Ball Robyn L, Bogue Molly A, Liang Hongping, Srivastava Anuj, Ashbrook David G, Lamoureux Anna, Gerring Matthew W, Hatoum Alexander S, Kim Matthew, He Hao, Emerson Jake, Berger Alexander K, Walton David O, Sheppard Keith, Kassaby Baha El, Castellanos Francisco, Kunde-Ramamoorthy Govind, Lu Lu, Bluis John, Desai Sejal, Sundberg Beth A, Peltz Gary, Fang Zhuoqing, Churchill Gary A, Williams Robert W, Agrawal Arpana, Bult Carol J, Philip Vivek M, Chesler Elissa J
bioRxiv. 2023 Aug 10:2023.08.08.552506. doi: 10.1101/2023.08.08.552506.
Hundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait - variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web- and programmatically-accessible data service called GenomeMUSter ( https://muster.jax.org ), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.
数百种近交系实验室小鼠品系和杂交群体已被用于使导致疾病的基因变异功能化。在小鼠中已经对数千种与疾病相关的性状进行了表征并公开提供。包括协作杂交、扩展的BXD和近交野生衍生品系在内的新菌株和群体增加了复杂疾病小鼠模型、遗传图谱资源以及用于评估工程突变的敏感背景的集合。许多近交系的基因组序列，以及其他品系的密集基因型，可能允许对不同群体的性状-变异关联进行综合分析，但由于可用基因型的稀疏性，这些分析并不可行。此外，这些数据与其他资源不易互操作。为了解决这些限制，我们通过协调多个变异数据集创建了一个统一密集的数据资源。使用维特比算法和结合局部系统发育信息的数据驱动技术对缺失的基因型进行插补，这种方法可扩展到其他模式生物物种。结果是一个名为GenomeMUSter (https://muster.jax.org) 的可通过网络和编程访问的数据服务，包含在1.068亿个分离位点覆盖657个品系的等位基因数据。与表型数据库、分析工具和其他资源的互操作实现了大量应用，包括多性状多群体荟萃分析。我们在2型糖尿病和物质使用障碍的荟萃分析的跨物种比较中证明了这一点，根据小鼠表型数据更具体地描述了人类变异效应的作用。其他应用包括细化定位的基因座和为疾病建模确定品系背景的优先级，以进一步释放现存小鼠的多样性，用于健康和疾病的遗传和基因组研究。
