We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.

Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births1, but the incidence of CHD is up to ten fold higher in human fetuses2,3. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk4. Here we report findings from a recessive forward genetic screen in fetal mice, showing the cilium and cilia transduced cell signaling play important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia transduced cell signaling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signaling. Surprisingly, many CHD genes encoded interacting proteins, suggesting an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note pathways identified show overlap with CHD candidate genes recovered in CHD patients5, suggesting they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations are sperm archived, creating a rich public resource for human disease modeling.

A novel mutation, mei8, was isolated in a forward genetic screen for infertility mutations induced by chemical mutagenesis of ES cells. Homozygous mutant mice are sterile. Mutant females exhibit ovarian dysgenesis and lack ovarian follicles at reproductive maturity. Affected males have small testes due to arrest of spermatogenesis during meiotic prophase I. Genetic mapping and positional cloning of mei8 led to the identification of a mutation in Rec8, a homolog of the yeast meiosis-specific cohesin gene REC8. Analysis of meiosis in Rec8(mei8)/Rec8(mei8) spermatocytes showed that, while initiation of recombination and synapsis occurs, REC8 is required for the completion and/or maintenance of synapsis, cohesion of sister chromatids, and the formation of chiasmata, as it is in other organisms. However, unlike yeast and Caenorhabditis elegans, localization of REC8 on meiotic chromosomes is not required for the assembly of axial elements.

We report full-length draft De novo genome assemblies for 16 widely used inbred mouse strains and reveal extensive strain-specific haplotype variation. We identify and characterise 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome resulting in the completion of 10 new gene structures and 62 new coding loci were added to the reference genome annotation. Notably these genomes revealed a large previously unannotated gene ( Efcab3-like ) encoding 5,874 amino acids. Efcab3-like mutant mice display anomalies in multiple brain regions suggesting a role in the regulation of brain development.

Ts65Dn is a mouse model of Down syndrome; a syndrome that results from Chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer’s Disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu 1716), with breakpoints that have not been defined previously. To molecularly characterize the Chr 16 and Chr 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput, paired end sequencing approach. Analysis of paired end reads flanking the Chr 16, Chr 17 junction on Mmu1716 and de-novo assembly of the reads directly spanning the junction provided the precise locations of the Chr 16 and Chr 17 breakpoints at 84,351,351 bp and 9,426,822 bp, respectively. These data provide the basis for low cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.