Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes

Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, weidentified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 and 6 million yr ago, but that are absent in the Hominidae. Hominidae show between four- and sevenfold lower rates of nucleotide change and feature turnover in both neutral and functional sequences, suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. Recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli, which resulted in thousands of novel, species-specific CTCF binding sites. Our results show that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology.

This project was supported by the Wellcome Trust (grant numbers WT108749/Z/15/Z, WT098051, WT202878/Z/16/Z, and WT202878/B/16/Z), the National Human Genome Research Institute (U41HG007234), Cancer Research UK (20412), the European Research Council (615584), the Biotechnology and Biological Sciences Research Council (BB/N02317X/a), and the European Molecular Biology Laboratory. The research leading to these results has received funding from the European Community’s Seventh FrameworkProgramme(FP7/2010-2014)undergrant agreement244356(NextGen)andfromtheEuropeanUnion’sSeventh Framework Programme (FP7/2007–2013) under grant agreement HEALTH-F4-2010-241504 (EURATRANS). We thank the genomics, bioinformatics, and BRU cores at the CRUK Cambridge Institute for technical support, the sequencing facilities at the Wellcome Sanger Institute, and computational support from EMBL-EBI and WSI as well as the Conservatoire Génétique de la Souris Sauvage (ISEM, France) and Plateforme Cytogénomique évolutive of the LabEx CeMEB.WealsothankBeeLingN, Beiyuan Fu, Sandra Louzada, and Mark Simmonds for assistance in chromosome sorting, chromosome painting, and array painting.