Dumont Beth L, Gatti Daniel M, Ballinger Mallory A, Lin Dana, Phifer-Rixey Megan, Sheehan Michael J, Suzuki Taichi A, Wooldridge Lydia K, Frempong Hilda Opoku, Lawal Raman Akinyanju, Churchill Gary A, Lutz Cathleen, Rosenthal Nadia, White Jacqueline K, Nachman Michael W
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, United States of America.
Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America.
PLoS Genet. 2024 Apr 10;20(4):e1011228. doi: 10.1371/journal.pgen.1011228. eCollection 2024 Apr.
The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently developed, sequenced, and phenotyped a set of 11 inbred strains derived from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from one of five environmentally distinct locations across North and South America. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the GRCm39 mouse reference, with 42.5% of variants in the Nachman strain genomes absent from current classical inbred mouse strain panels. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels. These novel wild-derived inbred mouse strain resources are set to empower new discoveries in both basic and preclinical research.
在一个多世纪的时间里,实验小鼠一直是基础研究和临床前研究的首要动物模型系统。然而,实验小鼠只捕获了野生小鼠群体中一部分遗传变异,最终限制了经典近交系在发现与表型相关的变异和通路方面的潜力。野生小鼠群体是遗传多样性的储存库,有助于发现新的功能和与疾病相关的等位基因,但市面上可获得的、特征明确的野生小鼠品系稀缺,限制了它们在生物医学研究中的更广泛应用。为了克服这一障碍,我们最近开发、测序并对一组从野生捕获的家鼠(Mus musculus domesticus)衍生而来的11个近交系进行了表型分析。这些“纳赫曼品系”中的每一个都使从北美和南美五个环境不同地点之一采样的独特野生单倍型得以永存。全基因组序列分析表明,相对于GRCm39小鼠参考基因组,每个品系携带473万至654万个单核苷酸差异,纳赫曼品系基因组中42.5%的变异在当前经典近交小鼠品系面板中不存在。我们在一个定制的流程上对纳赫曼品系进行了表型分析,以评估与疾病相关的神经行为、生化、生理、代谢和形态特征变异的范围。在1119个被调查的性状中,超过90%的性状在纳赫曼品系间表现出显著差异,并扩大了经典近交系面板中捕获的表型多样性范围。这些新的野生来源近交小鼠品系资源将助力基础研究和临床前研究中的新发现。