NSF-SNSF: Genetic, molecular, and behavioral characterization of inbreeding in a massive wild house mouse pedigree, followed by controlled experimental validations

As wildlife populations across the globe experience dramatic declines, the resulting shrinking population sizes often lead to inbreeding, which can severely threaten the health and long-term survival of a species by exposing harmful genetic mutations. Understanding exactly how mating between closely related individuals causes these negative health impacts, known as inbreeding depression, is a critical challenge for evolutionary biologists and conservationists striving to design effective wildlife management strategies. To address this fundamental issue, this project investigates a unique, extensively documented population of wild house mice that has been isolated in a natural barn environment for over twenty generations. Researchers will combine more than two decades of observational data on mouse behavior, physical development, and survival with advanced genetic sequencing of thousands of individuals to map exactly how inbreeding affects physical traits and social networks. Ultimately, by revealing the hidden genetic costs of inbreeding and exploring whether animals naturally alter their behavior to avoid it, this research will provide vital scientific justification and practical tools to guide wildlife conservation efforts, while also contributing broadly to our understanding of genetic diseases. This project advances NSF's priorities in Biotechnology. The core objective of this research is to comprehensively characterize the phenotypic, genetic, and behavioral consequences of inbreeding in a natural mammalian population. The project leverages an unprecedented longitudinal dataset from a free-living population of wild house mice that was founded by twelve wild-caught individuals in 2002. Over twenty generations, researchers have collected detailed phenotypic data, encompassing social behaviors, morphological measurements, survival rates, and reproductive outcomes, for more than 95% of the approximately 20,000 individuals in this closed population. To achieve the project goals, the research team has generated a highly detailed extended pedigree and genotyped over 2.2 million variants for 8,500 descendants. This was accomplished by sequencing the founder genomes at high coverage and imputing low-coverage sequence data from the descendants back to the founder haplotypes. Utilizing this robust genomic and demographic dataset, the project pursues three specific aims. First, the investigators will quantify the effects of inbreeding on reproductive output, survival, morphology, and temporal social network interactions, followed by genome-wide association studies utilizing a recessive model to precisely identify specific genetic loci contributing to inbreeding depression. Second, the project will identify strongly deleterious alleles that do not tolerate inbreeding by comparing observed homozygosity against pedigree-based simulations, detecting transmission distortion in parent-offspring trios, and validating candidate variants through controlled laboratory crosses. The functional nature of these heavily selected variants will be characterized and cross-referenced with human disease databases to identify shared genetic vulnerabilities. Third, the study will investigate behavioral inbreeding avoidance by developing temporal network models of social interactions and mating outcomes, comparing empirical inbreeding frequencies against simulated null models to determine if these mammals actively avoid mating with close kin. By integrating genomic, demographic, and behavioral data across multiple generations in a wild setting, this project will significantly advance the fields of evolutionary biology and conservation genetics. It will illuminate the specific genetic architecture underlying inbreeding depression, the efficacy of purifying selection in natural populations, and the role of social behavior in mediating genetic health, thereby providing broadly applicable models for managing and preserving endangered wildlife populations. NSF Award ID: 2624654 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Andres Bendesky | Institution: Columbia University, NEW YORK, NY | Award Amount: $1,450,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2624654 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2624654.html