R2d2 Drives Selfish Sweeps in the House Mouse

May 2016

A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether “selfish” genes are capable of fixation—thereby leaving signatures identical to classical selective sweeps—despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2HC) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2HC is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

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R2d2 Drives Selfish Sweeps in the House Mouse

R2d2 Drives Selfish Sweeps in the House Mouse John P. Didion,†,1,2,3* Andrew P. Morgan,†,1,2,3 Liran Yadgary,1,2,3 Timothy A. Bell,1,2,3 Rachel C. McMullan,1,2,3 Lydia Ortiz de Solorzano,1,2,3 Janice Britton-Davidian,4 Carol J. Bult,5 Karl J. Campbell,6,7 Riccardo Castiglia,8 Yung-Hao Ching,9 Amanda J. Chunco,10 James J. Crowley,1 Elissa J. Chesler,5 Daniel W. F€ orster,11 John E. French,12 Sofia I. Gabriel,13 Daniel M. Gatti,5 14 Theodore Garland Jr, Eva B. Giagia-Athanasopoulou,15 Mabel D. Gimenez,16 Sofia A. Grize,17 _Islam G€ und€ uz,18 Andrew Holmes,19 Heidi C. Hauffe,20 Jeremy S. Herman,21 James M. Holt,22 Kunjie Hua,1 Wesley J. Jolley,23 Anna K. Lindholm,17 Marıa J. L opez-Fuster,24 George Mitsainas,15 Maria da Luz Mathias,13 Leonard McMillan,22 Maria da Graça Morgado Ramalhinho,13 Barbara Rehermann,25 Stephan P. Rosshart,25 Jeremy B. Searle,26 Meng-Shin Shiao,27 Emanuela Solano,8 Karen L. Svenson,5 Patricia Thomas-Laemont,10 David W. Threadgill,28,29 Jacint Ventura,30 George M. Weinstock,31 Daniel Pomp,1,3 Gary A. Churchill,5 and Fernando Pardo-Manuel de Villena*,1,2,3 1 Department of Genetics, The University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill 3 Carolina Center for Genome Science, The University of North Carolina at Chapel Hill 4 Institut des Sciences de l’Evolution, Universite De Montpellier, CNRS, IRD, EPHE, Montpellier, France 5 The Jackson Laboratory, Bar Harbor, ME 6 Island Conservation, Puerto Ayora, Galapagos Island, Ecuador 7 School of Geography, Planning & Environmental Management, The University of Queensland, St Lucia, QLD, Australia 8 Department of Biology and Biotechnologies “Charles Darwin”, University of Rome “La Sapienza”, Rome, Italy 9 Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien City, Taiwan 10 Department of Environmental Studies, Elon University 11 Department of Evolutionary Genetics, Leibniz-Institute for Zoo and Wildlife Research, Berlin, Germany 12 National Toxicology Program, National Institute of Environmental Sciences, NIH, Research Triangle Park, NC 13 Department of Animal Biology & CESAM - Centre for Environmental and Marine Studies, Faculty of Sciences, University of Lisbon, Lisboa, Portugal 14 Department of Biology, University of California Riverside 15 Section of Animal Biology, Department of Biology, University of Patras, Patras, Greece 16 Instituto de Biologıa Subtropical, CONICET - Universidad Nacional de Misiones, Posadas, Misiones, Argentina 17 Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland 18 Department of Biology, Faculty of Arts and Sciences, University of Ondokuz Mayis, Samsun, Turkey 19 Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20 Department of Biodiversity and Molecular Ecology, Research and Innovation Centre, Fondazione Edmund Mach, San Michele All’adige, TN, Italy 21 Department of Natural Sciences, National Museums Scotland, Edinburgh, United Kingdom 22 Department of Computer Science, The University of North Carolina at Chapel Hill 23 Island Conservation, Santa Cruz, CA 24 Faculty of Biology, Universitat de Barcelona, Barcelona, Spain 25 Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 26 Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 27 Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 28 Department of Veterinary Pathobiology, Texas A&M University, College Station 29 Department of Molecular and Cellular Medicine, Texas A&M University, College Station 30 Departament de Biologia Animal, de Biologia Vegetal y de Ecologia, Facultat de Biociències, Universitat Autonoma de Barcelona, Barcelona, Spain 31 Jackson Laboratory for Genomic Medicine, Farmington, CT † These authors contributed equally to this work *Corresponding author: E-mail: . Associate editor: Matthew Hahn 2 1381 Fast Track Mol. Biol. Evol. 33(6):1381–1395 doi:10.1093/molbev/msw036 Advance Access publication February 15, 2016 Article Open Access ß The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact MBE Didion et al. . doi:10.1093/molbev/msw036 Abstract A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether “selfish” genes are capable of fixation—thereby leaving signatures identical to classical selective sweeps—despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2HC) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2HC is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution. Key words: R2d2, Meiotic Drive, Selfish Genes, Selective Sweep, House Mouse. Population-level sequencing data have enabled analyses of positive selection in many species, including mice (Staubach et al. 2012) and humans (Williamson et al. 2007; Grossman et al. 2013; Colonna et al. 2014). These studies seek to identify genetic elements, such as single nucleotide variants and copy number variants, that are associated with phenotypic differences between populations that share a common origin (Fu and Akey 2013 (...truncated)


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John P. Didion, Andrew P. Morgan, Liran Yadgary, Timothy A. Bell, Rachel C. McMullan, Lydia Ortiz de Solorzano, Janice Britton-Davidian, Carol J. Bult, Karl J. Campbell, Riccardo Castiglia, Yung-Hao Ching, Amanda J. Chunco, James J. Crowley, Elissa J. Chesler, Daniel W. Förster, John E. French, Sofia I. Gabriel, Daniel M. Gatti, Theodore Garland Jr, Eva B. Giagia-Athanasopoulou, Mabel D. Giménez, Sofia A. Grize, İslam Gündüz, Andrew Holmes, Heidi C. Hauffe, Jeremy S. Herman, James M. Holt, Kunjie Hua, Wesley J. Jolley, Anna K. Lindholm, María J. López-Fuster, George Mitsainas, Maria da Luz Mathias, Leonard McMillan, Maria da Graça Morgado Ramalhinho, Barbara Rehermann, Stephan P. Rosshart, Jeremy B. Searle, Meng-Shin Shiao, Emanuela Solano, Karen L. Svenson, Patricia Thomas-Laemont, David W. Threadgill, Jacint Ventura, George M. Weinstock, Daniel Pomp, Gary A. Churchill, Fernando Pardo-Manuel de Villena. R2d2 Drives Selfish Sweeps in the House Mouse, 2016, pp. 1381-1395, 33/6, DOI: 10.1093/molbev/msw036