IDEAS home Printed from https://ideas.repec.org/a/plo/pgen00/1002326.html
   My bibliography  Save this article

Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome

Author

Listed:
  • Kirk E Lohmueller
  • Anders Albrechtsen
  • Yingrui Li
  • Su Yeon Kim
  • Thorfinn Korneliussen
  • Nicolas Vinckenbosch
  • Geng Tian
  • Emilia Huerta-Sanchez
  • Alison F Feder
  • Niels Grarup
  • Torben Jørgensen
  • Tao Jiang
  • Daniel R Witte
  • Annelli Sandbæk
  • Ines Hellmann
  • Torsten Lauritzen
  • Torben Hansen
  • Oluf Pedersen
  • Jun Wang
  • Rasmus Nielsen

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.

Suggested Citation

  • Kirk E Lohmueller & Anders Albrechtsen & Yingrui Li & Su Yeon Kim & Thorfinn Korneliussen & Nicolas Vinckenbosch & Geng Tian & Emilia Huerta-Sanchez & Alison F Feder & Niels Grarup & Torben Jørgensen , 2011. "Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome," PLOS Genetics, Public Library of Science, vol. 7(10), pages 1-15, October.
  • Handle: RePEc:plo:pgen00:1002326
    DOI: 10.1371/journal.pgen.1002326
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002326
    Download Restriction: no

    File URL: https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002326&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pgen.1002326?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kirk E. Lohmueller & Amit R. Indap & Steffen Schmidt & Adam R. Boyko & Ryan D. Hernandez & Melissa J. Hubisz & John J. Sninsky & Thomas J. White & Shamil R. Sunyaev & Rasmus Nielsen & Andrew G. Clark , 2008. "Proportionally more deleterious genetic variation in European than in African populations," Nature, Nature, vol. 451(7181), pages 994-997, February.
    2. Kun Tang & Kevin R Thornton & Mark Stoneking, 2007. "A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome," PLOS Biology, Public Library of Science, vol. 5(7), pages 1-16, June.
    3. Joshua M Akey & Michael A Eberle & Mark J Rieder & Christopher S Carlson & Mark D Shriver & Deborah A Nickerson & Leonid Kruglyak, 2004. "Population History and Natural Selection Shape Patterns of Genetic Variation in 132 Genes," PLOS Biology, Public Library of Science, vol. 2(10), pages 1-1, September.
    4. Ryan N Gutenkunst & Ryan D Hernandez & Scott H Williamson & Carlos D Bustamante, 2009. "Inferring the Joint Demographic History of Multiple Populations from Multidimensional SNP Frequency Data," PLOS Genetics, Public Library of Science, vol. 5(10), pages 1-11, October.
    5. Pardis C. Sabeti & Patrick Varilly & Ben Fry & Jason Lohmueller & Elizabeth Hostetter & Chris Cotsapas & Xiaohui Xie & Elizabeth H. Byrne & Steven A. McCarroll & Rachelle Gaudet & Stephen F. Schaffner, 2007. "Genome-wide detection and characterization of positive selection in human populations," Nature, Nature, vol. 449(7164), pages 913-918, October.
    6. David A. Wheeler & Maithreyan Srinivasan & Michael Egholm & Yufeng Shen & Lei Chen & Amy McGuire & Wen He & Yi-Ju Chen & Vinod Makhijani & G. Thomas Roth & Xavier Gomes & Karrie Tartaro & Faheem Niazi, 2008. "The complete genome of an individual by massively parallel DNA sequencing," Nature, Nature, vol. 452(7189), pages 872-876, April.
    7. Augustine Kong & Gudmar Thorleifsson & Daniel F. Gudbjartsson & Gisli Masson & Asgeir Sigurdsson & Aslaug Jonasdottir & G. Bragi Walters & Adalbjorg Jonasdottir & Arnaldur Gylfason & Kari Th. Kristins, 2010. "Fine-scale recombination rate differences between sexes, populations and individuals," Nature, Nature, vol. 467(7319), pages 1099-1103, October.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Benjamin H Good & Aleksandra M Walczak & Richard A Neher & Michael M Desai, 2014. "Genetic Diversity in the Interference Selection Limit," PLOS Genetics, Public Library of Science, vol. 10(3), pages 1-1, March.
    2. Raul Torres & Zachary A Szpiech & Ryan D Hernandez, 2018. "Human demographic history has amplified the effects of background selection across the genome," PLOS Genetics, Public Library of Science, vol. 14(6), pages 1-27, June.
    3. Kelley Harris & Rasmus Nielsen, 2013. "Inferring Demographic History from a Spectrum of Shared Haplotype Lengths," PLOS Genetics, Public Library of Science, vol. 9(6), pages 1-20, June.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sol Katzman & Andrew D Kern & Katherine S Pollard & Sofie R Salama & David Haussler, 2010. "GC-Biased Evolution Near Human Accelerated Regions," PLOS Genetics, Public Library of Science, vol. 6(5), pages 1-13, May.
    2. Lauren A. Choate & Gilad Barshad & Pierce W. McMahon & Iskander Said & Edward J. Rice & Paul R. Munn & James J. Lewis & Charles G. Danko, 2021. "Multiple stages of evolutionary change in anthrax toxin receptor expression in humans," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Guillaume Laval & Etienne Patin & Luis B Barreiro & Lluís Quintana-Murci, 2010. "Formulating a Historical and Demographic Model of Recent Human Evolution Based on Resequencing Data from Noncoding Regions," PLOS ONE, Public Library of Science, vol. 5(4), pages 1-15, April.
    4. Raul Torres & Zachary A Szpiech & Ryan D Hernandez, 2018. "Human demographic history has amplified the effects of background selection across the genome," PLOS Genetics, Public Library of Science, vol. 14(6), pages 1-27, June.
    5. Ryan N Gutenkunst & Ryan D Hernandez & Scott H Williamson & Carlos D Bustamante, 2009. "Inferring the Joint Demographic History of Multiple Populations from Multidimensional SNP Frequency Data," PLOS Genetics, Public Library of Science, vol. 5(10), pages 1-11, October.
    6. Andrew H Chan & Paul A Jenkins & Yun S Song, 2012. "Genome-Wide Fine-Scale Recombination Rate Variation in Drosophila melanogaster," PLOS Genetics, Public Library of Science, vol. 8(12), pages 1-28, December.
    7. Julian Petersen & Lukas Englmaier & Artem V. Artemov & Irina Poverennaya & Ruba Mahmoud & Thibault Bouderlique & Marketa Tesarova & Ruslan Deviatiiarov & Anett Szilvásy-Szabó & Evgeny E. Akkuratov & D, 2023. "A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    8. Felix M Key & Benjamin Peter & Megan Y Dennis & Emilia Huerta-Sánchez & Wei Tang & Ludmila Prokunina-Olsson & Rasmus Nielsen & Aida M Andrés, 2014. "Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 (IFNL4)," PLOS Genetics, Public Library of Science, vol. 10(10), pages 1-12, October.
    9. Pei-Kuan Cong & Wei-Yang Bai & Jin-Chen Li & Meng-Yuan Yang & Saber Khederzadeh & Si-Rui Gai & Nan Li & Yu-Heng Liu & Shi-Hui Yu & Wei-Wei Zhao & Jun-Quan Liu & Yi Sun & Xiao-Wei Zhu & Pian-Pian Zhao , 2022. "Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Aurélien Tellier & Peter Pfaffelhuber & Bernhard Haubold & Lisha Naduvilezhath & Laura E Rose & Thomas Städler & Wolfgang Stephan & Dirk Metzler, 2011. "Estimating Parameters of Speciation Models Based on Refined Summaries of the Joint Site-Frequency Spectrum," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-13, May.
    11. Magnus Nordborg & Tina T Hu & Yoko Ishino & Jinal Jhaveri & Christopher Toomajian & Honggang Zheng & Erica Bakker & Peter Calabrese & Jean Gladstone & Rana Goyal & Mattias Jakobsson & Sung Kim & Yuri , 2005. "The Pattern of Polymorphism in Arabidopsis thaliana," PLOS Biology, Public Library of Science, vol. 3(7), pages 1-1, May.
    12. Melissa J Hubisz & Amy L Williams & Adam Siepel, 2020. "Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph," PLOS Genetics, Public Library of Science, vol. 16(8), pages 1-24, August.
    13. Sergio F. Nigenda-Morales & Meixi Lin & Paulina G. Nuñez-Valencia & Christopher C. Kyriazis & Annabel C. Beichman & Jacqueline A. Robinson & Aaron P. Ragsdale & Jorge Urbán R. & Frederick I. Archer & , 2023. "The genomic footprint of whaling and isolation in fin whale populations," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Carlos Eduardo G Amorim & Ziyue Gao & Zachary Baker & José Francisco Diesel & Yuval B Simons & Imran S Haque & Joseph Pickrell & Molly Przeworski, 2017. "The population genetics of human disease: The case of recessive, lethal mutations," PLOS Genetics, Public Library of Science, vol. 13(9), pages 1-23, September.
    15. Chen, Hua & Hey, Jody & Slatkin, Montgomery, 2015. "A hidden Markov model for investigating recent positive selection through haplotype structure," Theoretical Population Biology, Elsevier, vol. 99(C), pages 18-30.
    16. Richard Jiang & Prashant Singh & Fredrik Wrede & Andreas Hellander & Linda Petzold, 2022. "Identification of dynamic mass-action biochemical reaction networks using sparse Bayesian methods," PLOS Computational Biology, Public Library of Science, vol. 18(1), pages 1-21, January.
    17. Benjamin F Voight & Sridhar Kudaravalli & Xiaoquan Wen & Jonathan K Pritchard, 2006. "A Map of Recent Positive Selection in the Human Genome," PLOS Biology, Public Library of Science, vol. 4(3), pages 1-1, March.
    18. Mohammad Hossein Olyaee & Alireza Khanteymoori & Khosrow Khalifeh, 2020. "A chaotic viewpoint-based approach to solve haplotype assembly using hypergraph model," PLOS ONE, Public Library of Science, vol. 15(10), pages 1-19, October.
    19. Michael DeGiorgio & Zachary A Szpiech, 2022. "A spatially aware likelihood test to detect sweeps from haplotype distributions," PLOS Genetics, Public Library of Science, vol. 18(4), pages 1-37, April.
    20. Jiang Du & Robert D Bjornson & Zhengdong D Zhang & Yong Kong & Michael Snyder & Mark B Gerstein, 2009. "Integrating Sequencing Technologies in Personal Genomics: Optimal Low Cost Reconstruction of Structural Variants," PLOS Computational Biology, Public Library of Science, vol. 5(7), pages 1-15, July.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pgen00:1002326. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosgenetics (email available below). General contact details of provider: https://journals.plos.org/plosgenetics/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.