biology perfectly. And there is sexism. And you can talk about age the same way. A person’s chronological age does not correspond perfectly with his biological age for a variety of reasons, both inherited and non-inherited. Perhaps just using someone’s actual birth year is not a very good way of measuring age. Does that mean we should throw it out? No. Also, there is ageism—prejudice related to age in our society. A lot of these arguments, which have a political or social aspect to them, can be made about all categories, not just the race/ethnicity one.

Risch is not obscure. In the piece the author observes that Risch ‘was described by one of the field’s founding fathers [of the field] as “the statistical geneticist of our time.’

2005 is a long way from 2017. Risch may have changed his mind. In fact, it is probably best for him and his reputation if he has changed his mind. I wouldn’t be surprised if Risch comes out and engages in a struggle session where he disavows his copious output from 2005 and earlier defending the utilization of race as a concept in statistical genetics.

Also, genotyping is cheap enough and precise enough that one might actually make an argument for leaving off any self-reported ancestry questions. It’s really not necessary. This isn’t 2005.

But that section in the Vox piece is simply false. The existence of Risch refutes it. Vox is a high profile website which serves to “explain” things to people. The academics who co-wrote that piece are very smart, prominent, and known to me. I don’t plan on asking them why they put that section in there. I think I know why.

There will be no update to that piece I’m sure. It will be cited widely. It will become part of what “we” all know. Who I am to disagree with Vox? This is journalism from what have been able to gather and understand. The founders of Vox are rich and famous now. Incentives matter. There are great journalists out there  who don’t misrepresent topics which I know well. But the incentive structure is not to reward this. More often storytellers who tell you the story you like to be told are rewarded.

As for science and the academy? I am frankly too depressed to say more.

The population genetic structure of Sicily and Greece


By total coincidence a paper came out yesterday, Ancient and recent admixture layers in Sicily and Southern Italy trace multiple migration routes along the Mediterranean (I blogged about the topic). It’s open access, and it has a lot of statistics and analyses. I’d recommend you read it yourself.

You see the Sicilian and Greek populations and their skew toward the eastern Mediterranean. But in the supplements they displayed some fineSTRUCTURE clustering, and at K = 3 you see that Europe and the Middle East diverge into three populations. What this is showing seems to be: 1) in red, those groups least impacted by post-Neolithic migration 2) in blue, Middle Eastern groups characterized by the fusion between western & eastern Middle Eastern farmer which occurred after the movement west of the ancestors of the “Early European Farmers” (who gave rise to the red cluster), who were related to the western Middle Eastern farmers 3) the groups most impacted by Pontic steppe migration.

The authors confirm what I reported over two years ago on this blog: mainland and island Greeks are genetically distinct, probably because the former have recent admixture from Slavs and Slav-influenced people. And, many Southern Italians resemble island Greeks.

One has to be careful about dates inferred from genetic patterns. For example:

Significant admixture events successfully dated by ALDER reveal that all Southern Italian and Balkan groups received contributions from populations bearing a Continental European ancestry between 3.0 and 1.5 kya

The beginning of folk wanderings in the Balkans which reshaped its ethnographic landscape really dates to the later 6th century, when the proto-Byzantines began to divert all its resources to the eastern front with Persia, and abandoned the hinterlands beyond the Mediterranean coast in Europe to shift its focus toward the Anatolian core of the empire. The Slavic migrations were such that there were tribes resident in the area of Sparta in the early medieval period. Presumably because they were not a seafaring folk they don’t seem to have had much impact on the islands.

Such an early period in the interval though can not be the Slavs. What can it be? I suspect that that there are signals of Indo-European migrations in there that are being conflated due to low power to detect them since they are rather modest in demographic impact. The islands such as Sardinia, Crete and Cyprus had non-Indo-European speakers down to the Classical period.

Overall it’s an interesting paper. But it needs a deeper dig than I have time right now.

The Orantes has not mixed much with the Tiber


In a moment of weakness I decided to read some of Mary Beard’s SPQR: A History of Ancient Rome. I say weakness because I want to wean myself off of excessive reading of Roman history, as in terms of inferential utility I’ve long reached diminishing returns. But I quite enjoy the topic, and so here I am.

The author is an excellent writer as well as a scholar, and I quite enjoyed Roman Triumph, so I am entirely not surprised that SPQR has me hooked. Some of my correspondents have exhibited some disdain toward it because of Beard’s attempts to draw some connections to present day mores and values from that of Rome, presumably with a progressive bent.

Myself, this does not bother me. I don’t come into reading about Rome as an ignorant, so I can sort that from the nuggets of fact and positivistic interpretation. In any case, I think of it rather like how Islamic philosophers viewed Aristotle through their own religio-cultural lens. Obviously this was an issue that caused resistance to the transmission of Aristotle to the Christian West, but ultimately it did not stop what was inevitable. At the end of the day it was more about Aristotle than the glosses.

Though I highly recommend SPQR (I’m halfway through), that’s not the point of this post. Going along I kept thinking about the section on the Etruscans. The Rasena. Their origins have a genetic connection that is clouded and uncertain right now. I would like to dig deeper into this issue in the future; no doubt some day it will be cleared up. But that day is not this day.

Modern Italians have more “Indo-European” admixture than they do “Middle Eastern”

Rather, I want to address the idea that modern Italians are genetically a distinct people from ancient Roman Italians. Because on that score we have the answers. Ultimately the idea that this is even a debate goes back to Juvenal:

It is that the city is become Greek, Quirites, that I cannot tolerate; and yet how small the proportion even of the dregs of Greece! Syrian Orontes has long since flowed into the Tiber, and brought with it its language, morals, and the crooked harps with the flute-player, and its national tambourines, and girls made to stand for hire at the Circus. Go thither, you who fancy a barbarian harlot with embroidered turban….

These comments are rooted in the reality that Rome during Juvenal’s period was quite a cosmopolitan city, with large numbers of Greeks and people from the Eastern Mediterranean who were Hellenized to various degrees (in the early 3rd century Rome was ruled by a family of Hellenized Syrians). We know this because we have plenty of observations and complaints, and there are a plethora of inscriptions and graffiti in the new languages.

In the 19th and early 20th century the ascendency of Nordic racial theories about the origins of white supremacy across the world presented a problem. The Mediterranean peoples had been in decline for centuries, and were perceived to be Orientalized and inferior. Yet in the past they had achieved greatness which Northern Europeans were attempting to emulate. How could a racially inferior people have created such excellence?

A simple explanation for this condition for Victorians and their Continental fellow travelers was one of racial degradation. The ancient Romans were in this telling fundamentally a different people than modern Romans, with the latter being derived from migrants from the eastern Mediterranean who had arrived during the period of the Empire.

Though most of the racially derogatory elements are gone form this narrative, it is still strongly persistent in public consciousness. Being a Cavalli-Sforza nerd (there is such a thing), I have a copy of Consanguinity, Inbreeding, and Genetic Drift in Italy, and there was data in it which made me skeptical of wholesale replacement in the middle 2000s. Then there was Peter Ralph and Graham Coop’s 2013 paper, The Geography of Recent Genetic Ancestry across Europe, which reported lots of deep regional structure across Italy.

This is important because it suggests a local stability to the demographic character of the regions for a long time. Probably earlier than the period of the Roman Empire. Though one can imagine scenarios of demographic replacement which would produce this result, they’re generally less parsimonious than the model whereby modern Italian population structure maintains the general outline it had at the beginning of the Iron age.

Finally, over the past seven years I have done a lot of analysis and manipulation of tens of thousands of Europeans and Middle Easterners in relation to their genetic data for personal and professional reasons. Some patterns jump out at you, and some subtle tendencies come into the foreground. It is pretty clear that Italians are not a transplanted Middle Eastern population (though there is some recent non-Italian ancestry; Sicilians often have minor components of clear North African ancestry as well as small percentages of Sub-Saharan heritage, which I think is almost certainly due not to Greek and Roman cosmopolitanism, but the legacy of the Arab emirate which existed on the island for a few centuries).

But now I have realized probably the best illustration of this. The Reich lab has been generating a massive genotype dataset over the past five years on the Human Origins Array. And not only do you have modern populations, but you have ancient ones (from ancient DNA). The PCA plots in their papers make what I’m saying above pretty clear.

I’ve modified the PCA plot from Genomic insights into the origin of farming in the ancient Near East. Notice where various Italian groups and Greeks are. I’ve also labeled the Druze; they are almost certainly an excellent representation of Near Eastern Syrians from 2,000 years ago. They have been endogamous for nearly 1,000 years in the Lebanese highlands, and don’t have admixture that is more common in Syrian Muslims from the lowlands.

Notice that the most of the Greeks are shifted further toward Northwestern Europeans than Southern Italians. I say most, because I’ve had access to a larger data set of Greeks, and it becomes clear that a minority of Greeks cluster more with Southern Italians, and the majority have a minority admixture element from a Northern European population. This is Slavic ancestry that arrived after the middle of the 6th century, when the East Roman state basically abandoned most of the Balkans to focus on maintaining control over Constantinople, Salonika, and the Peloponnese.

Northern Italians are shifted toward Sardinians and Spaniards. The Sardinians are important, because we now know that they are the closest modern Europeans to the agriculturalists who arrived from the eastern Mediterranean during the early Neolithic. This population, “Early European Farmers” (EEF), once dominated most of the continent. But ~5,000 years ago migrations from the steppe brought a new element which replaced and assimilated them in Northern Europe.

But in Southern Europe their genetic legacy remains strong and to a great extent dominant. Iberia and the Italian peninsula have been impacted by the migrations out of the steppe, with Sardinia the least so. In the smaller plot above you can see that the early Neolithic individuals are close to the Sardinians, with mainland Italians being shifted toward other populations.

The Northern Italians in particular show some influence from Northern European populations. Some of this may be gene flow through diffusion due to proximity, but the Alps are a rather formidable barrier. Rather, I suspect it reflects episodic migration. I generally do not weight the Lombards too highly as a major influence. Rather, I suspect that it is a combination of Gaulish settlement in the Po river valley, and early impacts from the Indo-Europeans who arrived in the Italian peninsula.

The Southern Italian shift toward the Middle East probably does indicate some gene flow, but it is important to remember that this was also Magna Graecia, so there is probably a Greek element here similar to what occurs among those Greeks without Slavic admixture (please note that Byzantine Greek rule also persisted in Southern Italy up until the Norman conquest ). And if you look at how they relate to the Neolithic samples, they exhibit a lot of shift on the plane toward the steppe populations, parallel to the Levantines. In other words, a lot of the change since the Neolithic in Southern Italy is attributable to the influence of the steppe migration, not Roman era gene flow from Syrians.

I will probably do some formal analysis at some point so that the numbers can get out there now that there are so many ancient genotypes available too. But really this shouldn’t be a discussion anymore.

Addendum: You may be asking, if there are so many literary comments about non-Italians during the Roman Empire in Italy, where did they go? I think the big thing to remember is that there is an ascertainment bias toward what we know in urban areas. There is a high likelihood that urban areas were population sinks, which could not maintain themselves without constant migration.

The end of insurance (some if it)

Unless you’ve been sleeping under a rock you are aware that the cost of sequencing has been going down. Less clear to many is that genotyping has also been declining. At last year’s ASHG some physicians were talking about SNP-chips in the range of the low tens of dollars.

Right now most diseases for most people who buy health care are accounted for by the standard issue SNP-chips. If you have a rare mutation not on the chip, or are of a minority ethnic group not well ascertained by the chip, well, tough luck. My point is that chips probably have a near term future.

And that’s what’s at the heart of this piece in The New York Times, New Gene Tests Pose a Threat to Insurers:

So Ms. Reilly, 77, a retired social worker in Ann Arbor, Mich., applied for a long-term care insurance policy. Wary of enrolling people at risk for dementia, the insurance company tested her memory three times before issuing the policy.

But Ms. Reilly knew something the insurer did not: She has inherited the ApoE4 gene, which increases the lifetime risk of developing Alzheimer’s. “I decided I’d best get long-term care insurance,” she said.

I think the headline will mislead many people because when we hear “insurance” in relation to health, we assume health insurance. But long-term care insurance and life insurance are both relevant to health, and both of these have a major issue now with asymmetric information.

Many people are declaring that health insurance is over once everyone gets sequenced. I don’t think that’s necessarily true. The minority of the population that has a highly penetrant Mendelian disease may be in trouble without legal protection. But most disease variance is not going to be due to Mendelian disorders. Rather, people have risks based on family history and polygenic scores and lifestyle. And, a substantial proportion of disease and illness remains and will remain random.

With all that said, it’s not going to be a pretty picture when pockets of the insurance industry collapse. With greater knowledge comes the reckoning that we as a society have to make about the values who hold to be true.

When conquered pre-Greece took captive her rude Hellene conqueror


When I was a child in the 1980s I was captivated by Michael Wood’s documentary In Search of the Trojan War (he also wrote a book with the same name). I had read a fair amount of Greek mythology, prose translations of the Iliad, as well as ancient history. The contrast between the Classical Greeks and the strangeness of their mythology was always something that on the surface of my mind. The reality that Bronze Age Greeks were very different from Classical Greeks resolved this issue to some extent, as the mythos no doubt drew from the alien world of the former.

Though Classical Greeks were very different from us (e.g., slavery), to some extent Western civilization began with them, and they are very familiar to us for this reason. Rebecca Goldstein’s Plato at the Googleplex was predicated on the thesis that the ancient Greek philosopher had something to tell us, and that if he was alive today he would be a prominent public speaker.

I’m going to dodge the issue of Julian Jaynes’ bicameral mind, and just assert that people of the Bronze Age were fundamentally different from us in a way Plato was not. And that difference is preserved in aspects of Greek mythology. Though it is fashionable, and correct, to assert that Homer’s world was not that of Mycenaeans, but the barbarian period of the Greek Dark Age, it is not entirely true. Homer clearly preserved traditions where citadels such as Mycenae and Pylos were preeminent. Details such as the boar’s tusk helmets are also present in the Iliad. His corpus of oral history clearly preserved some ancient folkways which had fallen out of favor.

But aesthetic details or geopolitics are not what struck me about Greek mythology, but events such as the sacrifice of Iphigenia. Like Abraham’s near sacrifice of his son, this plot element seems to moderns cruel, barbaric, and unthinking. And though the Classical Greeks did not have our conception of human rights, they had turned against human sacrifice (and the Romans suppressed the practice when they conquered the Celts) on the whole. But it seems to have occurred in earlier periods.

The rupture between the world of the Classical Greeks and the strange edifices of Mycenaean Greece were such that scholars were shocked that the Linear B tablets of the Bronze Age were written in Greek when they were finally deciphered. In fact many of the names and deities on these tablets would be familiar to us today; the name Alexander and the goddess Athena are both attested to in Mycenaean tablets.

Preceding the Mycenaeans, who  emerge in the period between 1400-1600 BCE, are the Minoans, who seem to have developed organically in the Aegean in the 3rd millennium. This culture had relations with Egypt and the Near East, their own system of writing, and deeply influenced the motifs of the successor Mycenaean Greek civilization. The aesthetic similarities between Mycenaeans and Minoans is one reason that many were surprised that the former were Greek, because the Minoan language was likely not.

Mycenaean civilization seems to have been a highly militarized and stratified society. There is a reason that this is sometimes referred to as the “age of citadels.” Allusions to the Greeks, or Achaeans, in the diplomatic missives of the Egyptians and Hittites suggests that the lords of the Hellenes were reaver kings. In 1177 B.C. Eric Cline repeats the contention that a fair portion of the “sea peoples” who ravaged Egypt in the late Bronze Age were actually Greeks.

So when did these Greeks arrive on the shores of Hellas? In The Coming of the Greeks Robert Drews argued that the Greeks were part of a broader movement of mobile charioteers who toppled antique polities and turned them into their own. The Hittites and Mitanni were two examples of Indo-European ruling elites who took over a much more advanced civilizational superstructure. While the Hittites and other Indo-Europeans, such as the Luwians and Armenians, slowly absorbed the non-Indo-European substrate of Anatolia, the Indo-Aryan Mitanni elite were linguistically absorbed by their non-Indo-European Hurrian subjects. Indo-Aryan elements persisted only their names, their gods, and tellingly, in a treatise on training horses for charioteers.

Drews’ thesis is that the Greek language percolated down from the warlords of the citadels and their retinues over the Bronze Age, with the relics who did not speak Greek persisting into the Classical period as the Pelasgians. Set against this is the thesis of Colin Renfrew that Greek was one of the first Indo-European languages, as Indo-European languages began in Anatolia.

The most recent genetic data suggest to me that both theses are likely to be wrong. The data are presented in two preprints The Population Genomics Of Archaeological Transition In West Iberia and The Genomic History Of Southeastern Europe. The two papers cover lots of different topics. But I want to focus on one aspect: gene flow from steppe populations into Southern Europe.

We know that in the centuries after 2900 BCE there was a massive eruption of individuals from the steppe fringe of Eastern Europe, and Northern Europe from Ireland to to Poland was genetically transformed. Though there was some assimilation of indigenous elements, it looks to be that the majority element in Northern Europe were descended from migrants.

For various reasons this was always less plausible for Southern Europe. The first reason is that Southern Europeans shared a lot of genetic similarities to Sardinians, who resembled Neolithic farmers. Admixture models generally suggested that in the peninsulas of Southern Europe the steppe-like ancestry was the minority component, not the majority, as was the case in Northern Europe.

These data confirm it. The Bronze Age in Portugal saw a shift toward steppe-inflected populations, but it was not a large shift. There seems to have been later gene flow too. But by and large the Iberian populations exhibit some continuity with late Neolithic populations.  This is not the case in Northern Europe.

In The Genomic History Of Southeastern Europe the authors note that steppe-like ancestry could be found sporadically during early periods, but that there was a notable increase in the Bronze Age, and later individuals in the Bronze Age had a higher fraction. Nevertheless, by and large it looks as if the steppe-like gene flow in the southerly Balkans (focusing on Bulgarian samples) was modest in comparison to the northern regions of Europe. Unfortunately I do not see any Greece Bronze Age samples, but it seems likely that steppe-like influence came into these groups after they arrived in Bulgaria, which is more northerly.

Down to the present day a non-Indo-European language, Basque, is spoken in Spain. Paleo-Sardinian survived down to the Common Era, and it too was not Indo-European. Similarly, non-Indo-European Pelasgian communities continued down to the period of city-states in Greece.

These long periods of coexistence point to the demographic equality (or even superiority) of the non-Indo-European populations. The dry climate of the Mediterranean peninsulas are not as suitable for cattle based agro-pastoralism. This may have limited the spread and dominance of Indo-Europeans. Additionally, the Mediterranean peninsulas were likely touched by Indo-European migrations relatively late. Much of the early zeal for expansion may have already dissipated by them. The high frequency of likely Indo-European R1b lineages among the Basques is curious, and may point to the spreading of male patronization networks, and their assimilation into non-Indo-European substrates where necessary. R1b is also found in Sardinia, and in high frequencies in much of Italy.

The interaction and synthesis between native and newcomer was likely intensive in the Mediterranean. For example, of the gods of the Greek pantheon only Zeus is indubitably of Indo-European origin. Some, such as Artemis, have clear Near Eastern antecedents. But other Greek gods may come down from the pre-Greek inhabitants of what became Greece.

Ultimately these copious interactions and transformations should not be a great surprise. The sunny lands of the Mediterranean attracted Northern European tribes during Classical antiquity. The Cimbri invasion of Italy, Galatians in Thrace and Anatolia, the folk wandering of Vandals and Goths into Iberia, are all instances of population movements southward. These likely moved the needle ever so slightly toward convergence between Northern and Southern Europe in terms of genetic content.

In relation to the more general spread of Indo-Europeans, I believe there are a few areas like Northern Europe, where replacement was preponderant (e.g., the Tarim basin). But I also believe there were many more which presented a Southern European model of synthesis and accommodation.

Synergistic epistasis as a solution for human existence

Epistasis is one of those terms in biology which has multiple meanings, to the point that even biologists can get turned around (see this 2008 review, Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems, for a little background). Most generically epistasis is the interaction of genes in terms of producing an outcome. But historically its meaning is derived from the fact that early geneticists noticed that crosses between individuals segregating for a Mendelian characteristic (e.g., smooth vs. curly peas) produced results conditional on the genotype of a secondary locus.

Molecular biologists tend to focus on a classical, and often mechanistic view, whereby epistasis can be conceptualized as biophysical interactions across loci. But population geneticists utilize a statistical or evolutionary definition, where epistasis describes the extend of deviation from additivity and linearity, with the “phenotype” often being fitness. This goes back to early debates between R. A. Fisher and Sewall Wright. Fisher believed that in the long run epistasis was not particularly important. Wright eventually put epistasis at the heart of his enigmatic shifting balance theory, though according to Will Provine in Sewall Wright and Evolutionary Biology even he had a difficult time understanding the model he was proposing (e.g., Wright couldn’t remember what the different axes on his charts actually meant all the time).

These different definitions can cause problems for students. A few years ago I was a teaching assistant for a genetics course, and the professor, a molecular biologist asked a question about epistasis. The only answer on the key was predicated on a classical/mechanistic understanding. But some of the students were obviously giving the definition from an evolutionary perspective! (e.g., they were bringing up non-additivity and fitness) Luckily I noticed this early on and the professor approved the alternative answer, so that graders would not mark those using a non-molecular answer down.

My interested in epistasis was fed to a great extent in the middle 2000s by my reading of Epistasis and the Evolutionary Process. Unfortunately not too many people read this book. I believe this is so because when I just went to look at the Amazon page it told me that “Customers who viewed this item also viewed” Robert Drews’ The End of the Bronze Age. As it happened I read this book at about the same time as Epistasis and the Evolutionary Process…and to my knowledge I’m the only person who has a very deep interest in statistical epistasis and Mycenaean Greece (if there is someone else out there, do tell).

In any case, when I was first focused on this topic genomics was in its infancy. Papers with 50,000 SNPs in humans were all the rage, and the HapMap paper had literally just been published. A lot has changed.

So I was interested to see this come out in Science, Negative selection in humans and fruit flies involves synergistic epistasis (preprint version). Since the authors are looking at humans and Drosophila and because it’s 2017 I assumed that genomic methods would loom large, and they do.

And as always on the first read through some of the terminology got confusing (various types of statistical epistasis keep getting renamed every few years it seems to me, and it’s hard to keep track of everything). So I went to Google. And because it’s 2017 a citation of the paper and further elucidation popped up in Google Books in Crumbling Genome: The Impact of Deleterious Mutations on Humans. Weirdly, or not, the book has not been published yet. Since the author is the second to last author on the above paper it makes sense that it would be cited in any case.

So what’s happening in this paper? Basically they are looking to reduced variance of really bad mutations because a particular type of epistasis amplifies their deleterious impact (fitness is almost always really hard to measure, so you want to look at proxy variables).

Because de novo mutations are rare, they estimate about 7 are in functional regions of the genome (I think this may be high actually), and that the distribution should be Poisson. This distribution just tells you that the mean number of mutations and the variance of the the number of mutations should be the same (e.g., mean should be 5 and variance should 5).

Epistasis refers (usually) to interactions across loci. That is, different genes at different locations in the genome. Synergistic epistasis means that the total cumulative fitness after each successive mutation drops faster than the sum of the negative impact of each mutation. In other words, the negative impact is greater than the sum of its parts. In contrast, antagonistic epistasis produces a situation where new mutations on the tail of the distributions cause a lower decrement in fitness than you’d expect through the sum of its parts (diminishing returns on mutational load when it comes to fitness decrements).

These two dynamics have an effect the linkage disequilibrium (LD) statistic. This measures the association of two different alleles at two different loci. When populations are recently admixed (e.g., Brazilians) you have a lot of LD because racial ancestry results in lots of distinctive alleles being associated with each other across genomic segments in haplotypes. It takes many generations for recombination to break apart these associations so that allelic state at one locus can’t be used to predict the odds of the state at what was an associated locus. What synergistic epistasis does is disassociate deleterious mutations. In contrast, antagonistic epistasis results in increased association of deleterious mutations.

Why? Because of selection. If a greater number of mutations means huge fitness hits, then there will strong selection against individuals who randomly segregate out with higher mutational loads. This means that the variance of the mutational load is going to lower than the value of the mean.

How do they figure out mutational load? They focus on the distribution of LoF mutations. These are extremely deleterious mutations which are the most likely to be a major problem for function and therefore a huge fitness hit. What they found was that the distribution of LoF mutations exhibited a variance which was 90-95% of a null Poisson distribution. In other words, there was stronger selection against high mutation counts, as one would predict due to synergistic epistasis.

They conclude:

Thus, the average human should carry at least seven de novo deleterious mutations. If natural selection acts on each mutation independently, the resulting mutation load and loss in average fitness are inconsistent with the existence of the human population (1 − e−7 > 0.99). To resolve this paradox, it is sufficient to assume that the fitness landscape is flat only outside the zone where all the genotypes actually present are contained, so that selection within the population proceeds as if epistasis were absent (20, 25). However, our findings suggest that synergistic epistasis affects even the part of the fitness landscape that corresponds to genotypes that are actually present in the population.

Overall this is fascinating, because evolutionary genetic questions which were still theoretical a little over ten years ago are now being explored with genomic methods. This is part of why I say genomics did not fundamentally revolutionize how we understand evolution. There were plenty of models and theories. Now we are testing them extremely robustly and thoroughly.

Addendum: Reading this paper reinforces to me how difficult it is to keep up with the literature, and how important it is to know the literature in a very narrow area to get the most out of a paper. Really the citations are essential reading for someone like me who just “drops” into a topic after a long time away….

Citation: ScienceNegative selection in humans and fruit flies involves synergistic epistasis.

Africa’s great demographic transformation

Stonehenge has been a preoccupation for moderns since the Victorian period. It was built over 5,000 years ago, and its usage in some fashion continued down to about 2,500 years ago. For a long while it had been associated with the Celts, but more recently there has been some suspicion that its roots must be pre-Celtic.

And that is almost certainly true. The original site of Stonehenge had a wooden structure. But during the arrival of the Bell Beaker culture it was extensively rebuilt, and eventually stone monoliths were erected in the fashion we are used to seeing today.

Bernard Cornwell’s novel Stonehenge deals with this period. There is no major focus on physical conflict between the native populations, and the Bell Beaker groups. Rather, the plot centers around the cultural tumult and innovation that was triggered by the arrival of the newcomers.

In Stonehenge the Bell Beakers occupied more marginal, out of the way, territory. The novel presumed that ultimately there would be cultural fusion between the two groups, as there was a lot of interaction inter-personally among the characters of the two groups. We now know that the reality was likely one of near total replacement. From the abstract to be presented on shortly on the Bell Beakers:

British individuals associated with Beakers are genetically indistinguishable from continental individuals associated with the same material culture and genetically nearly completely discontinuous with the previously resident population.

This is not entirely surprising. Ancient Ireland seems to have been characterized by discontinuity with the arrival of Bell Beakers genetically.

Ancient DNA is not magic. But it can literally put some flesh on the bones of cultural shifts that archaeologists have seen in the material culture. One key element here is that the predominant ancestry across the British Isles today derives from migrations that date to the early Bronze Age.* I do not know if this has any relevance as to the arrival of the Celtic languages to the Britain and Ireland, but I suspect it does.

This was percolating in my mind because there’s a new paper which attempts to explore in more detail the Bantu expansions which occurred between 1000 BCE and 500 CE. It’s pretty incredible that from Gabon to Capetown Africans speak one language family, with similarities at least as close as that of the Romance language family.

But then is it incredible? Indo-European languages span the North Sea to the Bay of Bengal. The Bantu expansion in some ways serves as a template for the argument in First Farmers, as an agricultural revolution triggered a demographic expansion which did not stop until they reached the their geographic limits.

The paper in Science, which is open access, Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America, focuses on two issues. First, the demographic history and phylogenomics of the Bantu populations. Second, using population genomic methods it explores the dynamics of natural selection in these peoples. They utilize and extensive SNP data set, with more than 500,000 markers in their core analyses.

In general I think there are lots of interesting results in this paper. But the one angle I was unsatisfied by was their purported increase in coverage. As you can see it’s highly localized to a few countries. This is probably common sense since much of Africa is not accessible due to political issues (e.g., sampling in the Democratic Republic of Congo is treacherous right now). But one always has to be careful of the limitations of the data when making inferences. Though they have samples from the southwest (Angola, Namibia), the the African Great Lakes region around Uganda, and in South Africa, huge zones between are missing. And, they are highly over sampled in and around Gabon.

With all that said, I think with a variety of methods they probably have confirmed a major aspect of Bantu migration. I’ll quote:

Two hypotheses have been proposed concerning the dispersal of Bantu-speaking populations across sub-Saharan Africa (2–4). According to the “early-split” hypothesis, the western and eastern branches split early, within the Bantu heartland, into separate migration routes. By contrast, the “late-split” model suggests an initial spread southward from the Bantu homeland into the equatorial rainforest (i.e., Gabon/Angola), followed by expansions toward the rest of the subcontinent. We tested these hypotheses by determining whether eBSPs and seBSPs were genetically closer to wBSPs from the southern part, relative to wBSPs from the northern part, of western central Africa….

…Although additional sampling of African populations may further refine these patterns, our results, together with previous genetic data supporting the late-split model (2, 3), indicate that BSPs [Bantu-speaking peoples] first moved southward through the rainforest before migrating toward eastern and southern Africa, where they admixed with local populations. This model is further supported by linguistics (15) and archaeoclimate data (16), suggesting that a climatic crisis ~2500 years ago fragmented the rainforest into patches and facilitated the early movements of BSPs farther southward from their original homeland.

That being said, their sample limitations produce interesting assertions. E.g., “The GLOBETROTTER method estimated that eBSPs resulted from two consecutive admixture events (P < 0.05) occurring 1000 to 1500 years ago and 150 to 400 years ago between a wBSP (~75% contribution) and an Afroasiatic-speaking population from Ethiopia (~10% contribution).” GLOBETROTTER is powerful, but too often people use it in a manner where they assume that the inferences it generates from the data it has are the truth, as opposed to the closest GLOBETROTTER can get to the truth with the tools its given.

In this case I would contend that because there aren’t any Nilotic samples it leaves a major hole in their power to be able to accurately infer what really happened. The presence of pastoralist Nilotic people in close proximity to Bantu agriculturalists has been one of the major dynamics which define the East African landscape. The admixture into eastern Bantu agriculturalists therefore is almost certainly from Nilotic peoples, though there has been Afro-Asiatic (Cushitic) influence as far south as Tanzania, evident in enigmatic peoples such as the Sandawe.

The point here is that just because the GLOBETROTTER method inferred gene flow from a population in the sample set, it does not mean that the gene flow was necessarily from that population. The sampling of the region is sparse, so obviously this is only a first approximation. To some extent I assume the authors assume the readers will connect the dots, but often this sort of thing gets lost in translation, and then it gets into the media….

Though it is difficult to make in the admixture plot above, there are subtle differences in the eastern Bantu groups. The Luyha, who are from Kenya, do not show evidence of the blue component which is clearly Eurasian, while the Bakiga from Rwanda do. But even in the Bakiga the ratio of the violet element that seems to be associated with an indigenous African component which is distinct from that of the Bantu and the blue Eurasian is far higher than in the Afro-Asiatic populations in their data set (this does not mean they don’t have Eurasian ancestry, since admixture plots aren’t perfect proxies).

Because of the nature of the sampling and the utilization of admixture to frame their results I do feel that we don’t get a good sense of the variation among the Bantu across their full range. Granted, the between population genetic distance is actually quite low across this zone, on the order of 0.01, because of the recent shared ancestry. Africans may have much greater total diversity than Eurasians in their genomes, but their between population distance is actually not much different or even lower than Eurasians because of the recent demographic expansions. But did the Bantu expand into empty lands? The Khoisan, Pygmy and Nilotic (I’m sure that’s what it is) contribution to the Bantus across their range is clear, but that’s because we have close enough reference populations to model this contribution. What about areas like Tanzania? Or Mozambique? Were they empty? I suspect the issue here is that we don’t have any non-Bantu indigenous groups as they’ve all been absorbed.

But it is in the selection component that they offer a possible way to ascertain non-Bantu ancestry from ghost populations in the future. They found lots and lots of selection around immune genes. This is not surprising. There were local diseases which they had to adapt to. Therefore, “the HLA region in wBSPs showed a strong excess of ancestry from rainforest hunter-gatherers, at 38%, 6.74 SD higher than the genome-wide average of 16%…..”

In places like Mozambique it would be curious if the regions known to be under selection or enriched for indigenous ancestry in other areas where there are still indigenous populations exhibited a higher Fst against other groups. That is, the Mozambique ghost populations should leave an inordinate impact on regions of the genome associated with immunological function.

Which brings me back to Stonehenge. We do have ancient genomes. But not that many. Especially further back. Apparently the names of rivers and mountains often have very deep histories. For example, the river Humber has a name which may date back to pre-Celtic times (consider the Mississippi river, which has an American Indian origin). These serve as shadows of cultures long gone and replaced. The Bantu expansion is close enough to the margins of history that we don’t have so much time interposed between it and concrete records. We can skein out its outlines with more rigor and surety. And the patterns we see among the Bantus can give us a sense of how past demographic-cultural expansions may have occurred.

* The papers coming out of the PoBI project suggest that a significant minority of the ancestry in eastern England is Anglo-Saxon. But only there.

Addendum: I can’t find the data to download and test some things myself.

The coming of the Milesians: abstract of “The Bell Beaker Paper” (tBBp)

I get asked about this all the time, and promised I’d post something first I heard anything, so here is a foretaste, Western Europe during the third millennium BCE: A genetic characterization of the Bell Beaker
Complex
:

The Bell Beaker Complex (BBC) was the first widely distributed archaeological phenomenon of western Europe, arising after 2800 BCE probably in Iberia and spreading to the north and east before disappearing at the latest by 1800 BCE. An open question is the extent to which the cultural elements associated with the BBC spread through movement of ideas or people. We present new genome-wide DNA data from 196 Neolithic and Bronze Age Europeans – the largest report of genome-wide data in a single study to date – and merge it with published data to form a dataset with 109 BBC individuals that provides a genomic characterization of the BBC across its geographic and temporal range. In contrast to people of the Corded Ware Complex who were partly contemporaries of the BBC in central and eastern Europe and who brought steppe ancestry into central Europe through mass migration and replacement of local populations, we show that the initial spread of the BBC into central Europe from the Iberian Peninsula was not mediated by a large-scale migration but rather through communication of ideas. However, the further spread of the BBC beyond central Europe did involve mass movement of people. Focusing on Britain, which includes 81 of our new samples in a time transect from 3900-1300 BCE, we show that the arrival of the BBC around 2400 BCE was mediated by migration from the continent: British individuals associated with Beakers are genetically indistinguishable from continental individuals associated with the same material culture and genetically nearly completely discontinuous with the previously resident population. Such discontinuity persists through to samples from the Bronze Age, documenting a demographic turnover at the onset of the Bronze Age that was crucial to understand the formation of the present-day British gene pool. The arrival of the BBC in Britain can thus be viewed as the western continuation of the massive movement of people that brought the Corded Ware Complex and steppe ancestry into central Europe a few hundred years before.

Ancient DNA has revolutionized our understanding of the history of the past. In a fundamental manner many archaeologists were wrong in assuming that the dominant dynamic of the spread of culture was that of the diffusion of ideas, as opposed to the movement of peoples. But to interpret these results it is clear that archaeological knowledge must be brought to bear, albeit updated with knew prior assumptions.

It would not be entirely surprising if the originators of a cultural complex transmitted it to another group, and then that culture “hitchhiked” on the demographic expansion of the receiving group. A good example would be Roman Catholic Christianity. The Iberians spread it to the New World, along with substantial demographic movement. But the religion itself did not spread to Iberia through migration, but rather cultural shift.