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Tuesday, March 24, 2009

Signals of Positive Selection in Humans?

Signals of recent positive selection in a worldwide sample of human populations is the title of a paper that has just been published in Genome Research (Pickrell et al. 2009).

These workers looked for signs of positive selection using techniques similar to those employed by Hawks et al. in their 2007 paper. That 2007 paper serves as one of the important bits of evidence in the recently published book, The 10,000 Year Explosion.

The idea is to pick out regions of the genome that have linked clusters of polymorphisms (SNPs = single nucleotide polymorphisms). These cluster are called haplotypes and they indicate that a region of the genome has not undergone much recombination in the recent past, because recombination tends to shuffle polymorphisms. One way this linkage could be preserved is when a part of the genome is under positive selection so its increase in frequency is rapid. This is called a selective sweep.

Pickrell et al. (2009) examined a database of 657,143 SNPs called the Human Genome Diversity-CEPH Panel (HGDP). These polymorphisms come from a global sample of 53 populations. The Hawks et al. (2007) paper examined the HapMap database of 3.1 million SNPs from three populations.

Pickrell et al. (2009) also detect a large number of regions that are candidates for positive selection. Their sites overlap those of the earlier study—about half of their sites were also identified by Hawks et al. (2007).

A number of candidates for positive selection are discussed in the paper but the authors note that many of the potential sites are not near any genes that have been well-characterized. It's important to look at individual cases in order to get a feel for the data, especially since the possibility of false positives is a concern.

Specific Examples

Here are a few of the single genes that were identified in one or more groups (e.g. Bantu, Europeans, native American etc.) They are from the top ten strongest signals so they presumably represent some of the best cases for selection.

Heat Shock Transcription Factor 2 (HSF2): This is one of two genes for the major heat shock transcription factor. The heat shock genes are highly conserved and so is their regulation. It's very unlikely that a mutation in the native North American population would be beneficial relative to the allele in all other populations.

succinate-CoA ligase, GDP-forming, β-subunit (SUCLG2) This is the gene for succinyl-CoA synthetase, one of the enzymes of the Krebbs cycle. The data suggest that an allele of this gene was positively selected in the population of Oceania (Pacific Ocean). This doesn't seem very likely.

oxoacyl-ACP synthase, mitochondrial (OXSM) This is the mitochondrial version of a β-ketoacyl synthetase, a standard enzyme required for fatty acid synthesis. An allele shows signs of positive selection in Eurasian populations but not in any other population. It doesn't seem likely that there's an allele conferring a beneficial effect that hasn't already become fixed in mammals over 100 million years ago.

mannosidase, alpha, class 2A, member 1 (MAN2A1) This is a mannosidase located in the Golgi. It's required for one of the last stages in the oligosaccharide maturation pathway—a pathway that's found in all eukaryotes. Pickrell et al. (2009) suggest that an allele of this gene has been selected in the pygmy and Bantu populations. Again, it isn't likely that a standard metabolic gene would be selected in this way.

False Positives?

The patterns of potential selective sweeps strongly suggest local and/or regional sweeps. Since this is the pattern you might expect from random genetic drift, it raises a question about false positives. The authors of the 2009 paper say, ...
Further exploration of the geographic patterns in these data and their implications is warranted, but from the point of view of identifying candidate loci for functional verification, the fact that putatively selected loci often conform to the geographic patterns characteristic of neutral loci is somewhat worrying. This suggests that distinguishing true cases of selection from the tails of the neutral distribution may be more difficult than sometimes assumed, and raises the possibility that many loci identified as being under selection in genome scans of this kind may be false positives. Reports of ubiquitous strong (s = 1-5%) positive selection in the human genome (Hawks et al. 2007) may be considerably overstated. [My emphasis-LAM]
It should come as no surprise that John Hawks disagrees. He has posted a rebuttal on his blog at: Overstating the obvious.

It's an interesting debate but let's not lose sight of the most important point—it is a scientific debate. The case for massive amounts of accelerated human evolution has not been proven in spite of what you might read in The 10,000 Year Explosion and in articles in the popular press.

UPDATE: See Razib's posting: Signals of recent positive selection in a worldwide sample of human populations...maybe

Hawks, J., Wang, E.T., Cochran, G.M., Harpending, H.C., and Moyzis, R.K. (2007) Recent acceleration of human adaptive evolution. Proc. Natl. Acad. Sci. (USA) 104:20753-20758. Epub 2007 [PubMed] [DOI:10.1073/pnas.0707650104]

Pickrell, J.K., Coop, G., Novembre, J., Kudaravalli, S., Li, J.Z., Absher, D., Srinivasan, B.S., Barsh, G.S., Myers, R.M., Feldman, M.W., and Pritchard, J.K. (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Research 23 published in advance March 23, 2009 [DOI: 10.1101/gr.087577.108]

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