A heterogeneous stock paradigm of dissecting complex traits in Peromyscus leucopus, a major natural host of Lyme disease and other emerging infections

The cricetine rodent Peromyscus leucopus is a major reservoir for several emerging infectious diseases, including Lyme disease, the most common arthropod-­?borne infection in North America. While collective work to date has identified several quantitative traits relevant to understanding inter-­? individual variation in an animal?s ability to serve as a pathogen host, other unidentified genes account for the bulk of standing genetic variation in the full range of host responses in humans and other animals. The use of heterogeneous stocks (HS; a population derived several dozen generations ago from a small number of founders) is a promising approach for dissecting complex traits in this system. In the case of P. leucopus, a closed population exists: the LL colony, which was founded ~30 years ago from 38 individuals and has been subsequently maintained at a large population size. Our preliminary data show that the LL colony has extensive genetic variation at SNPs. Furthermore, LD extends over much longer distances than in wild populations, but much less than a mapping panel of Mus musculus. Assembly of a draft genome of an individual from the LL colony is underway. We will carry out experiments exploiting the LL colony to identify and localize genes that contribute to a complex trait of relevance to parasitism by a hematophagous arthropod vector ? bleeding time, a measure of hemostasis. Bleeding time is highly heritable and can be easily and replicably measured. In order to genetically dissect bleeding time, we will carry out a P. leucopus genome annotation and SNP identification project. We expect to annotate roughly half of all coding exons in P. leucopus and identify over >1M SNPs segregating in the LL colony. We will then develop a cost-­?effective scalable method for genotyping P. leucopus individuals for a large but ?fixed? set of SNPs, and use this method to genotype ~500 LL colony individuals on which bleeding time will also be measured. These data and a HS strategy will be employed to identify the genetic regions that contribute to variation in bleeding time. The ultimate goal of this two year project is to demonstrate that the unique LD structure of LL colony P. leucopus mice allows high-­?powered genome-­?wide association studies to be carried out with ~50K SNPs, and to show that identified QTL can be localized to 0.5-­?2.0 Mb windows.