PoBI paper BTFO

We next analyzed UK Biobank population structure in conjunction with ancient DNA samples. Modern European populations are known to have descended from three ancestral populations: Steppe, Mesolithic Europeans and Neolithic farmers 21,22 . We projected ancient samples from these three populations as well as ancient Saxon samples 24 onto the UK Biobank PCs (Figure 3, Supplementary Figure 4, see Online Methods). These populations were primarily differentiated along PC1 and PC3, indicating higher levels of Steppe ancestry in northern UK populations.

Additionally, the lack of any ancient sample correlation with PC2 suggests that Welsh populations are not differentially admixed with any ancient population in our data set, and likely underwent Welsh-specific genetic drift. We confirmed these findings by projecting pan- European POPRES 26 samples onto the UK Biobank PCs (see Online Methods, Supplementary Figure 5) noting that of the continental European populations, Russians (who have the most Steppe ancestry) lie on one side and Spanish and Italians (who have least) 22 lie on the other side along PC1 and PC3, and that none of the continental European populations projected onto the same regions as the Welsh on PC2 and PC5.

In addition to the impact of ancient Eurasian populations, we know that the genetics of the UK has been strongly impacted by Anglo-Saxon migrations since the Iron Age 24 , with the Angles arriving in eastern England and the Saxons in southern England. The Anglo-Saxons interbred with the native Celts, which explains much of the genetic landscape in the UK. We analyzed a variety of samples from Celtic (Scotland and Wales) and Anglo-Saxon (southern and eastern England) populations from modern Britain in conjunction with the PoBI samples 20 and 10 ancient Saxon samples from eastern England 24 in order to assess the relative amounts of Steppe ancestry. [. . .] We consistently obtained significantly positive f4 statistics, implying that both the modern Celtic samples and the ancient Saxon samples have more Steppe ancestry than the modern Anglo-Saxon samples from southern and eastern England. This indicates that southern and eastern England is not exclusively a genetic mix of Celts and Saxons. There are a variety of possible explanations, but one is that the present genetic structure of Britain, while subtle, is quite old, and that southern England in Roman times already had less Steppe ancestry than Wales and Scotland.

Population structure of UK Biobank and ancient Eurasians reveals adaptation at genes influencing blood pressure. Kevin Galinsky, Po-Ru Loh, Swapan Mallick, Nick J Patterson, Alkes L Price doi: http://dx.doi.org/10.1101/055855

Note: I find it unlikely the pattern they observe is a holdover from Roman times. I suspect it will turn out the decrement of Steppe ancestry in England stems from a continual trickle of continental genes into England over the past 1000 years (from which the fringes of the British Isles were comparatively isolated).

Also supports my impression that the Wellcome Trust paper still overestimated the degree of Iron Age British admixture in modern England (given that the authors had assumed a simple two-way admixture, while the authors of the above preprint provide evidence "southern and eastern England is not exclusively a genetic mix of Celts and Saxons").

Related:

• People of the British Isles project paper
• Iron Age and Anglo-Saxon genomes from East England reveal British migration history

Gene-environment interaction for human fertility

Mega-analysis of 31,396 individuals from 6 countries uncovers strong gene-environment interaction for human fertility

Family and twin studies suggest that up to 50% of individual differences in human fertility within a population might be heritable. However, it remains unclear whether the genes associated with fertility outcomes such as number of children ever born (NEB) or age at first birth (AFB) are the same across geographical and historical environments. By not taking this into account, previous genetic studies implicitly assumed that the genetic effects are constant across time and space. We conduct a mega-analysis applying whole genome methods on 31,396 unrelated men and women from six Western countries. Across all individuals and environments, common single-nucleotide polymorphisms (SNPs) explained only ~4% of the variance in NEB and AFB. We then extend these models to test whether genetic effects are shared across different environments or unique to them. For individuals belonging to the same population and demographic cohort (born before or after the 20th century fertility decline), SNP-based heritability was almost five times higher at 22% for NEB and 19% for AFB. We also found no evidence suggesting that genetic effects on fertility are shared across time and space. Our findings imply that the environment strongly modifies genetic effects on the tempo and quantum of fertility, that currently ongoing natural selection is heterogeneous across environments, and that gene-environment interactions may partly account for missing heritability in fertility. Future research needs to combine efforts from genetic research and from the social sciences to better understand human fertility.

No comment

Race Is a Social Construct, Scientists Argue:

In an article published today (Feb. 4) in the journal Science, four scholars say racial categories are weak proxies for genetic diversity and need to be phased out. [Unraveling the Human Genome: 6 Molecular Milestones]

They've called on the U.S. National Academies of Sciences, Engineering and Medicine to put together a panel of experts across the biological and social sciences to come up with ways for researchers to shift away from the racial concept in genetics research.

"It's a concept we think is too crude to provide useful information, it's a concept that has social meaning that interferes in the scientific understanding of human genetic diversity and it's a concept that we are not the first to call upon moving away from," said Michael Yudell, a professor of public health at Drexel University in Philadelphia.

Yudell said that modern genetics research is operating in a paradox, which is that race is understood to be a useful tool to elucidate human genetic diversity, but on the other hand, race is also understood to be a poorly defined marker of that diversity and an imprecise proxy for the relationship between ancestry and genetics.

"Essentially, I could not agree more with the authors," said Svante Pääbo, a biologist and director of the Max Planck Institute for Evolutionary Anthropology in Germany, who worked on the Neanderthal genome but was not involved with the new paper. [. . .]

So what other variables could be used if the racial concept is thrown out? Pääbo said geography might be a better substitute in regions such as Europe to define "populations" from a genetic perspective. However, he added that, in North America, where the majority of the population has come from different parts of the world during the past 300 years, distinctions like "African Americans" or "European Americans" might still work as a proxy to suggest where a person's major ancestry originated.

Update: A commenter points to this previous contribution from Michael Yudell:

Rooting human variation in blood or in kinship was a relatively new way to categorize humans. The idea gained strength towards the end of the Middle Ages as anti-Jewish feelings, which were rooted in an antagonism towards Jewish religious beliefs, began to evolve into anti-Semitism. These blood kinship beliefs rationalized anti-Jewish hatred instead as the hatred of a people. For example, Marranos, Spanish Jews who had been baptized, were considered a threat to Christendom by virtue of their ancestry because they could not prove purity of blood to the Inquisition.

But it's hard to imagine Yudell's ethnic neuroses could have anything to do with his totally non-tendentious (not to mention fresh, novel) advocacy for "Taking race out of human genetics". Who could disagree with his "simple goal", as stated in the concluding paragraph of his current paper: "to improve the scientific study of human difference and commonality" and "strengthen research by thinking more carefully about human genetic diversity". Please suppress any cognitive dissonance engendered by the second to last paragraph:

Phasing out racial terminology in biological sciences would send an important message to scientists and the public alike: Historical racial categories that are treated as natural and infused with notions of superiority and inferiority have no place in biology. We acknowledge that using race as a political or social category to study racism and its biological effects, although fraught with challenges, remains necessary. Such research is important to understand how structural inequities and discrimination produce health disparities in socioculturally defined groups.

Who would argue impartial, objective science is not synonymous with the promotion of minority grievance politics?

Visscher's commentary on "Limitations of GCTA as a solution to the missing heritability problem"

Commentary on "Limitations of GCTA as a solution to the missing heritability problem" (abstract; pdf):

In a recent publication entitled "Limitations of GCTA as a solution to the missing heritability problem" Krishna Kumar et al. (2015 PNAS) claim that "GCTA applied to current SNP data cannot produce reliable or stable estimates of heritability". Here we show that those claims are false and that results presented by Krishna Kumar et al. are in fact entirely consistent with and can be predicted from the theory underlying GCTA.

More ancient DNA from Britain supporting significant later Anglo-Saxon genomic impact

Genomic signals of migration and continuity in Britain before the Anglo-Saxons:

The purported migrations that have formed the peoples of Britain have been the focus of generations of scholarly controversy. However, this has not benefited from direct analyses of ancient genomes. Here we report nine ancient genomes (~1 ×) of individuals from northern Britain: seven from a Roman era York cemetery, bookended by earlier Iron-Age and later Anglo-Saxon burials. Six of the Roman genomes show affinity with modern British Celtic populations, particularly Welsh, but significantly diverge from populations from Yorkshire and other eastern English samples. They also show similarity with the earlier Iron-Age genome, suggesting population continuity, but differ from the later Anglo-Saxon genome. This pattern concords with profound impact of migrations in the Anglo-Saxon period. Strikingly, one Roman skeleton shows a clear signal of exogenous origin, with affinities pointing towards the Middle East, confirming the cosmopolitan character of the Empire, even at its northernmost fringes.

The full text is freely accessible. More:

Ancient sample ancestry within Britain

To place our ancient genomes within a detailed British context, we next plotted these in a background PCA using 3,075 published genotypes from British3, Irish23 and southern Netherlands samples24. The modern samples were analysed using SNP genotypes at ~250,000 loci and projected into a single plot using smartpca (Fig. 3a). As in Burton et al.3 the first component of the variation was informative for the structure within Britain. Given the close ancestral relationships between these populations and their well-known history of migrational exchange, a substantial overlap between regional groups was both expected and observed. However, by considering median values, one can see a clear progression from Irish samples at one pole through Scottish, Welsh, English to the Dutch cohort at the other extreme. In this plot the York Romans cluster centrally close to the modern Welsh median value, along with the Iron-Age genome. The local Anglo-Saxon is placed differently, closest to modern East Anglians between the English and Dutch medians.

This first component also offers an opportunity to compare within the English sample. Figure 3b shows a boxplot of PC1 values for each subsample and structure is evident, with higher median values in Eastern regions such as East Anglia, East Midlands, intermediate values in the southern and western parts and lower values in the north and northwest. This pattern is more clearly seen in a geographical plot of interpolated values (Fig. 5a). When the York Romans are compared together with each modern cohort, they are most similar to the Welsh distribution of PC1 values and differ significantly from all other regional groups, apart from those from North and Northwest England (Mann–Whitney test; Fig. 3b, Supplementary Note 2 and Supplementary Table 13). An interesting difference is the marked one between the Driffield Terrace ancient and contemporary Yorkshire samples (P=0.003), implying regional discontinuity. It is also worth noting that the PC1 coordinate of the Anglo-Saxon individual is closer to the median PC1 value of East Anglians, possibly reflecting a more pronounced contribution of Germanic immigrants to eastern British populations. However, we note the inherent uncertainty in drawing inference from a single sample.

Ancient Irish genomes confirm Bronze Age steppe incursion

Press release: First ancient Irish human genomes sequenced.

BBC: Ancient DNA sheds light on Irish origins.

Guardian: Origins of the Irish down to mass migration, ancient DNA confirms.

These settlers were followed by people, initially from the Pontic steppe of southern Russia, who knew how to mine for copper and work with gold, and who carried the genetic variant for a blood disorder called haemochromatosis, a hereditary genetic condition so common in Ireland that it is sometimes called Celtic disease.

These people also brought with them the inherited variation that permits the digestion of milk in maturity – much of the world becomes intolerant to the milk sugar lactose after infancy – and they may even have brought the language that became what is now Irish. Some of them, too, had blue eyes.

“There was a great wave of genome change that swept into Europe from above the Black Sea into Bronze Age Europe and we now know it washed all the way to the shores of its most westerly island,” said Dan Bradley, professor of population genetics at Trinity College Dublin.

“And this degree of genetic change invites the possibility of other associated changes, perhaps even the introduction of language ancestral to western Celtic tongues.”

The Dublin team and colleagues from Queens University Belfast report in the Proceedings of the National Academy of Sciences that the two great changes in European prehistory – the emergence of agriculture and the advance of metallurgy – were not just culture shifts: they came with new blood. An earlier population of hunter gatherers was successively overwhelmed by new arrivals. And in Ireland, these new settlers began to define a nation.

But the latest study throws more light on the birth of a nation. All three dead men from Rathlin Island carried what is now the most common type of Irish Y chromosome, inherited only from male forebears. [. . .]

And Lara Cassidy, a researcher in genetics at Trinity College Dublin and another co-author, said “Genetic affinity is strongest between Bronze Age genomes and modern Irish, Scottish and Welsh, suggesting establishment of central attributes of the insular Celtic genome 4,000 years ago.”

The PNAS paper: Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome

The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343–3020 cal BC) from a megalithic burial (10.3× coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter–gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026–1534 cal BC), including one high coverage (10.5×) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago.

Ancient DNA: Late Upper Paleolithic Swiss and Caucasus hunter-gatherers sequenced

Upper Palaeolithic genomes reveal deep roots of modern Eurasians (open access):

We extend the scope of European palaeogenomics by sequencing the genomes of Late Upper Palaeolithic (13,300 years old, 1.4-fold coverage) and Mesolithic (9,700 years old, 15.4-fold) males from western Georgia in the Caucasus and a Late Upper Palaeolithic (13,700 years old, 9.5-fold) male from Switzerland. While we detect Late Palaeolithic–Mesolithic genomic continuity in both regions, we find that Caucasus hunter-gatherers (CHG) belong to a distinct ancient clade that split from western hunter-gatherers ~45 kya, shortly after the expansion of anatomically modern humans into Europe and from the ancestors of Neolithic farmers ~25 kya, around the Last Glacial Maximum. CHG genomes significantly contributed to the Yamnaya steppe herders who migrated into Europe ~3,000 BC, supporting a formative Caucasus influence on this important Early Bronze age culture. CHG left their imprint on modern populations from the Caucasus and also central and south Asia possibly marking the arrival of Indo-Aryan languages.

Press release: 'Fourth strand' of European ancestry originated with hunter-gatherers isolated by Ice Age

Selection against Neanderthal introgression (two biorxiv preprints)

The Strength of Selection Against Neanderthal Introgression

Ivan Juric, Simon Aeschbacher, Graham Coop
doi: http://dx.doi.org/10.1101/030148

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that there are systematically lower levels of initial introgression on the X chromosome, a finding consistent with a strong sex bias in the initial matings between the populations. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.

The Genetic Cost of Neanderthal Introgression

Kelley Harris, Rasmus Nielsen
doi: http://dx.doi.org/10.1101/030387

Approximately 2-4% of the human genome is in non-Africans comprised of DNA intro- gressed from Neanderthals. Recent studies have shown that there is a paucity of introgressed DNA around functional regions, presumably caused by selection after introgression. This observation has been suggested to be a possible consequence of the accumulation of a large amount of Dobzhansky-Muller incompatibilities, i.e. epistatic effects between human and Neanderthal specific mutations, since the divergence of humans and Neanderthals approx. 400-600 kya. However, using previously published estimates of inbreeding in Neanderthals, and of the distribution of fitness effects from human protein coding genes, we show that the average Neanderthal would have had at least 40% lower fitness than the average human due to higher levels of inbreeding and an increased mutational load, regardless of the dominance coefficients of new mutations. Using simulations, we show that under the assumption of additive dominance effects, early Neanderthal/human hybrids would have experienced strong negative selection, though not so strong that it would prevent Neanderthal DNA from entering the human population. In fact, the increased mutational load in Neanderthals predicts the observed reduction in Neanderthal introgressed segments around protein coding genes, without any need to invoke epistasis. The simulations also predict that there is a residual Neanderthal derived mutational load in non-African humans, leading to an average fitness reduction of at least 0.5%. Although there has been much previous debate about the effects of the out-of-Africa bottleneck on mutational loads in non-Africans, the significant deleterious effects of Neanderthal introgression have hitherto been left out of this discussion, but might be just as important for understanding fitness differences among human populations. We also show that if deleterious mutations are recessive, the Neanderthal admixture fraction would gradually increase over time due to selection for Neanderthal haplotypes that mask human deleterious mutations in the heterozygous state. This effect of dominance heterosis might partially explain why adaptive introgression appears to be widespread in nature.

"Eight thousand years of natural selection in Europe" preprint - updated with Anatolian Neolithic and other data

Eight thousand years of natural selection in Europe

The arrival of farming in Europe around 8,500 years ago necessitated adaptation to new environments, pathogens, diets, and social organizations. While indirect evidence of adaptation can be detected in patterns of genetic variation in present-day people, ancient DNA makes it possible to witness selection directly by analyzing samples from populations before, during and after adaptation events. Here we report the first genome-wide scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture, who we show were members of the population that was the source of Europe's first farmers, and whose genetic material we extracted by focusing on the DNA-rich petrous bone. We identify genome-wide significant signatures of selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. [. . .]

Our sample of 26 Anatolian Neolithic individuals represents the first genome-wide ancient DNA data from the eastern Mediterranean. Our success at analyzing such a large number of samples is likely due to the fact that at the Barcin site–the source of 21 of the working samples–we sampled from the cochlea of the petrous bone 9 , which has been shown to increase the amount of DNA obtained by up to two orders of magnitude relative to teeth (the next-most-promising tissue) 3 . Principal component (PCA) and ADMIXTURE 10 analysis, shows that the Anatolian Neolithic samples do not resemble any present-day Near Eastern populations but are shifted towards Europe, clustering with Neolithic European farmers (EEF) from Germany, Hungary, and Spain 7 (Fig. 1b, Extended Data Fig. 2). Further evidence that the Anatolian Neolithic and EEF were related comes from the high frequency (47%; n=15) of Y-chromosome haplogroup G2a typical of ancient EEF samples 7 (Supplementary Data Table 1), and the low F ST (0.005-0.016) between Neolithic Anatolians and EEF (Supplementary Data Table 2). These results support the hypothesis 7 of a common ancestral population of EEF prior to their dispersal along distinct inland/central European and coastal/Mediterranean routes. The EEF are slightly more shifted to Europe in the PCA than are the Anatolian Neolithic (Fig. 1b) and have significantly more admixture from Western hunter-gatherers (WHG), shown by f 4 -statistics (|Z|>6 standard errors from 0) and negative f 3 -statistics (|Z|>4) 11 (Extended Data Table 3). We estimate that the EEF have 7- 11% more WHG admixture than their Anatolian relatives (Extended Data Fig. 2, Supplementary Information section 2).

On the presence of the "East Asian" EDAR variant in Scandinavian hunter-gatherers:

We find a surprise in six Scandinavian hunter-gatherers (SHG) from the Motala site in southern Sweden. In three out of six samples, we observe the haplotype carrying the derived allele of rs3827760 in the EDAR gene (Extended Data Fig. 5), which affects tooth morphology and hair thickness and has been the subject of a selective sweep in East Asia 24 , and today is at high frequency in East Asians and Native Americans. The EDAR derived allele is largely absent in present-day Europe except in Scandinavia, plausibly due to Siberian movements into the region millennia after the date of the Motala samples. The SHG have no evidence of East Asian ancestry 4,7 , suggesting that the EDAR derived allele may not have originated not in East Asians as previously suggested 24 . A second surprise is that, unlike closely related western hunter-gatherers, the Motala samples have predominantly derived pigmentation alleles at SLC45A2 and SLC24A5.

Polygenic selection on height in Europe:

We also tested for selection on complex traits. The best-documented example of this process in humans is height, for which the differences between Northern and Southern Europe have driven by selection 25 . To test for this signal in our data, we used a statistic that tests whether trait-affecting alleles are both highly correlated and more differentiated, compared to randomly sampled alleles 26 . We predicted genetic heights for each population and applied the test to all populations together, as well as to pairs of populations (Fig. 4). Using 180 height-associated SNPs 27 (restricted to 169 where we successfully targeted at least two chromosomes in each population), we detect a significant signal of directional selection on height (p=0.002). Applying this to pairs of populations allows us to detect two independent signals. First, the Iberian Neolithic and Chalcolithic samples show selection for reduced height relative to both the Anatolian Neolithic (p=0.042) and the Central European Early and Middle Neolithic (p=0.003). Second, we detect a signal for increased height in the steppe populations (p=0.030 relative to the Central European Early and Middle Neolithic). These results suggest that the modern South-North gradient in height across Europe is due to both increased steppe ancestry in northern populations, and selection for decreased height in Early Neolithic migrants to southern Europe. We do not observe any other significant signals of polygenetic selection in five other complex traits we tested: body mass index 28 (p=0.20), waist-to-hip ratio 29 (p=0.51), type 2 diabetes 30 (p=0.37), inflammatory bowel disease 21 (p=0.17) and lipid levels 16 (p=0.50).

Linguistics, Archaeology & Genetics conference abstracts

This conference, aimed at "integrating new evidence for the origin and spread of the Indo-European languages", will take place next week. Some abstracts (pdf):

Close genetic relationship of Neolithic Anatolians to early European farmers

Iosif Lazaridis 1,2 , Songül Alpaslan 3 , Daniel Fernandes 4 , Mario Nowak 4 , Kendra Sirak 4 , Nadin Rohland 1,2 , Swapan Mallick 1,2,5 , Kristin Stewardson 1,5 , Fokke Gerritsen 6 , Nick Patterson 2 , Ron Pinhasi 4, *, David Reich 1,2,5, *

We study 1.2 million genome-wide single nucleotide polymorphisms on a sample of 26 Neolithic individuals (~6,300 years BCE) from northwestern Anatolia. Our analysis reveals a homogeneous population that was genetically similar to early farmers from Europe (F ST =0.004±0.0003 and frequency of 60% of Y-chromosome haplogroup G2a). We model Early Neolithic farmers from central Europe and Iberia as a genetic mixture of ~90% Anatolians and ~10% European hunter-gatherers, suggesting little influence by Mesolithic Europeans prior to the dispersal of European farmers into the interior of the continent. Neolithic Anatolians differ from all present-day populations of western Asia, suggesting genetic changes have occurred in parts of this region since the Neolithic period. We suggest that the language spoken by the homogeneous Anatolian-European Neolithic farmers is unlikely to have been the same as that spoken by the Yamnaya steppe pastoralists whose ancestry was derived from eastern Europe and a different population from the Caucasus/Near East [Haak et al. 2015], and discuss implications for alternative models of Indo-European dispersals.

The Genetic History and Structure of Britain

Nick Patterson, Broad Institute, Boston and David Reich, Harvard Medical School and Broad Institute, Boston

The recently published paper on the genetic structure of Britain (Leslie et al. Nature 2015) has shown subtle genetic variation correlating with geography. Here we reexamine the evidence in the light of our understanding of the genetics of Ancient Europe and comment on some implications for how Indo-Europeans spread into Europe.

In search for initial Indo-European gene pool from genome-wide data on IE popula- tions as compared with their non-IE neighbors

Oleg Balanovsky, Vavilow Institue of General Genetics, Russian Academy of Sci- ences, Moscow

From Yamnaya to Bell Beakers: Mechanisms of Transmission in an Interconnected Europe, 3500–2000 BC

Volker Heyd, Universtiy Bristol, Bistol and University of Helsinki, Helsinki

Yamnaya Peoples in the East and Bell Beakers Users in the West are rightly seen as the apogees in a long-term process of individualisation, gender differentiation, warrior display and internationalisation/unification that fundamentally change the face of the European Continent from the mid fourth and throughout the third millennium BC. We can only approach the reasons why prehistoric peoples and cultures from regions across Europe, which were no more than marginally in touch before, join in the same emblematic pottery, new drinking habits, similar burial customs, anthropomorphic stelae, ostentatious display of weapons and other paraphernalia, and thus common values. However rather than seeing this development as an internal European progress I want to point to the importance of the Pontic-Caspian steppes, and a 2000 years lasting interaction scenario of infiltrating Suvorovo-Novodanilovka, Nizhnemikhailovka-Kvityana and Yamnaya peoples and populations with their more sedentary contemporaries in southeast Europe, the Carpathian basin and northeast of the Carpathian bow. A crucial part of this interaction –besides migrations and the exchange of genes and goods as recently highlighted in several publications not only in Nature and Science– is the forwarding of innovations in the sphere of subsistence economy. We see this archaeologically in a further importance of animal husbandry, with larger herds, specialised breeding and new forms of herding management in particular for cattle. This obviously sets in motion a substantial shift in general mobility patterns and of communication networks.

It is easily conceivable that this interaction must also have had a profound impact on the whole settlement organisation and people’s way-of-life, in consequence probably fundamentally affecting the basics of societies and thus challenging the whole system of ideas, imaginations, morale, symbols and terms – a new world-view and ultimately the base for a new language.

Pre-Indo-European speech carrying a Neolithic signature emanating from the Aegean

Guus Kroonen, Institute for Nordic Studies and Linguistics, Copenhagen University, Copenhagen

When different Indo-European speaking groups settled Europe, they did not arrive in terra nullius. Both from the perspective of the Anatolian hypothesis 1,2,3 and the Steppe hypothesis, 4,5,6 the carriers of Indo-European speech likely encountered existing populations that spoke dissimilar, unrelated languages. Relatively little is known about the Pre-Indo-European linguistic landscape of Europe, as the Indo-Europeanization of the continent caused a largely unrecorded, massive linguistic extinction event. However, when the different Indo-European groups entered Europe, they incorporated lexical material from Europe’s original languages into their own vocabularies. 7 By integrating these “natural samples” of Pre-Indo-European speech, the original European linguistic and cultural landscape can partly be reconstructed and matched against the Anatolia and the Steppe hypotheses. My results reveal that Pre-Indo-European speech contains a clear Neolithic signature emanating from the Aegean, 8 and thus patterns with the prehistoric migration of Europe’s first farming populations. 9,10,11 These results also imply that Indo-European speech came to Europe following a later migration wave, and therefore favor the Steppe Hypothesis as a likely scenario for the spread of the Proto-Indo-Europeans. 12

More carriers of deeply diverged Y lineage (haplogroup A00) found in Cameroon

This possibly archaic African Y lineage was discovered a few years ago by hobbyists, and a project run and funded by hobbyists to collect and test additional A00 samples has started to report results:

There are some striking patterns in the results already. 85% of the A00 so far are from the Bangwa (Nweh) people, and 15% from the Nkongho-Mbo. This is despite the fact that nearly 57% of the samples collected were from Mbo, and only 37% were from Bangwa. Once all the results have been fully tabulated, we can provide more complete statistics. It will take a while to transcribe all the rich data from those handwritten sheets into electronic spreadsheets. [. . .]

What's next? Matthew would like to head back to the field quite soon, in the second half of October, when the school where he teaches has a break. Our current plan is for him to visit the region of the Bamileke people. Matthew, an ethno-historian, has said "The similarity in names, language, dancing style and all other aspects of life suggest that the Bangwa are 90 percent Bamileke." By testing a good number of Bamileke, we'll be able to see whether the heritage they share includes A00, or not. It is possible that the A00 among the Bangwa comes from the indigenous people who originally inhabited the hills, before they arrived several centuries ago, or it could also have been present among the Bamileke earlier. Our results should give strong evidence to answer that question.

The next field trips should be even more exciting. One of our goals is to collect the most diverse samples of A00 possible, to uncover its internal structure. By sequencing the Y-DNA of A00 lines that have diverged and settled in different parts of Cameroon, we should be able to get a good idea of when those different lineages had a common ancestor, and understand better how the peoples among whom it's found are related.

One trip will take Matthew westward into the lowland regions close to Nigeria, where the Banyangi and Ejagham peoples live, toward the Cross River, home of the endangered Cross River Gorilla. These villages are also on the roads that led to the old Nigerian port of Calabar, where captives from Cameroon's highlands, including some Bangwa, were sold into slavery in the past. He has never before sampled in the western regions, and only 16 Banyangi have been tested in his past research, but there are versions of Bangwa history which say that these peoples make up a significant element of their founders. Members of the A0 haplogroup have been found in Nigeria, but we have no idea yet whether A00 are also found in that direction. The famed Iwo Eleru cave is in southern Nigeria, where a skull with archaic features has been found that dates to only 13,000 years ago, suggesting long survival of diverse humans in that region.

In his other trip, he'll seek to sample members of several of the different Pygmy communities of Cameroon, who live to the South and East. Among the Pygmy peoples, Matthew collected 53 samples in 2006, and two of them belonged to A00! These communities are far from the highlands where the Bangwa and Mbo live, so we can expect that their A00 will be quite distinct. This should be extremely interesting!

1000 Genomes phase 3 papers

Both papers are freely accessible:

A global reference for human genetic variation

An integrated map of structural variation in 2,504 human genomes

Minor sub-Saharan and substantial Levantine admixture in Southern Europe

According to "The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape", something like a third of Southern Italian and Tuscan genetic ancestry appears to derive from the Levant in Roman times:

Moorjani et al [S?], who use a method based on allele frequency comparisons, and not haplotypes (ROLLOFF), found evidence for sub-Saharan African admixture in Sardinia 71±28 generations ago, at a proportion of 3%. These are the same Sardinians included in our analysis. In the largest Sardinian (sardi13) cluster in our analysis we infer West African admixture 66 (53-82) generations ago at a proportion of 2%.

S5.2 Continuous low level African admixture in the Mediterranean and Anatolia

We infer West African admixture across broad date ranges, but at low admixture proportions (admixture α < 0.07; Figs. 2 and S3) in several Mediterranean groups, consistent with a long term movement be- tween sub-Saharan Africa and southern Europe [S?,S?]. Specific West African admixture dating to the Arabic conquest of the Mediterranean [S?] is seen in Spanish (spani27: 1042 (740-1201CE)), Southern Italian and Sicilian (sicil30: 1105 (882-1250CE)), and Basque (basqu24: 886 (283-1162CE)) clusters. Earlier African admixture at low admixture proportion is inferred in the Cypriots (cypri12: 427(107- 734CE)), and a Sardinian cluster (sardi13: 36 (458BCE-430CE); α = 0.02). This latter event is con- sistent with the occurrence of A3b2-M13 (0.6%) and E1a-M44 (0.4%) African Y chromosome lineages in Sardinia [S?]. and the dating is more compatible with documented exchanges between the island and Mauretania Cesariensis in Roman times (2 nd century BCE to 2 nd century CE) than later displacements of northern-African males to Sardinia at the time of the Vandals rule (5 th century CE) [S?]. [. . .]

S5.3 A key role for the Levant in the genetic history of the Mediterranean

Early admixture involving source groups most similar to contemporary populations from in and around the Levant (which we define as the World Region containing individuals from Syria, Palestine, Lebanon, Jordan, Saudi, Yemen and Egypt) is seen at high proportions in several clusters from Italy dating to the first half of the first millennium CE, from Southern Italy (itali8: 295CE (72BCE-604CE); α = 0.34), Tuscany (tsi23: 400CE(30BCE-686); α = 0.29), and Sardinia, as well as in a large cluster from Armenia at an early date (armen27: 363BCE(1085BCE-383CE)). [. . .] these events loosely coincide with the formation of the pan-Mediterranean Roman Empire [S?], which may also have allowed increased gene flow from east to west Mediterranean. [. . .] We infer more recent Levant admixture in the French (frenc24: 728(424-1011CE)) and in a complex multiway event in a Spanish cluster (spani9: 668 (286-876CE)). The dates and sources of admixture in these cases are consistent with movements of Middle Eastern and North African individuals during the Islamic Conquest of Spain [S?], and suggest a legacy of this key moment in southern European history in the genomes of French as well as Spanish populations.

Autosomal DNA from Atapuerca pre- or proto-Neanderthals

DNA from Neandertal relative may shake up human family tree

The Sima people, who lived before Neandertals, were thought to have emerged in Europe. Yet their teeth, jaws, and large nasal cavities were among the traits that closely resembled those of Neandertals, according to a team led by paleontologist Juan-Luis Arsuaga of the Complutense University of Madrid. As a result, his team classified the fossils as members of Homo heidelbergensis, a species that lived about 600,000 to 250,000 years ago in Europe, Africa, and Asia. Many researchers have thought H. heidelbergensis gave rise to Neandertals and perhaps also to our species, H. sapiens, in the past 400,000 years or so. [. . .]

After 2 years of intense effort, paleogeneticist Matthias Meyer of the Max Planck Institute for Evolutionary Anthropology has finally sequenced enough nuclear DNA from fossils of a tooth and a leg bone from the pit to solve the mystery. [. . .] They scanned this DNA for unique markers found only in Neandertals or Denisovans or modern humans, and found that the two Sima fossils shared far more alleles—different nucleotides at the same address in the genome—with Neandertals than Denisovans or modern humans. “Indeed, the Sima de los Huesos specimens are early Neandertals or related to early Neandertals,” suggesting that the split of Denisovans and Neandertals should be moved back in time, Meyer reported at the meeting. [. . .]

“It resolves one controversy—that they’re in the Neandertal clade,” says paleoanthropologist Chris Stringer of the Natural History Museum in London. “But it’s not all good news: From my point of view, it pushes back the origin of H. sapiens from the Neandertals and Denisovans.” The possibility that humans were a distinct group so early shakes up the human family tree, promising to lead to new debate about when and where the branches belong.

Darren Curnoe points out:

What are the broader implications of the research for understanding the evolution of living humans?

First, the finding pushes the age of the shared human-Neanderthal ancestor well beyond 400,000 years ago, suggesting our species, H. sapiens, might also be at least this old.

Also, with the Atapuerca group living in Europe, it’s even possible that our species evolved in this or an adjacent region of Eurasia, and later migrated back into Africa.

And being close to the common ancestor, the Atapuerca fossils give us real insights into what it must have looked like and the ancestral body form of our own species.

The fossils from Europe, Asia and Africa from around this time are physically very diverse, with some researchers thinking they represent multiple species, only one of which could be the ancestor of living humans.

Question is, which one?

This new research suggests the European branch is closest among them all and deserves much more attention in this regard.

In contrast, we don’t know, and will doubtless ever know, whether Homo naledi had anything to do with the evolution of living humans, least of all whether its brain, mind or behaviour were anything like our own.

ASHG 2015: growth rate estimates from whole Y chromosome sequences

Estimation of growth rates for populations and haplogroups using full Y chromosome sequences.

F. L. Mendez; G. D. Poznik; C. D. Bustamante; 1000 Genomes Project Consortium

Department of Genetics, Stanford University, Stanford, CA.

Evolutionary processes affecting a population influence gene genealogies across the genome. Coalescent theory provides the mathematical framework to connect realized genealogies to the underlying evolutionary processes. However, in most cases, information about the genealogies is obtained only indirectly through the observation of genetic variation. Therefore, in general, very limited information about any individual locus is available. As the longest non-recombining portion of the human genome, the Y chromosome accumulates mutations relatively quickly. When large amounts of sequence are used, the Y chromosome provides an unparalleled ability to resolve the structure and coalescence times of its genealogy. Because patterns of variation in the Y chromosome are only influenced by processes affecting men, they can be used to study both demographic and social phenomena. The 1000 Genomes Project includes whole Y-chromosome data from more than 1000 men and has an extensive representation of most lineages that have experienced recent massive expansions in size. Though the dynamics of population growth have likely changed over time, we are more interested in the growth rates at the times of these rapid expansions than on an average effect. To study this, we have developed a new method that takes advantage of the temporal resolution provided by Y-chromosome data and of historical data, while accounting for the uncertainties associated with the coalescent and mutational processes. We estimate the growth rates for several branches of the Y-chromosome tree, including those in Europe, sub-Saharan Africa and South Asia. We estimate that several lineages within the European R1b, sub-Saharan African E1b, and South Asian R1a haplogroups experienced growth rates of at least 20-60% per generation at the onset of their massive expansions, some 3-5 thousand years ago. These high growth rates are comparable to those experienced by human populations during the 20th century. However, we find that most observed genealogies are unlikely to be the result of whole population expansion or of natural selection.

ASHG 2015: Population differentiation analysis of 54,734 European Americans

Population differentiation analysis of 54,734 European Americans reveals independent evolution of ADH1Bgene in Europe and East Asia.

K. J. Galinsky1,2 ; G. Bhatia2,3 ; P. Loh2,3 ; S. Georgiev4 ; S. Mukherjee5 ; N. J. Patterson2 ; A. L. Price1,2,3

Population differentiation is a widely used approach to detect the action of natural selection. Existing methods search for unusual differentiation in allele frequencies across discrete populations, e.g. using FST. Loci that are unusually differentiated with respect to the genome-wide FST or with respect to a null distribution of F­ST are reported as signals of selection. These approaches are particularly powerful for closely related populations with large sample sizes.However, population genetic data often is not naturally partitioned into discrete populations. We developed a test for selection that uses SNP loadings from principal components analysis (PCA). For a given PC reflecting geographic ancestry, under the null hypothesis of no selection, the square of the SNP loadings, rescaled by a scaling factor derived from the eigenvalue of the PC, follows a chi-square (1 d.o.f.) distribution. This statistic is able to infer selection with genome-wide significance, a key consideration in genome scans for selection. We confirmed via simulations that this statistic has correct null calibration under a wide range of demographies and is well-powered to detect selection at large sample sizes.We applied the method to a cohort of 54,734 European Americans genotyped on genome-wide arrays. PCs were inferred using our FastPCA software (running time: 57 minutes). The top 4 PCs corresponded to clines of Irish, Eastern European, Northern European, Southeast European and Ashkenazi Jewish ancestry, validated via PCA projection of samples of known ancestry. We detected genome-wide significant signals of selection at 4 known selected loci (LCT, HLA, OCA2 and IRF4) and 3 novel loci: ADH1B, IGFBP3 and IGH. 2 of the 3 novel loci could not be detected using discrete-population tests (or other existing tests). The ADH1B gene is associated with alcoholism (via the same coding SNP rs1229984 producing a signal in our selection scan) and has been shown to be under recent selection in East Asians (via a haplotype-based test for recent selection); we show here that it is a rare example of independent evolution on two continents. The IGFBP3 gene and IGH locus have been implicated in breast cancer and multiple sclerosis, respectively. Our results show that application of our PC-based selection statistic to large data sets can infer novel, genome-wide significant signals of selection at loci linked to disease traits.

ASHG 2015: The lingering load of archaic admixture in modern human populations

The lingering load of archaic admixture in modern human populations.

K. Harris1,2 ; R. Nielsen2,3

1) Stanford University, Stanford, CA; 2) University of California Berkeley, Berkeley, CA; 3) Center for Bioinformatics, University of Copenhagen, Copenhagen, Denmark.

Founder effects and bottlenecks can damage fitness by letting deleterious alleles drift to high frequencies. This almost certainly imposed a burden on Neanderthals and Denisovans, archaic hominid populations whose genetic diversity was less than a quarter of the level seen in humans today. A more controversial question is whether the out-of-Africa bottleneck created differences in genetic load between modern human populations. Some previous studies concluded that this bottleneck saddled non-Africans with potentially damaging genetic variants that could affect disease incidence across the globe today (e.g. Lohmueller, et al. 2009; Fu, et al. 2014), while other studies have concluded that there is little difference in genetic load between Africans and non-Africans (e.g. Simons, et al. 2014; Do, et al. 2015). Although previous studies have devoted considerable attention to simulating the accumulation of deleterious mutations during the out-of-Africa bottleneck, none to our knowledge have incorporated the fitness effects of introgression from Neanderthals into non-Africans. We present simulations showing that archaic introgression may have had a greater fitness effect than the out-of-Africa bottleneck itself, saddling non-Africans with weakly deleterious alleles that accumulated as nearly neutral variants in Neanderthals. Assuming that the exome experiences deleterious mutations with additive fitness effects drawn from a previously inferred gamma distribution, we predict that the fitness of the average Neanderthal was about 50% lower than the fitness of the average human, implying the existence of strong selection against early Neanderthal-human hybrids. This is a direct consequence of mutation accumulation during a period of low Neanderthal population size that is thought to have lasted ten times longer than the out-of-Africa bottleneck (Pruefer, et al. 2014). Although our model predicts some transmission of deleterious Neanderthal variation to present-day non-Africans, it also predicts that many Neanderthal alleles have been purged away, depleting conserved genomic regions of Neanderthal ancestry as observed empirically by Sankararaman, et al. (2014). Our results imply that the deficit of Neanderthal DNA from functional genomic regions can be explained without the action of epistatic reproductive incompatibilities between human and Neanderthal alleles.

ASHG 2015: The genetic structure of the Saudi Arabian population

The genetic structure of the Saudi Arabian population.

H. Al-Saud1 ; SM. Wakil1 ; BF. Meyer1 ; M. Falchi2 ; N. Dzimiri1

1) Genetics Department, King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia; 2) Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom.

Saudi Arabia is the largest Gulf Cooperation Council (GCC) country. Its population consists of different tribes that originated in the northern, western, eastern, middle and south regions of Saudi Arabia, respectively. Due to political and cultural reasons, there has historically been very limited admixture between different tribes. People from the different Saudi tribes then migrated from Saudi Arabia, contributing to foundation of the populations now inhabiting other Gulf countries. Few population genetics research projects have been conducted on this highly consanguineous population that has been shown to have one of the highest prevalence in the world of recessive disorders and common metabolic diseases, especially diabetes. It is therefore important to identify the genetic substructures of the Saudi population, both to help in tracing the migratory genetic flows that contributed to other Gulf populations, and to permit designing of efficient genetic studies aimed at the identification of risk factors underlying common and rare diseases in the GCC countries. We carried out the largest population genetic study in Saudi Arabia to date, by genotyping 2,150 Saudi nationals sampled from different regions of Saudi Arabia using Axiom GWH-96 Array (Affymetrix) arrays. Model-based and model-free clustering were applied to these data, including in our analyses data on eight populations (encompassing Europe, America, Oceana, East Asia, Central South Asia, Middle East, Africa and Qatari populations) from the Human Genetic Diversity Project (HGDP) data set. We identified clear clustering of the Saudi samples into different subgroups, with some tribes showing similarity with both Central East Asian (Kalash Pakistan, Balochi Pakistan, Sindhi Pakistan, Makrani Pakistan and Brahui Pakistan subpopulations) European (Orkney Islands Europe, Russian Europe and Russian Caucasus subpopulations) and Qatari populations, while other tribes appear to show specificity of background.These data strongly support the presence of genetic stratification within the Saudi population, and suggest the presence of subgroups that are characterized by a unique genetic background different from other Arabian populations. Our findings constitute a valuable resource for the investigation of both general and population-specific genetic risk variants associated with different disorders in this population.

Population genetic differentiation of height and body mass index across Europe

From Visscher and colleagues:

Population genetic differentiation of height and body mass index across Europe

Across-nation differences in the mean values for complex traits are common1, 2, 3, 4, 5, 6, 7, 8, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10−8; BMI, P < 5.95 × 10−4), and we find an among-population genetic correlation for tall and slender individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

ASHG 2015: ancient Anatolians similar to European Neolithic farmers and distinct from modern Near Easterners

Genome-wide data on 34 ancient Anatolians identifies the founding population of the European Neolithic.

I. Lazaridis1,2 ; D. Fernandes3 ; N. Rohland1,2 ; S. Mallick1,2,4 ; K. Stewardson1,4 ; S. Alpaslan5 ; N. Patterson2 ; R. Pinhasi*3 ; D. Reich*1,2,4

1) Department of Genetics, Harvard Medical School, Boston, MA USA; 2) Broad Institute of MIT and Harvard, Cambridge, MA USA; 3) Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; 4) Howard Hughes Medical Institute, Harvard Medical School, Boston, MA USA; 5) Independent physical anthropologist, Netherlands.

It has hitherto been difficult to obtain genome-wide data from the Near East. By targeting the inner ear region of the petrous bone for extraction [Pinhasi et al., PLoS One 2015] and using a genome-wide capture technology [Haak et al., Nature, 2015] we achieved unprecedented success in obtaining genome-wide data on more than 1.2 million single nucleotide polymorphism targets from 34 Neolithic individuals from Northwestern Anatolia (~6,300 years BCE), including 18 at greater than 1× coverage. Our analysis reveals a homogeneous population that is genetically a plausible source for the first farmers of Europe in the sense of (i) having a high frequency of Y-chromosome haplogroup G2a, and (ii) low Fst distances from early farmers of Germany (0.004 ± 0.0004) and Spain (0.014 ± 0.0009). Model-free principal components and model-based admixture analyses confirm a strong genetic relationship between Anatolian and European farmers. We model early European farmers as mixtures of Neolithic Anatolians and Mesolithic European hunter-gatherers, revealing very limited admixture with indigenous hunter-gatherers during the initial spread of Neolithic farmers into Europe. Our results therefore provide an overwhelming support to the migration of Near Eastern/Anatolian farmers into southeast and Central Europe around 7,000-6,500 BCE [Ammerman & Cavalli Sforza, 1984, Pinhasi et al., PLoS Biology, 2005]. Our results also show differences between early Anatolians and all present-day populations from the Near East, Anatolia, and Caucasus, showing that the early Anatolian farmers, just as their European relatives, were later demographically replaced to a substantial degree.