Mammalian Genetics, The Jackson Laboratory, 600 Main Street, USA.
G3 (Bethesda). 2023 Apr 11;13(4). doi: 10.1093/g3journal/jkad015.
Outbred laboratory mice (Mus musculus) are readily available and have high fecundity, making them a popular choice in biomedical research, especially toxicological and pharmacological applications. Direct high throughput genome sequencing (HTS) of these widely used research animals is an important genetic quality control measure that enhances research reproducibility. HTS data have been used to confirm the common origin of outbred stocks and to molecularly define distinct outbred populations. But these data have also revealed unexpected population structure and homozygosity in some populations; genetic features that emerge when outbred stocks are not properly maintained. We used exome sequencing to discover and interrogate protein-coding variation in a newly established population of Swiss-derived outbred stock (J:ARC) that is closely related to other, commonly used CD-1 outbred populations. We used these data to describe the genetic architecture of the J:ARC population including heterozygosity, minor allele frequency, LD decay, and we defined novel, protein-coding sequence variation. These data reveal the expected genetic architecture for a properly maintained outbred stock and provide a basis for the on-going genetic quality control. We also compared these data to protein-coding variation found in a multiparent outbred stock, the Diversity Outbred (J:DO). We found that the more recently derived, multiparent outbred stock has significantly higher interindividual variability, greater overall genetic variation, higher heterozygosity, and fewer novel variants than the Swiss-derived J:ARC stock. However, among the novel variants found in the J:DO stock, significantly more are predicted to be protein-damaging. The fact that individuals from this population can tolerate a higher load of potentially damaging variants highlights the buffering effects of allelic diversity and the differing selective pressures in these stocks. While both outbred stocks offer significant individual heterozygosity, our data provide a molecular basis for their intended applications, where the J:DO are best suited for studies requiring maximum, population-level genetic diversity and power for mapping, while the J:ARC are best suited as a general-purpose outbred stock with robust fecundity, relatively low allelic diversity, and less potential for extreme phenotypic variability.
远交实验室小鼠（Mus musculus）繁殖力强、易于获得，是生物医学研究中常用的模式动物，尤其是在毒理学和药理学研究中。对这些广泛使用的研究动物进行高通量全基因组直接测序（HTS）是一种重要的遗传质量控制措施，可以提高研究的可重复性。HTS 数据已被用于确认远交种群的共同起源，并从分子上定义不同的远交种群。但是，这些数据还揭示了一些种群中出乎意料的群体结构和纯合性；当远交种群没有得到适当维护时，就会出现这些遗传特征。我们使用外显子组测序来发现和分析新建立的瑞士远交种群（J:ARC）中的蛋白质编码变异，该种群与其他常用的 CD-1 远交种群密切相关。我们使用这些数据描述了 J:ARC 种群的遗传结构，包括杂合性、次要等位基因频率、LD 衰减，并定义了新的蛋白质编码序列变异。这些数据揭示了适当维护的远交种群的预期遗传结构，并为正在进行的遗传质量控制提供了基础。我们还将这些数据与多亲本远交种群 Diversity Outbred（J:DO）中的蛋白质编码变异进行了比较。我们发现，最近衍生的多亲本远交种群个体间的变异性显著更高，整体遗传变异更大，杂合性更高，新变异更少，而瑞士衍生的 J:ARC 种群则相反。然而，在 J:DO 种群中发现的新变异中，预测有更多的变异会导致蛋白质损伤。事实上，该种群个体能够耐受更高的潜在有害变异负担，这突出了等位基因多样性的缓冲作用以及这些种群中不同的选择压力。虽然这两种远交种群都提供了显著的个体杂合性，但我们的数据为它们的预期应用提供了分子基础，其中 J:DO 最适合需要最大种群遗传多样性和作图能力的研究，而 J:ARC 最适合作为具有稳健繁殖力、相对较低等位基因多样性和较少潜在极端表型变异性的通用远交种群。
