@article {53, title = {Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies.}, journal = {Elife}, volume = {8}, year = {2019}, month = {2019 Mar 21}, abstract = {

Genetic predictions of height differ among human populations and these differences have been interpreted as evidence of polygenic adaptation. These differences were first detected using SNPs genome-wide significantly associated with height, and shown to grow stronger when large numbers of sub-significant SNPs were included, leading to excitement about the prospect of analyzing large fractions of the genome to detect polygenic adaptation for multiple traits. Previous studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the analyses in the UK Biobank, a much more homogeneously designed study. We show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population stratification. More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor{\textquoteright}s assessment is that all the issues have been addressed (see decision letter).

}, issn = {2050-084X}, doi = {10.7554/eLife.39702}, author = {Sohail, Mashaal and Maier, Robert M and Ganna, Andrea and Bloemendal, Alex and Martin, Alicia R and Turchin, Michael C and Chiang, Charleston Wk and Hirschhorn, Joel and Daly, Mark J and Patterson, Nick and Neale, Benjamin and Mathieson, Iain and Reich, David and Sunyaev, Shamil R} } @article {13, title = {Negative selection in humans and fruit flies involves synergistic epistasis.}, journal = {Science}, volume = {356}, year = {2017}, month = {2017 May 05}, pages = {539-542}, abstract = {

Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

}, keywords = {Alleles, Animals, Drosophila melanogaster, Epistasis, Genetic, Genetic Fitness, Genome, Human, Genome, Insect, Humans, Linkage Disequilibrium, Mutation Rate, Mutation, Missense, Selection, Genetic}, issn = {1095-9203}, doi = {10.1126/science.aah5238}, author = {Sohail, Mashaal and Vakhrusheva, Olga A and Sul, Jae Hoon and Pulit, Sara L and Francioli, Laurent C and van den Berg, Leonard H and Veldink, Jan H and de Bakker, Paul I W and Bazykin, Georgii A and Kondrashov, Alexey S and Sunyaev, Shamil R} }