Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome
Kirk E. Lohmueller1*, Anders Albrechtsen2,Yingrui Li3, Su Yeon Kim4, Thorfinn Korneliussen2, Nicolas Vinckenbosch1, Geng Tian5,6, Emilia Huerta-Sanchez4, Alison F. Feder1,7, Niels Grarup8,9, Torben Jørgensen10,11, Tao Jiang3, Daniel R. Witte12, Annelli Sandbæk13, Ines Hellmann14, Torsten Lauritzen13, Torben Hansen8,9,15, Oluf Pedersen8,9,16,17#, Jun Wang2,3,8#, Rasmus Nielsen1,2,3,4#
1 Department of Integrative Biology, University of California Berkeley, Berkeley, California, United States of America, 2Department of Biology, University of Copenhagen, Copenhagen, Denmark, 3 BGI-Shenzhen, Shenzhen, China, 4 Department of Statistics, University of California Berkeley, Berkeley, California, United States of America, 5 Beijing Institute of Genomics, Chinese Academy of Science, Beijing, China, 6 The Graduate University of Chinese Academy of Sciences, Beijing, China, 7 University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 8 The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 9 Hagedorn Research Institute, Gentofte, Denmark, 10 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark, 11 Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 12 Steno Diabetes Center, Gentofte, Denmark, 13 Department of General Practice, University of Aarhus, Aarhus, Denmark, 14 Department of Mathematics, University of Vienna, Vienna, Austria, 15 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, 16 Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 17 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
Abstract
A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.
Author Summary
While researchers have identified candidate genes that have evolved under positive Darwinian natural selection, less is known about how much of the human genome has been affected by natural selection or whether positive selection has had a greater role at shaping patterns of variation across the human genome than negative selection acting against deleterious mutations. To address these questions, we have combined patterns of genetic variation in three genome-wide resequencing datasets with population genetic models of natural selection. We find that genetic diversity and average minor allele frequency are reduced in regions of the genome with low recombination rate. Additionally, genetic diversity, human-chimp divergence, and average minor allele frequency have been reduced near genes. Overall, while we cannot exclude positive selection at a fraction of mutations, models that include many weakly deleterious mutations throughout the human genome better explain multiple aspects of the genome-wide resequencing data. This work points to negative selection as an important force for shaping patterns of variation and suggests that there are many weakly deleterious mutations at both coding and noncoding sites throughout the human genome. Understanding such mutations will be important for learning about human evolution and the genetic basis of common disease.
Citation: Lohmueller KE, Albrechtsen A, Li Y, Kim SY, Korneliussen T, et al. (2011) Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome. PLoS Genet 7(10): e1002326. doi:10.1371/journal.pgen.1002326
Editor: Joshua M. Akey, University of Washington, United States of America
Received: February 3, 2011; Accepted: August 16, 2011; Published: October 13, 2011
Copyright: © 2011 Lohmueller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded by Lundbeck Foundation and produced by The Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention, and Care (www.LuCAMP.org). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). KEL was supported by a Ruth Kirschstein National Research Service Award from the National Human Genome Research Institute (F32HG005308) and a Miller Research Fellowship from the Miller Research Institute at UC Berkeley. E Huerta-Sanchez was supported by a National Science Foundation Minority Postdoctoral Research Fellowship (DBI-0906065). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: k.lohmueller@berkeley.edu
# These authors contributed equally to this work.
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