The Best Kept Secret in Populaton Genetics, or Truth about African Genetic Diversity
Nature (2014) doi:10.1038/nature13997
The African Genome Variation Project Shapes Medical Genetics in Africa
Gurdasani, Deepti, Tommy Carstensen, Fasil Tekola-Ayele, Luca Pagani, Ioanna Tachmazidou, Konstantinos Hatzikotoula, Savita Karthikeyan, Louise Iles, Martin O. Pollard, Ananyo Choudhury, Graham R. S. Ritchie, Yali Xue, Jennifer Asimit, Rebecca N. Nsubuga, Elizabeth H. Young, Cristina Pomilla, Katja Kivinen, Kirk Rockett, Anatoli Kamali, Ayo P. Doumatey, Gershim Asiki, Janet Seeley, Fatoumatta Sisay-Joof, Muminatou Jallow, Stephen Tollman, Ephrem Mekonnen, Rosemary Ekong, Tamiru Oljira, Neil Bradman, Kalifa Bojang, Michele Ramsay, Adebowale Adeyemo, Endashaw Bekele, Ayesha Motala, Shane A. Norris, Fraser Pirie, Pontiano Kaleebu, Dominic Kwiatkowski, Chris Tyler-Smith, Charles Rotimi, Eleftheria Zeggini, and Manjinder S. Sandhu.
Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
Gurdasani et al. (2014) is a very important paper as it dispels with one sway four long-standing and hard-working myths, namely that 1) Africa is the most genetically diverse continent; 2) genetic diversity is an indicator of population age; 3) non-African diversity is a subset of African diversity; 4) serial bottlenecks out of Africa are responsible for the observed global patterns of genetic diversity.
Fundamentally, there are two kinds of genetic diversity: intergroup (between-group, among-groups) diversity and intragroup (within-group) diversity. The two diversity measures are dialectically intertwined, so that an increase in one kind of diversity leads to a decrease in the other kind of diversity. As divergent populations merge, they lose some of their intergroup diversity and become more similar to each other but they gain intragroup diversity because now they are enriched with two or more sets of alleles that evolved separately during the time the populations were isolated from each other. As populations drift apart, their intergroup diversity increases, while their intragroup diversity decreases as alleles get lost through drift.
It has become a truism (pace Lewontin) that most genetic variation (some 85%) among humans happens within populations and not between them. The 15% of variation that happens between populations is claimed to be indicative of the young age of the human species. So, it’s intergroup diversity that’s associated with population age and not intragroup diversity (see more here). Continental populations are uneven in their apportionment of inter- vs. intragroup diversity. Sub-Saharan Africans are rich in only one kind of diversity – intragroup diversity, which is a function of effective population size and may reflect (as in the case of admixed post-1492 New World populations that are also rich in intragroup diversity or heterozygosity) layers of admixture. When it comes to intergroup diversity, Africans are only moderately differentiated and so are far from being the “most diverse” among human populations. Amerindians who are the most distant from Africa geographically are the exact opposite from Africans genetically: they have the lowest intragroup diversity among all human continental groups but world highest intergroup diversity values. This pattern is fully captured in the following tables from Tishkoff et al. 2009 (left) and Rosenberg, Noah. “A Population-Genetic Perspective on the Similarities and Differences Among Worldwide Human Populations,” Human Biology 83, no. 6 (2011), 670 (right).
Gurdasani et al. (2014) drill deeper into this remarkable pattern. They provide a composite table (Suppl Table 1) of worldwide Fst (fixation index) values. (The Africa-America Fst is unusually low, which suggest that they used an Amerindian sample that’s admixed with African blacks. Fst between unadmixed Amerindians and Africans reaches 0.281; see Verdu et al. 2014 “Patterns of Admixture and Population Structure in Native Populations of Northwest North America.” PLoS Genet 10(8): e1004530). The limited extent of intergroup differentiation in Africa is evident if we compare Fst across all Khoisan groups (0.019) or between Nilo-Saharan- and Khoisan-speakers (0.058) with Fst between two Amerindian tribes such as Pima and Seri (0.094) (Verdu et al. 2014).
Recently expanded populations within Africa, such as Niger-Congo and Afroasiatic speakers, have one of the lowest intergroup diversity values within Africa. Foragers such as Khoisan have higher intergroup diversity values and are therefore more Amerindian-like than farmers. Niger-Congo and Afroasiatic populations show intragroup diversity that’s higher than that of Khoisan (see Tishkoff et al.’s table above). It’s the same pattern as I observed between Taiwanese aborigines and Polynesians: the former are more homozygous than the latter, hence the colonization of Polynesia from Taiwan was accompanied by heterozygosity increase, not heterozygosity reduction, as a serial bottleneck approach to interpreting worldwide patterns of genetic diversity would suggest.
Gurdasani et al. (2014) ran several statistics (straight f4, f4 with ancestry masking, Z-score and ADMIXTURE) to test for Eurasian gene flow in Sub-Saharan Africa and found that it reaches 50% in some populations. The oldest trace of Eurasian admixture in Africa (7,500-10,000 years ago) was found in Yoruba, which is consistent with previous finding of Neandertal genes in Yoruba. East Africa is the region most affected by Eurasian admixture. Among all the statistics, ADMIXTURE runs proved to yield the most evidence for Eurasian gene flow in Sub-Saharan Africa, which suggests that the other statistics may be prone to genetic drift that can change negative values to positive and hence obfuscate ancient admixture. Eurasian admixture increases African Fst and, once it’s masked, mean pairwise Fst in Africa declines from 0.021 to 0.015, which is similar to Fst values encountered between geographically separated populations in Europe. They identified two “pockets” of elevated Fst (after masking for Eurasian ancestry) – one in Ethiopia and the other one in West Africa. In the latter case, West African Igbo showed admixture with a foraging population, which is closer to Khoisan than to Pygmies.
Finally, another gem into my Kunstkamera collection. Writing about Gurdasani et al. (2014), Razib “Cat Lady” Khan made a ridiculous claim:
“the genetic variation across African populations once you remove Eurasian ancestry is not that high. This is curious in light of the truism that most genetic variation in humans is found within Africa, but as Nick Patterson pointed out to me years ago: this applies to variation within populations, not across them.”
Nick Patterson must be the chief secret keeper among population geneticists because he never published anything to this effect. Instead, he chose to whisper this secret into the ear of no one else but Razib Khan. The truth is that it’s me and not Nick who mentored Razib on this matter and did it in a public forum. This happened in the Comments section of Gene Expression and, according to the log, it was 4 years ago.