Recent Nature and Science papers on Patterns in Human Genetic Variation

In last week’s issue of Nature, we saw two really important papers on large scale human population genetic structure be published. The first was, “Proportionally more deleterious genetic variation in European than in African populations,” and the second was, “Genotype, haplotype and copy-number variation in worldwide human populations.” Not to be outdone by Nature, Science also published a very important paper on large scale human population genetic structure, “Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation.” If I wasn’t so deathly ill, I woulda been one of the first to cover it. Thankfully, Razib, Dienekes, Yann, and John Hawks all picked up at least one of these papers and posted about them in their respective blogs.

Now that I’m finally feeling a bit better, I feel really motivated to blog about these papers. I’ll be focusing on the copy number variation Nature paper as well as the variation and relationship of worldwide human populations Science paper, since they come to similar results but from different approaches. I’ll briefly touch on the deleterious genetic variation Nature paper, because it integrates a key concept into the fold.

Before I get into the thick of it, I wanna give a quick run down on a basic population genetic concept, linkage disequilibrium, because it is screened in all of these papers. It is crucial to understand this concept because it is what is fundamentally what is studied in nearly all population genetic studies. Okay, I’m sure you understand the importance… For any given gene, a sequence of DNA that is transcribed there could exist more than one variant or alleles. These alleles can differ from one another in many different ways, but for simplicity’s sake, we’ll consider only single nucleotide polymorphisms (SNPs) today. SNPs are differences in the same sequence of DNA between two or more alleles in only one base pair.

If SNPs exist in coding regions of a gene, they can be synonymous or nonsynonymous mutations. Mutations may have a bad connotation to you, and I’ll explain how synomymous mutations aren’t necessarily bad. The genetic code has a lot of redundancy; every three nucleotides that are in frame, may encode for an amino acid… but since there’s only 20 different amino acids but 64 different combinations of three nucleotides, some combinations encode for the same amino acid. Thus, if a SNP mutation exists in a coding region, but the two variants do not encode for different amino acids, the mutation is called a synonymous mutation. A nonsynonymous mutation can be more impactful, because in this situation, one of the SNPs alter the three base pair codon, and encode for a different amino acid that can change the structure and function of the resultant protein. Does this mean all nonsynonymous mutations are deleterious? No, often the amino acid difference isn’t that big and the protein’s function isn’t changed much… some other times the mutation can be dramatic and create a totally different protein, knocking down or out a cascade of functions the cell, tissue, organ, etc. maybe reliant upon.

SNPs can be inherited, if you didn’t know. Often they are inherited in long blocks, and that’s because of a unique phenomenon called homologous recombination. Homologous recombination occurs during DNA replication, when overlapping segments of DNA have two homologous regions which swap out with one another. I won’t get into the gory details, but it is really cool! If this occurs during meiosis, during gamete formation, the organism that develops from the recombined gametes inherits blocks of SNPs. The length of DNA that travels with a SNP during recombination varies dependent on how ‘new’ the SNP is. Newer SNPs fall in long areas of recombinant DNA, whereas older SNPs travel in shorter areas. People study the length of DNA associated with a SNP to determine ages of new alleles. The difference between lengths of DNA that travel with SNPs is ultimately what is linkage disequilibrium. I won’t get too into haplogroups, other than the situation when one or more SNPs travel together.

Okay that being said, I hope you have a general understanding of what’s happening at a molecular level to makes us vary in segments of DNA. These variations can be used to study our similarities and differences, figure out who came from whom, etc. The first of the papers that I wanna focus in on is Nature‘s “Genotype, haplotype and copy-number variation in worldwide human populations.” The authors of that study took about 526,000 SNPs and 400 copy number variations (the differences in the number of copies of a gene in the genomes of different people) found in 485 people from about 30 different populations. They observe that larger linkage disequilibrium is found in populations that are farther away from Africa? The indicates these “far from Africa” populations are newer compared to African populations, which suggest that African populations are ancestral to outside populations.

Next up to bat is the Science paper on the same topic. This paper one-ups the other in that it has more SNPs (650,000) from 938 people from 51 different populations. It is, as the authors quote, “the most comprehensive characterization to date of human genetic variation.” Population DendogramWith more data, the authors were able to reconstruct a phylogenetic tree based upon genetic relationships. I consider the figure they were able to draw up a poster-board example for the Out of Africa hypothesis on human origins, even though I acknowledge John Hawks’ critique that this figure “assumes an Out of Africa” model of human migration, and tells us nothing on the mode and time when this migration occurs. What John Hawks points out is a problem with cladistics. In this study the authors establish an outgroup, the most ancestral group, which happens to be Africa. Thus, they force the phylogenetic tree to pattern as if Out of Africa happened. I don’t think their aim is to show us the timing of the out of Africa event, though, it is merely supposed to document a shared ancestry in Africa.

And here’s where I transition to the last paper, the Nature one on deleterious mutations are more prominent in a newer population, Europeans compared to Africans. This paper, “Proportionally more deleterious genetic variation in European than in African populations” kinda gives us a relative date that Hawks criticizes for. Once, newer populations, ones that are founded by comparatively smaller groups, occupy a niche and expand in populations size — mutations manifest bountifully. Mutations again, can be deleterious as well as advantageous, and in Europeans, a population that’s newer, negative selection has had less time compared to African populations to remove deleterious alleles from European populations.

I’m really happy these three papers came out when they did. Fresh on my mind, is still that one discussion on human genetic identity and human genetic variation. Ancestry and identity are two terms that often get muddled into easily digestible public relations burrito many anthropologists have been fed. There’s a real genetic basis for groups, we haven’t really known about it until now. Part of that has been because we’ve focused on identifying genetic ancestry in one or two loci, such as mtDNA and Y-chromosome, before. Now with more and more SNPs identified, we can point out unique ancestry markers with much greater resolution and begin to understand how our ancestry is structured genetically.

    Jakobsson, M., Scholz, S.W., Scheet, P., Gibbs, J.R., VanLiere, J.M., Fung, H., Szpiech, Z.A., Degnan, J.H., Wang, K., Guerreiro, R., Bras, J.M., Schymick, J.C., Hernandez, D.G., Traynor, B.J., Simon-Sanchez, J., Matarin, M., Britton, A., van de Leemput, J., Rafferty, I., Bucan, M., Cann, H.M., Hardy, J.A., Rosenberg, N.A., Singleton, A.B. (2008). Genotype, haplotype and copy-number variation in worldwide human populations. Nature, 451(7181), 998-1003. DOI: 10.1038/nature06742
    Li, J.Z., Absher, D.M., Tang, H., Southwick, A.M., Casto, A.M., Ramachandran, S., Cann, H.M., Barsh, G.S., Feldman, M., Cavalli-Sforza, L.L., Myers, R.M. (2008). Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation. Science, 319(5866), 1100-1104. DOI: 10.1126/science.1153717
    Lohmueller, K.E., Indap, A.R., Schmidt, S., Boyko, A.R., Hernandez, R.D., Hubisz, M.J., Sninsky, J.J., White, T.J., Sunyaev, S.R., Nielsen, R., Clark, A.G., Bustamante, C.D. (2008). Proportionally more deleterious genetic variation in European than in African populations. Nature, 451(7181), 994-997. DOI: 10.1038/nature06611

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