The genetic history of a free-living population of 10,000 wild house mice over 18 years

Inbreeding is an important phenomenon in all diploid organisms, including humans. It can lead to a reduction in fitness (“inbreeding depression”) due to increased homozygosity (carrying the same allele twice) of individuals, which leads to the expression of recessive deleterious mutations. Inbreeding is therefore an important trait that is being studied in a diverse range of fields, including medicine, agriculture, evolution, and conservation. Dramatic population declines, caused by climate change, deforestation, hunting, and other human impacts, are expected to increase inbreeding levels, which can drive populations to extinction. The specific regions of the genome involved in inbreeding depression, the mechanisms of resistance to inbreeding, and how common inbreeding depression is remains unknown. Due to modern genomics, it is possible to calculate levels of inbreeding in more powerful ways. A few studies using genomics-based inbreeding estimates in wild populations have emerged, but only on larger mammals with slower life cycles. In contrast, I will study house mice, a small mammal with a fast life cycle. Barbara König at the University of Zurich has established a successful long-term study on free-living wild house mice. 18 years of intense monitoring has provided a wealth of individual phenotypes on 10,000 mice, with all of them having been sampled genetically. I laid the groundwork of genotyping these mice using powerful statistical methods that allow for cost-efficient genotyping at millions of loci. Now, I aim to expand this work and use these resources for the largest study on inbreeding depression in the wild to date. I propose two main projects that I will conduct after finalizing the genotyping process (Aim 1) and measuring genomics-based inbreeding coefficients (Aim 2):Aim 3) I will correlate a wealth of fitness-related traits with individualized inbreeding levels to detect inbreeding depression. To do so, I will make use of phenotypic data from the long-term study that will need only limited work on my part to make fully available to this study. I will control for environmental factors that could influence these phenotypic traits and will correct for multiple testing appropriately.Aim 4) I aim to find the regions of the genome that are linked to inbreeding depression. I will use the inbreeding-depressed traits that I found in 1) and model the presence or absence of homozygosity at each locus as a predictor. I also aim to find alleles that allow for resistance to inbreeding at other loci by correlating the presence/absence of homozygosity at focal loci with genotypes at other loci.This study will vastly expand the limited empirical data on inbreeding depression in the wild and has the potential to find genomic bases for inbreeding depression in specific traits and resistance to inbreeding depression, which remains an understudied area of research. The few comparable studies on smaller populations and with less powerful methods have so far been published in journals of broader impact.