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

<div><p>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, <i>R2d</i>) emerged as the strongest candidate for the causative allele. We mapped <i>R2d</i> sequences to two loci within the candidate interval. <i>R2d1</i> is located near the proximal boundary, and contains a single copy of <i>R2d</i> in all strains tested. <i>R2d2</i> maps to a 900 kb interval, and the number of <i>R2d</i> 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 (<i>R2d2^WSBdel1</i>) that eliminates the majority of the <i>R2d2^WSB</i> copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for <i>R2d2^WSBdel1</i>, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for <i>R2d2^WSBdel1</i>, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in <i>R2d2^WSB</i> 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 <i>R2d2^WSB</i> 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.</p>