Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

Santosh S Atanur ,Kathirvel Gopalakrishnan,Enrico Petretto,Giuseppe Bianchi,Tadao Serikawa,Bina Joe,Paul Flicek,Klio Maratou,Lorena Citterio,Kathrin Saar,Victor Guryev,Maxime Rotival,Oliver Hummel,Edwin Cuppen,Dominique Guyader ,G Otto ,David J Adams ,Ana García Díaz ,Allison B Sarkis ,Man Chun John ,Howard J Jacob ,Anne E Kwitek ,Laurence Gamé ,Michael Tschannen ,Thomas M Keane ,Martin W Mcbride ,Michael R Garrett ,Weiwei Chen ,Pamela J Kaisaki ,Anna F Dominiczak ,Norbert Hübner ,Timothy J Aitman

doi:10.1016/j.cell.2013.06.040

Abstract

SummaryLarge numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.PaperClip

Highlights

In the past 100 years, more than 500 inbred rat strains have been derived for a range of physiological and pathophysiological phenotypes (Aitman et al, 2008; Lindsey, 1979) but have been predominantly used to study cardiovascular and metabolic phenotypes, which are complex traits governed by the interaction between multiple genetic factors and the environment
Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes
Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans

Summary

Introduction

In the past 100 years, more than 500 inbred rat strains have been derived for a range of physiological and pathophysiological phenotypes (Aitman et al, 2008; Lindsey, 1979) but have been predominantly used to study cardiovascular and metabolic phenotypes, which are complex traits governed by the interaction between multiple genetic factors and the environment. Inbred rat models of cardiovascular and metabolic phenotypes have been derived from various founder colonies or stocks at various geographic locations by crossing relatively small numbers of rats within the colony and selecting for the desired disease phenotypes over several generations, with simultaneous or subsequent brother-sister mating to develop genetically homogeneous inbred strains (Jong, 1984; Rapp, 2000). The majority of inbred rat models of hypertension and diabetes were generated from outbred Wistar colonies, efforts have been made to derive disease models on various other genetic backgrounds (Jong, 1984). Significant genotypic and phenotypic heterogeneity in the genetic models of hypertension and diabetes provides a unique resource to study molecular mechanisms behind different etiological forms of hypertension. Metabolic phenotypes such as insulin resistance and dyslipidaemia, which were frequently co-inherited with hypertension and may form part of the hypertension phenotype, may have inadvertently been coselected with hypertension, as well as compensatory alleles that protect against target organ damage mediated by phenotypes such as hypertension (St Lezin et al, 1999)

Results

Discussion

Conclusion