Razib Khan One-stop-shopping for all of my content

October 22, 2017

Selection swimming against the genomic tide

Filed under: Africa Genetics,Africa Genomics,Genetics,Genomics — Razib Khan @ 1:32 pm

One of the major issues that confuses people is that the distribution of a trait or gene is often only weakly correlated with overall phylogeny and the rest of the genome.

To give a strange but classic example, the MHC loci are subject to strong balancing selection. This means that novel alleles do not substitute and replace ancestral alleles. Substitution of this sort results in “lineage sorting,” so that when you look at chimpanzees and humans you can see many polymorphic loci where all humans carry one variant and all chimpanzees the other. In contrast at the MHC loci there is frequency-dependent selection for rare variants, so the normal cycling process does not occur. Humans and chimpanzees overlap quite a bit on MHC, and any given human may have a more similar profile to a given chimpanzee than another human.

There are 19,000 human genes. At 3 billion base pairs only about ~100 million are polymorphic on a worldwide scale (using some liberal definitions). There are lots of unique stories to tell here.

A new preprint, Inferring adaptive gene-flow in recent African history, illustrates how certain genes with functional significance may differ from genome-wide background. The authors find that among the Fula (Fulani) people of West Africa there has been introgression from a Eurasian mutation that confers lactase persistence. The area of the genome around this gene is much more Eurasian than the rest of the genome. In contrast, the area around the Duffy allele is much less Eurasian. The variation in this locus is related to malaria resistance. Finally, in other African populations, they found gene flow of MHC variants.

None of this is entirely surprising, though the authors apply novel haplotype-based methods which should have wider utility.

October 6, 2017

Genetic variation and disease in Africa

Filed under: Africa Genetics,Africa Genomics,African Genetics,Human Genetics — Razib Khan @ 4:17 am


Very readable review, Gene Discovery for Complex Traits: Lessons from Africa. It’s open access, so I recommend it. The summary:

The genetics of African populations reveals an otherwise “missing layer” of human variation that arose between 100,000 and 5 million years ago. Both the vast number of these ancient variants and the selective pressures they survived yield insights into genes responsible for complex traits in all populations.

The main issue I might have is I’m not sure that focusing on 5 million year time spans is particularly useful. Rather, looking at the last major bottleneck for modern humans before the “Out of Africa” event would be key, since that’s when a lot of the common variation would disappear, and very rare variants probably don’t have deep time depth in any case. With all that being said, the qualitative analysis is on point.

One of the major issues in the “SNP-chip” era has been that ascertainment of variation has been skewed toward Europeans. Though more recent techniques have tried to fix this…this review points out that if you by necessity constrain the SNPs of interest to those that vary outside of Africa (most of the world’s population), you are taking may alleles private to Africa off the table. This is relevant because the “Out of Africa” bottleneck ~50,000 years ago means that African populations harbor a lot more genetic variation than non-African populations do.

The move to high-quality whole genome sequencing obviates these concerns. As a matter of course African variation will be “picked up” since the marker set is not constrained ahead of time.

Importantly the authors focus on South Africa and the Xhosa population. This group has about ~20% Khoisan genetic ancestry, which is very diverse, and, very distinct, from that of the remaining ~80% of its ancestry. With its large African immigrant population and highly diverse native groups, some of them quite admixed, South Africa could actually provide some hard-to-substitute value in biomedical genetics.

August 29, 2010

People, not pots, in Africa

324_1035_F5Last weekend I mentioned a paper, The Genetic Structure and History of Africans and African Americans, which had the best coverage of disparate African populations we’ve seen so far. The map to the left shows the various ancestral population clusters inferred from the samples they had. Really the only failing is that they didn’t have samples from Angola, Zambia, Zimbabwe and Mozambique. Unfortunately, that’s not totally trivial. These are regions which were effected by the Bantu Expansion, with southern Angola in particular still having remnants of Khoisan language speakers which likely attest to the pre-Bantu populations. Luckily for us innovation and scientific ingenuity are such that minor questions can quickly be answered because of how cheap the basic methods have become. A new paper in The European Journal of Human Genetics tackles Mozambique in particular, and discerns a heretofore unknown possible population cluster. A genomic analysis identifies a novel component in the genetic structure of sub-Saharan African populations:

Studies of large sets of single nucleotide polymorphism (SNP) data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2841 SNPs in 12 sub-Saharan African populations, including a previously unsampled region of southeastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the southeastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region.

The main value-add of the research were the 279 individuals from Mozambique, who they plugged into previous data sets (e.g., HGDP, HapMap3). It must also be noted that they limited their genetic survey to ~2800 SNPs.This is sufficient for their purposes. Below are the figures of interest from the paper. Note immediately how Mozambique separates out at K = 4 in the first image. The subsequent figures are from PCA. The axes represent components of variation. The last panel shows a PCA plot transposed onto a map. In this case, PC 1 & PC3.t

The first figure is important because it suggests population structure we hadn’t known of in the Bantu Expansion. This doesn’t mean that it should be surprising. With Africa’s current level of genetic variation it seems implausible that the carriers of the Bantu culture would not have assimilated other groups along the wave of advance. In fact, as a cultural movement gains steam through positive feedback loops different societies may become co-opted into them, and spread the culture in their own turn. As an American example, I will give the Irish American Catholic hierarchy’s campaigns against German language parochial school instruction in the 19th century. Old English aside the language of the Irish was originally not English, but by the early 19th century apparently English had already become dominant among the Roman Catholic peasantry of Ireland. So they brought English, not Gaelic, to the United States. Similarly, the spread of Islam in India occurred predominantly under the ageis of Turks and Afghans, not Arabs, while the spread of Islam in Southeast Asia was promoted by South Asian Muslim merchants in their turn. So you have Arab cultural forms in eastern Indonesia thanks to cultural expansions at two removes from the original Arab source (in fact, it could be argued that the Turks and Afghans were Islamicized through a Persian intermediate as well).

But it is the PCA plots which are of more curiosity for me. They note that it is the third component of variation which maps well onto geographic distance. In the paper they say:

This is the PC that is mostly correlated with geography…and the fact that it is the third rather than the first component, as would be expected if isolation by distance was the predominant force shaping genetic diversity…implies that directional population movements (such as the Bantu expansion) and barriers to gene flow (such as that between food producers and hunter gatherers) are more relevant than geographic distance to understand the genetic landscape of sub-Saharan Africa….

There were folk migrations in Africa. They might simply not have been the ones we are aware of, at least in our sparest conceptions. Those folk migrations were very recent, within the last ~2,000 years or so. Which is why the distinctive correlations between language and genes persist, especially on the outer edge of the wave of advance in southern Africa (in contrast, the Pygmies of the Congo have lost their native language, and the western Pygmies are highly admixed with their neighbors).

Citation: A genomic analysis identifies a novel component in the genetic structure of sub-Saharan African populations

Addendum: The life of Shaka may give us a clue as the disturbances which pushed the Bantu ever outward.

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