Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models.

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.

Molecular evolution of the mammalian kinetochore complex.

Mammalian centromeres are satellite-rich chromatin domains that serve as sites for kinetochore complex assembly. Centromeres are highly variable in sequence and satellite organization across species, but the processes that govern the co-evolutionary dynamics between rapidly evolving centromeres and their associated kinetochore proteins remain poorly understood. Here, we pursue a course of phylogenetic analyses to investigate the molecular evolution of the complete kinetochore complex across primate and rodent species with divergent centromere repeat sequences and features. We show that many protein components of the core centromere associated network (CCAN) harbor signals of adaptive evolution, consistent with their intimate association with centromere satellite DNA and roles in the stability and recruitment of additional kinetochore proteins. Surprisingly, CCAN and outer kinetochore proteins exhibit comparable rates of adaptive divergence, suggesting that changes in centromere DNA can ripple across the kinetochore to drive adaptive protein evolution within distant domains of the complex. Our work further identifies kinetochore proteins subject to lineage-specific adaptive evolution, including rapidly evolving proteins in species with centromere satellites characterized by higher-order repeat structure and lacking CENP-B boxes. Thus, features of centromeric chromatin beyond the linear DNA sequence may drive selection on kinetochore proteins. Overall, our work spotlights adaptively evolving proteins with diverse centromere-associated functions, including centromere chromatin structure, kinetochore protein assembly, kinetochore-microtubule association, cohesion maintenance, and DNA damage response pathways. These adaptively evolving kinetochore protein candidates present compelling opportunities for future functional investigations exploring how their concerted changes with centromere DNA ensure the maintenance of genome stability.