The utility of a closed breeding colony of Peromyscus leucopus for dissecting complex traits

Abstract

Deermice of the genus Peromyscus are well suited for addressing several questions of biologist interest, including the genetic bases of longevity, behavior, physiology, adaptation, and their ability to serve as disease vectors. Here we explore a diversity outbred approach for dissecting complex traits in Peromyscus leucopus, a non-traditional genetic model system. We take advantage of a closed colony of deer-mice founded from 38 individuals and subsequently maintained for ∼40-60 generations. From 405 low-pass short-read sequenced deermice we accurately imputed genotypes at 16 million SNPs. Conditional on observed genotypes simulations were conducted in which three different sized QTL contribute to a complex trait under three different genetic models. Using a stringent significance threshold power was modest, largely a function of the % variation attributable to the simulated QTL, with the underlying genetic model having only a subtle impact. We additionally simulated 2000 pseudo-individuals, whose genotypes were consistent with those observed in the genotyped cohort and carried out additional power simulations. In experiments employing more than 1000 mice the power is high to detect QTL contributing greater than 2.5% to a complex trait, with a localization ability of ∼100kb. We finally carried out a GWAS on two demonstration traits, bleeding time and body weight, and uncovered one significant region. Our work suggests that complex traits can be dissected in founders-unknown P. leucopus colony mice and similar colonies in other systems using easily obtained genotypes from low-pass sequencing.

The infection-tolerant white-footed deermouse tempers interferon responses to endotoxin in comparison to the mouse and rat

“…While a strength of the study was use of an outbred population of M. musculus to approximate the genetic diversity of the P. leucopus in the study, this meant that some genes of potential relevance might have gone undetected, that is from type II error. The variances for a sample of genetically diverse outbred animals, like the LL stock of P. leucopus ( Long et al, 2019 ; Long et al, 2022 ), would be expected to be greater than for the same sized sample of inbred animals. For some traits, especially ones that are complex or under balancing selection, even sample sizes of 10 in each group may not have provided sufficient power for discrimination between deermice and mice.…”

“…As a species native to North America, P. leucopus is an advantageous alternative to the Eurasian-origin house mouse for study of natural variation in populations that are readily accessible ( Bedford and Hoekstra, 2015 ; Long et al, 2022 ). A disadvantage for the study of any Peromyscus species is the limited reagents and genetic tools of the sorts that are applied for mouse studies.…”

The white-footed deermouse, an infection-tolerant reservoir for several zoonotic agents, tempers interferon responses to endotoxin in comparison to the mouse and rat

“…from type II error. The variances for a sample of genetically diverse outbred animals, like the LL stock of P. leucopus (52, 53) , would be expected to be greater than for the same sized sample of inbred animals. For some traits, especially ones that are complex or under balancing selection, even sample sizes of 10 in each group may not have provided sufficient power for discrimination between deermice and mice.…”

“…The variances for a sample of genetically diverse outbred animals, like the LL stock of P. leucopus (A. Long et al 2019;P. Long et al 2022), would be expected to be greater than for the same sized sample of inbred animals.…”

“…As a species native to North America, P. leucopus is an advantageous alternative to the house mouse, which is of Eurasian origin, for study of natural variation in populations that are readily athand (Bedford and Hoekstra 2015;Long et al 2022). A disadvantage is the limited reagents and genetic tools of the sorts that are applied for mouse studies.…”