R2d2 drives selfish sweeps in the house mouse

Mitsainas, George/0000-0003-4976-8275; Lindholm, Anna K/0000-0001-8460-9769; Mathias, Maria da Luz/0000-0003-3876-958X; Foerster, Daniel/0000-0002-6934-0404; Hauffe, Heidi Christine C/0000-0003-3098-8964; Threadgill, David W/0000-0003-3538-1635; Gabriel, Sofia I/0000-0003-3702-4631; Chesler, Elissa/0000-0002-5642-5062; Didion, John/0000-0002-8111-6261; solano, emanuela/0000-0001-8482-9243; Weinstock, George/0000-0002-2997-4592; McMullan, Rachel/0000-0003-0297-4549; Holt, James/0000-0001-6411-9236; Rehermann, Barbara/0000-0001-6832-9951 WOS: 000376170300001 PubMed: 26882987 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 (R2d2(HC)) in natural populations. We replicate this finding inmultiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) 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. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32GM067553, F30MH103925, P50GM076468, K01MH094406, DK-076050, DK-056350, AG038070]; National Science FoundationNational Science Foundation (NSF) [IOS-1121273]; Vaadia-BARD Postdoctoral Fellowship AwardUS-Israel Binational Science Foundation [FI-478-13]; U.S. Army Medical Research and Materiel CommandU.S. Army Medical Research & Materiel Command (USAMRMC) [W81XWH-11-1-0762]; Jackson Laboratory new investigator funds; National Center for Scientific Research, France [ISEM 2016-002]; University of Rome "La Sapienza"; Claraz-Stiftung; Natural Environment Research Council (UK)NERC Natural Environment Research Council; EU Human Capital and Mobility Programme [CHRX-CT93-0192]; Foundation for Science and Technology, PortugalPortuguese Foundation for Science and Technology [PTDC/BIA-EVF/116884/2010, UID/AMB/50017/2013]; Spanish "Ministerio de Ciencia y Tecnologia"Spanish Government [CGL2007-62111]; "Ministerio de Economia y Competitividad"Spanish Government [CGL2010-15243]; School of Medicine at University of North Carolina We wish to thank all the scientists and research personnel who collected and processed the samples used in this study. In particular we acknowledge Luanne Peters and Alex Hong-Tsen Yu for providing critical samples; Ryan Buus and T. Justin Gooch for isolating DNA for high-density genotyping of wild-caught mice; and Vicki Cappa, A. Cerveira, Guila Ganem, Ron and Annabelle Lesher, K. Said, Toni Schelts, Dan Small, and J. Tapisso for aiding in mouse trapping. We thank Muriel Davisson at the Jackson Laboratory for maintaining, for several decades, tissue samples from breeding colonies used to generate wild-derived inbred strains. We also thank Francis Collins, Jim Evans, Matthew Hahn, and Corbin Jones for comments on an earlier version of this manuscript. This work was supported by the National Institutes of Health T32GM067553 to J.P.D. and A.P.M., F30MH103925 to A.P.M., P50GM076468 to E.J.C., G.A.C., and F.P.M.V., K01MH094406 to J.J.C., DK-076050 and DK-056350 to D.P., AG038070 to G.A.C, and the intramural research program to B.R. and S.P.R.; National Science Foundation IOS-1121273 to T.G.; Vaadia-BARD Postdoctoral Fellowship Award FI-478-13 to L.Y.; U.S. Army Medical Research and Materiel Command W81XWH-11-1-0762 to C.J.B.; The Jackson Laboratory new investigator funds to E.J.C.; The National Center for Scientific Research, France to J.B.D. (this is contribution no ISEM 2016-002); the University of Rome "La Sapienza" to R.C. and E.S.; Claraz-Stiftung to S.G. and A.L.; Natural Environment Research Council (UK) to M.D.G., H.C.H., and J.B.S.; EU Human Capital and Mobility Programme (CHRX-CT93-0192) to H.C.H. and J.B.S.; Foundation for Science and Technology, Portugal PTDC/BIA-EVF/116884/2010 and UID/AMB/50017/2013 to S.I.G., M.L.M., and J.B.S.; Spanish "Ministerio de Ciencia y Tecnologia" CGL2007-62111 and "Ministerio de Economia y Competitividad" CGL2010-15243 to J.V.;and the Oliver Smithies Investigator funds provided by the School of Medicine at University of North Carolina to F.P.M.V. All data are made available at http://csbio.unc.edu/r2d2/. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to F.P.M.V. (fernando@med.unc.edu).