A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2

February A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2 John P. Didion 0 1 2 Andrew P. Morgan 0 1 2 Amelia M.-F. Clayshulte 0 1 2 Rachel C. Mcmullan 0 1 2 Liran Yadgary 0 1 2 Petko M. Petkov 0 1 2 Timothy A. Bell 0 1 2 Daniel M. Gatti 0 1 2 James J. Crowley 0 1 2 Kunjie Hua 0 1 2 David L. Aylor 0 1 2 Ling Bai 0 1 2 Mark Calaway 0 1 2 Elissa J. Chesler 0 1 2 John E. French 0 1 2 Thomas R. Geiger 0 1 2 Terry J. Gooch 0 1 2 Theodore Garland Jr. 0 1 2 Alison H. Harrill 0 1 2 Kent Hunter 0 1 2 Leonard McMillan 0 1 2 Matt Holt 0 1 2 Darla R. Miller 0 1 2 Deborah A. O'Brien 0 1 2 Kenneth Paigen 0 1 2 Wenqi Pan 0 1 2 Lucy B. Rowe 0 1 2 Ginger D. Shaw 0 1 2 Petr Simecek 0 1 2 Patrick F. Sullivan 0 1 2 Karen L. Svenson 0 1 2 George M. Weinstock 0 1 2 David W. Threadgill 0 1 2 Daniel Pomp 0 1 2 Gary A. Churchill 0 1 2 Fernando Pardo-Manuel de Villena 0 1 2 0 1 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 3 Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 4 The Jackson Laboratory, Bar Harbor, Maine, United States of America, 5 Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 6 Department of Biological Sciences, North Carolina State University , Raleigh , North Carolina, United States of America, 7 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda , Maryland, United States of America, 8 National Toxicology Program, National Institute of Environmental Sciences, NIH, Research Triangle Park, North Carolina, United States of America, 9 Department of Biology, University of California Riverside, Riverside, California, United States of America, 10 Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences , Little Rock , Arkansas, United States of America, 11 Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 12 Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, United States of America, 13 Department of Veterinary Pathobiology and Department of Molecular and Cellular Medicine, Texas A&M University, College Station , Texas , United States of America 1 Funding: We acknowledge grants National Institute of General Medical Sciences/National Institutes of Health GM076468 and GM078452 (PMP); National Institute of General Medical Sciences/National Institutes of Health 2 P50GM076468-06 (EJC , GAC); National Institute of Mental Health/National Institutes of Health K01MH094406 (JJC); The National Institute of Diabetes and Digestive and Kidney Diseases/ National Institutes of Health RC1DK087510 (DWT, AHH); National Cancer Institute/National Institutes of 2 Editor: Bret A. Payseur, University of Wisconsin- Madison, UNITED STATES Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation - Health ZIA BC011255 (KHun); National Institute of Child Health and Human Development/National Institutes of Health R01HD065024 (DAO, FPMdV); NHGRI/National Institutes of Health R01 HG00941 (LBR); National Cancer Institute/National Institutes of Health U01CA105417 (DWT, DP); National Cancer Institute/National Institutes of Health R01CA079869 (DWT); National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health DK056350 (DP); National Cancer Institute/National Institutes of Health RC1 CA145504-02 (GAC); National Institute of Mental Health/National Institutes of Health 1R21 MH096261-01 (FPMdV); National Institute of Mental Health/National Institutes of Health 1F30 MH103925 (APM); National Human Genome Research Institute/National Institutes of Health 1U54 HG004968 (GMW); National Human Genome Research Institute/National Institutes of Health (funded the JAX interspecific backcross panels); the National Science Foundation IOS-1121273 (TG). This research was supported also by Vaadia-BARD Postdoctoral Fellowship Award No. FI-478-13 from BARD, The United States - Israel Binational Agricultural Research and Development Fund (LY). 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. (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system. One of the strongest expectations in genetics is that chromosomes segregate randomly during meiosis. However, genetic loci that exhibit transmission ratio distortion (TRD) are sometimes observed in offspring of F1 hybrids. Meiotic drive is a type of non-Mendelian inheritance in which a selfish genetic element exploits asymmetric female meiotic cell division to promote its preferential inclusion in ova. We previously reported TR (...truncated)