title: A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2.
abstract: 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 (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.
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: John P
authors: JP
authors: Didion
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Andrew P
authors: AP
authors: Morgan
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Amelia M-F
authors: AM
authors: Clayshulte
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Rachel C
authors: RC
authors: Mcmullan
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Liran
authors: L
authors: Yadgary
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Petko M
authors: PM
authors: Petkov
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Timothy A
authors: TA
authors: Bell
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Daniel M
authors: DM
authors: Gatti
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: James J
authors: JJ
authors: Crowley
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Kunjie
authors: K
authors: Hua
authors: Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: David L
authors: DL
authors: Aylor
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Ling
authors: L
authors: Bai
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Mark
authors: M
authors: Calaway
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Elissa J
authors: EJ
authors: Chesler
authors: National Toxicology Program, National Institute of Environmental Sciences, NIH, Research Triangle Park, North Carolina, United States of America.
authors: John E
authors: JE
authors: French
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Thomas R
authors: TR
authors: Geiger
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Terry J
authors: TJ
authors: Gooch
authors: Department of Biology, University of California Riverside, Riverside, California, United States of America.
authors: Theodore
authors: T
authors: Garland
authors: Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Alison H
authors: AH
authors: Harrill
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Kent
authors: K
authors: Hunter
authors: Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Leonard
authors: L
authors: McMillan
authors: Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Matt
authors: M
authors: Holt
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Darla R
authors: DR
authors: Miller
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Deborah A
authors: DA
authors: O'Brien
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Kenneth
authors: K
authors: Paigen
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Wenqi
authors: W
authors: Pan
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Lucy B
authors: LB
authors: Rowe
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Ginger D
authors: GD
authors: Shaw
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Petr
authors: P
authors: Simecek
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Patrick F
authors: PF
authors: Sullivan
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Karen L
authors: KL
authors: Svenson
authors: Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, United States of America.
authors: George M
authors: GM
authors: Weinstock
authors: Department of Veterinary Pathobiology and Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, United States of America.
authors: David W
authors: DW
authors: Threadgill
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Daniel
authors: D
authors: Pomp
authors: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors: Gary A
authors: GA
authors: Churchill
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Fernando
authors: F
authors: Pardo-Manuel de Villena
mesh_terms: D000483:Alleles; D000818:Animals; D002875:Chromosomes / Q000235:genetics; D003433:Crosses, Genetic; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D023281:Genomics; D060005:Genotyping Techniques; D006239:Haplotypes / Q000235:genetics; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D009154:Mutation