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.

Divergence patterns of genic copy number variation in natural populations of the house mouse (Mus musculus domesticus) reveal three conserved genes with major population-specific expansions

“…Therefore, an initial increase in copy number could lead to the rapid propagation of even more copies within a population when the segregation distortion favors its own transmission of alleles with a larger number of copies. However, it remains unclear which molecular processes would cause this phenomenon and why Cwc22 expansion has only been found in one population to date (our study) and in association with particular genetic backgrounds (Didion et al 2015).…”

“…The high copy number variation of Cwc22 was also shown to correlate with variability in H3K4me3 methylation marks and the expression of the gene in the livers of wild mice (Börsch-Haubold et al 2014). Intriguingly, an expansion of Cwc22 has been implicated in a segregation distortion effect in heterozygous female mice (Didion et al 2015). Therefore, an initial increase in copy number could lead to the rapid propagation of even more copies within a population when the segregation distortion favors its own transmission of alleles with a larger number of copies.…”

Genetics of Rapid and Extreme Size Evolution in Island Mice

“…A region on chromosome 2 shows remarkable transmission ratio distortion in favor of the WSB allele (allele frequency = 0.65; peak marker located at 79.6 Mb) in F 2 's descended from one GI line but not the other ( Figure S6). Biased transmission of the WSB allele in this interval is also observed in the Collaborative Cross (Aylor et al 2011) and seems to be generated by maternal meiotic drive (Didion et al 2015). …”

Spindle asymmetry drives non-Mendelian chromosome segregation

“…The asymmetry in cell fate is well established (6), and chromosomal rearrangements and amplifications of repetitive sequences (e.g., centromeres) are associated with biased segregation (7)(8)(9)(10). Asymmetry within the meiotic spindle was noted in grasshopper in 1976 (11), but not studied further, and molecular mechanisms regulating such asymmetry are unknown.…”