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.