A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: The NIH heterogeneous stock

Abstract

The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance.The rat has for long been a favored organism for physiological and behavioral analyses and is increasingly attracting the attention of geneticists (Jacob and Kwitek 2002). Over the last century, a wealth of disease models have been developed, which compared with the mouse have proved easier to analyze at an organ and cellular level because of the rat's larger size. Rat models of cardiovascular disease, inflammatory diseases, and susceptibility to cancer and toxic substances have been crucial in understanding the biology of common human disorders. The rat has also been a focus of classical neuroanatomical studies and electrophysiological slice studies; rat experiments have been critical for understanding many neurobiological processes, including learning and memory, and for providing models for the neuropsychology of human behavioral disorders (Weiss and Feldon 2001).

Fine-mapping a locus for glucose tolerance using heterogeneous stock rats

“…), and this imposes a cluster structure in the data that, if not accounted for analytically, results in spurious associations in addition to genuine QTLs (13,40). A previous study using the HS rat population accounted for family structure by employing a significance threshold that takes into account these family relationships (18). In the current study, we have developed this approach further by not only taking family into account when determining the significance threshold, but also by including family as a random intercept in the regression model.…”

“…When only a region of the genome is genotyped, however, multiple QTL modeling is not applicable. In their fine-mapping of a fear-related locus on a single chromosome, Johannesson et al (18) overcame this excess of potential false positives by adopting a stricter significance threshold in which family structure is incorporated into the threshold procedure. Here we developed this approach further by including sibship as a random intercept both in the HAPPY regression model (see Ref.…”

“…1 against one that omits locus specific information but retains sibship and other effects (the null model). A region-wide significance threshold was then obtained by repeating the region scan on 200 sets of phenotypes generated by parametric bootstrap from the fitted null model and using the maximum logP's from those scans to fit a generalized extreme value distribution from which the upper 5% quantile was taken as the 5% region-wide significance threshold (18,41). All models were fitted using the statistical language R (R- (18) we also performed a region-wide scan by fitting the model in Eq.…”

“…Multiple phenotypes have been finemapped using the HS mouse (41). To date, however, the HS rat colony has only been used to fine-map a single locus for fear-related behavior (18).…”

Helplessness-like escape deficits of NIH-HS rats predict passive behavior in the forced swimming test: Relevance for the concurrent validity of rat models of depression

“…With this aim, the NIH-HS rat stock was formed through an eight-way cross among eight inbred rat strains (see "Methods" below; Hansen and Spuhler [22]). Recent genetic studies have demonstrated that the NIH-HS rat stock is a unique animal model for the simultaneous identification and fine mapping of QTLs (Quantitative Trait Loci) even to a gene resolution level (for reviews see [23,24]). From the phenotypic stand point, our behavioural and hormonal studies of the heterogeneous rat stock clearly indicate that the NIH-HS rat colony (established in our laboratory, at Autonomous University of Barcelona, in 2004) exhibits a behavioural "defensive" profile indicating that these animals are rather fearful and anxious, presenting a predominantly passive/reactive coping style as well as stressprone (i.e.…”