Status and access to the Collaborative Cross population.

The Collaborative Cross (CC) is a panel of recombinant inbred lines derived from eight genetically diverse laboratory inbred strains. Recently, the genetic architecture of the CC population was reported based on the genotype of a single male per line, and other publications reported incompletely inbred CC mice that have been used to map a variety of traits. The three breeding sites, in the US, Israel, and Australia, are actively collaborating to accelerate the inbreeding process through marker-assisted inbreeding and to expedite community access of CC lines deemed to have reached defined thresholds of inbreeding. Plans are now being developed to provide access to this novel genetic reference population through distribution centers. Here we provide a description of the distribution efforts by the University of North Carolina Systems Genetics Core, Tel Aviv University, Israel and the University of Western Australia.

The Association of Mitochondrial Copy Number With Sarcopenia in Adult Survivors of Childhood Cancer.

BACKGROUND: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors. METHODS: Among 1762 adult childhood cancer survivors (51.6% male; median age = 29.4 years, interquartile range [IQR] = 23.3-36.8), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided. RESULTS: The prevalence of sarcopenia was 27.0%, higher among female than male survivors (31.5% vs 22.9%; P < .001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (P = .01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (odds ratio [OR] = 1.84, 95% confidence interval [CI] = 1.32 to 2.59) and alkylating agents (OR = 1.34, 95% CI = 1.04 to 1.72) increased, whereas glucocorticoids decreased odds (OR = 0.72, 95% CI = 0.56 to 0.93) of sarcopenia. mtDNAcn decreased with age (ß = -0.81, P = .002) and was higher among female survivors (ß = 9.23, P = .01) and among survivors with a C allele at mt.204 (ß = -17.9, P = .02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20, 95% CI = 1.07 to 1.34). CONCLUSIONS: A growing body of evidence supports peripheral blood mtDNAcn as a biomarker for adverse health outcomes; however, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors.

The Mouse Universal Genotyping Array: From Substrains to Subspecies.

Genotyping microarrays are an important resource for genetic mapping, population genetics, and monitoring of the genetic integrity of laboratory stocks. We have developed the third generation of the Mouse Universal Genotyping Array (MUGA) series, GigaMUGA, a 143,259-probe Illumina Infinium II array for the house mouse (Mus musculus). The bulk of the content of GigaMUGA is optimized for genetic mapping in the Collaborative Cross and Diversity Outbred populations, and for substrain-level identification of laboratory mice. In addition to 141,090 single nucleotide polymorphism probes, GigaMUGA contains 2006 probes for copy number concentrated in structurally polymorphic regions of the mouse genome. The performance of the array is characterized in a set of 500 high-quality reference samples spanning laboratory inbred strains, recombinant inbred lines, outbred stocks, and wild-caught mice. GigaMUGA is highly informative across a wide range of genetically diverse samples, from laboratory substrains to other Mus species. In addition to describing the content and performance of the array, we provide detailed probe-level annotation and recommendations for quality control.

Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.

Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals.

Accelerating the inbreeding of multi-parental recombinant inbred lines generated by sibling matings.

Inbred model organisms are powerful tools for genetic studies because they provide reproducible genomes for use in mapping and genetic manipulation. Generating inbred lines via sibling matings, however, is a costly undertaking that requires many successive generations of breeding, during which time many lines fail. We evaluated several approaches for accelerating inbreeding, including the systematic use of back-crosses and marker-assisted breeder selection, which we contrasted with randomized sib-matings. Using simulations, we explored several alternative breeder-selection methods and monitored the gain and loss of genetic diversity, measured by the number of recombination-induced founder intervals, as a function of generation. For each approach we simulated 100,000 independent lines to estimate distributions of generations to achieve full-fixation as well as to achieve a mean heterozygosity level equal to 20 generations of randomized sib-mating. Our analyses suggest that the number of generations to fully inbred status can be substantially reduced with minimal impact on genetic diversity through combinations of parental backcrossing and marker-assisted inbreeding. Although simulations do not consider all confounding factors underlying the inbreeding process, such as a loss of fecundity, our models suggest many viable alternatives for accelerating the inbreeding process.

High-resolution genetic mapping using the Mouse Diversity outbred population.

The JAX Diversity Outbred population is a new mouse resource derived from partially inbred Collaborative Cross strains and maintained by randomized outcrossing. As such, it segregates the same allelic variants as the Collaborative Cross but embeds these in a distinct population architecture in which each animal has a high degree of heterozygosity and carries a unique combination of alleles. Phenotypic diversity is striking and often divergent from phenotypes seen in the founder strains of the Collaborative Cross. Allele frequencies and recombination density in early generations of Diversity Outbred mice are consistent with expectations based on simulations of the mating design. We describe analytical methods for genetic mapping using this resource and demonstrate the power and high mapping resolution achieved with this population by mapping a serum cholesterol trait to a 2-Mb region on chromosome 3 containing only 11 genes. Analysis of the estimated allele effects in conjunction with complete genome sequence data of the founder strains reduced the pool of candidate polymorphisms to seven SNPs, five of which are located in an intergenic region upstream of the Foxo1 gene.

Subspecific origin and haplotype diversity in the laboratory mouse.

Here we provide a genome-wide, high-resolution map of the phylogenetic origin of the genome of most extant laboratory mouse inbred strains. Our analysis is based on the genotypes of wild-caught mice from three subspecies of Mus musculus. We show that classical laboratory strains are derived from a few fancy mice with limited haplotype diversity. Their genomes are overwhelmingly Mus musculus domesticus in origin, and the remainder is mostly of Japanese origin. We generated genome-wide haplotype maps based on identity by descent from fancy mice and show that classical inbred strains have limited and non-randomly distributed genetic diversity. In contrast, wild-derived laboratory strains represent a broad sampling of diversity within M. musculus. Intersubspecific introgression is pervasive in these strains, and contamination by laboratory stocks has played a role in this process. The subspecific origin, haplotype diversity and identity by descent maps can be visualized using the Mouse Phylogeny Viewer (see URLs).