Crespi on rare variants in expanding populations

Three new articles in Science provide a dramatic detailed picture of how selection acts on rare variants in expanding populations.  In the below post, Bernard Crespi draws out the implications for personalized medicine.

An expanding population grows on a double-edged population-genetic sword.  On one edge, we have increasing scope for beneficial mutations, because more people means a larger number of genome targets for rare, good mutations, and less chance of early loss by drift.  This process of accelerating positive selection in a growing population has been documented by Hawks et al. (2007). So far, so good.

On the other edge, new, rare variants, most of which should be deleterious, are less likely to be lost in a growing population, so they accumulate until purifying  selection manages to remove them, which can take many scores of generations.  This process, of myriad rare variants accruing within genomes as a population swells, has now been documented in a trio of studies, all (curiously) published within the past week in Science (Keinan and Clark 2012, Nelson et al. 2012; Tennesen et al. 2012).  The latter studies have also inferred, from amino acid variant frequencies and algorithms that seek to predict functionality of amino acid variants, that a substantial proportion of the rare variants are probably deleterious, and may thus contribute to polygenic disease risks.

Has the ‘missing’ heritability of complex, polygenic diseases – multitudinous rare, deleterious variants, many of them specific to a single individual, and a single population – finally been found?  Perhaps, and perhaps not.  We require validation that such rare variants are indeed bad enough to contribute substantially to polygenic disease – and there’s the rub.  When variants are so rare, or even unique, generating evidence on functionality – good, or bad and disease linked – becomes extremely challenging statistically and logistically.   Huge samples, and more pedigree-based studies, may help.  But gene-based medicine may, if ultra-rare and unique variants are truly important, and complex at all in their effects, become so personalized that abilities to predict, and use our shiny new genomic information to help understand and fight disease, vaporizes in a swirling cloud of Darwinian variation-with-a-vengeance.

Whatever the answers, understanding human disease genetics has now been shown to depend critically on our expanding population structure, and our population subdivision from culture to tribe, family to self.   What’s missing now?  The forces and phenotypic targets of positive and purifying selection that have surfed and shaped our demographic tsunami, and how they – the forces of evolution – are associated with risks of polygenic disease.

Hawks J, Wang ET, Cochran GM, Harpending HC, Moyzis RK. Recent acceleration of human adaptive evolution. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20753-8.

Keinan A, Clark AG. Recent explosive human population growth has resulted in an excess of rare genetic variants. Science. 2012 May 11;336(6082):740-3.

Nelson MR, Wegmann D, Ehm MG, Kessner D, St Jean P, Verzilli C, Shen J, Tang Z, Bacanu SA, Fraser D, Warren L, Aponte J, Zawistowski M, Liu X, Zhang H, Zhang Y, Li J, Li Y, Li L, Woollard P, Topp S, Hall MD, Nangle K, Wang J, Abecasis G, Cardon LR, Zöllner S, Whittaker JC, Chissoe SL, Novembre J, Mooser V. An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People. Science. 2012 May 17. [Epub ahead of print]

Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM; Broad GO; Seattle GO; on behalf of the NHLBI Exome Sequencing Project. Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes.  Science. 2012 May 17. [Epub ahead of print]