The evolutionary fates of a large segmental duplication in mouse

Abstract

Gene duplication and loss are major sources of genetic polymorphism in populations, and are important forces shaping the evolution of genome content and organization. We have reconstructed the origin and history of a 127 kbp segmental duplication, R2d, in the house mouse (Mus musculus). R2d contains a single protein-coding gene, Cwc22. De novo assembly of both the ancestral (R2d1) and the derived (R2d2) copies reveals that they have been subject to non-allelic gene conversion events spanning tens of kilobases. R2d2 is also a hotspot for structural variation: its diploid copy number ranges from zero in the mouse reference genome to more than 80 in wild mice sampled from around the globe. Hemizgyosity for high-copy-number alleles of R2d2 is associated in cis with meiotic drive, suppression of meiotic crossovers, and copy-number instability, with a mutation rate in excess of 1 per 100 transmissions in laboratory populations. We identify an additional 57 loci covering 0.8% of the mouse genome with patterns of sequence variation similar to those at R2d1 and R2d2. Our results provide a striking example of allelic diversity generated by duplication and demonstrate the value of de novo assembly in a phylogenetic context for understanding the mutational processes affecting duplicate genes.

Sequence and structural diversity of mouse Y chromosomes

“…Because the pedigree of each CC line is known, mutation rates — for each Y haplogroup, and overall — can be estimated directly, assuming each new allele corresponds to a single mutational event. Our estimate of 0.30 (95% Poisson CI 0.098 − 0.70) mutations per 100 father-son transmissions is about tenfold higher than ampliconic regions of the human Y chromosome (Repping et al 2006), and places the mouse Yq among the most labile sequences known in mouse or human (Egan et al 2007; Itsara et al 2010; Morgan et al 2016b). New Yq alleles also provide opportunities to investigate the effects of Yq copy number on fertility, sperm phenotypes and sex ratio (as in, among others, Styrna et al (1991); Touré et al (2004); Yamauchi et al (2010); Cocquet et al (2012); Fischer et al (2016)).…”

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross

“…Lines that overcame this bottleneck had either lower contribution of CAST/EiJ and PWK/PhJ genome-wide by chance, or were able to purge these alleles before the line became inbred. Selection in the autosomes was not restricted to a few loci with major effects because the only consistent transmission ration distortion (TRD) observed was the overrepresentation of WSB/EiJ on chromosome 2, now known to be due to responder to meiotic drive 2 (R2d2) (Didion et al 2015(Didion et al , 2016Morgan et al 2016b). TRD at R2d2 was present in the DO and drove an almost complete selfish sweep without an increase in infertility (Chesler et al 2016).…”

Mouse protein coding diversity: What’s left to discover?

“…In 2015, an analysis of 351 high-density microarray data for mouse tail samples highlighted 9,634 putative autosomal CNVs affecting 6.87% of the mouse genome [20]. In 2016, Morgan and colleagues performed a genome-wide subsequence diversity test in seven mouse strains and two wild mice samples and reported at least 0.8% of the mouse genome is a ‘genomic revolving door’ with high mutation and recombination rates [21]. In 2018, the first draft de novo assemblies of 16 mouse strains successfully assembled some of these regions, reporting a total of 2,567 SSDRs that encompass 0.5%–2.8% of the mouse genome (Fig 2A and S1 Data), encoding 1,828 coding genes.…”

“…Locke and colleagues [20] identified genome regions with high copy number variation calls in 351 different mouse strains and wild-caught mice (yellow). Morgan and colleagues [21] used a combination of wild and inbred mouse strains to define copy number variable regions (orange). Lilue and colleagues [16] used de novo assembly of 16 mouse strains (red).…”