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

被引：131

作者：

Atanur, Santosh S. ^{[1
,2
]}

Diaz, Ana Garcia ^{[1
]}

Maratou, Klio ^{[1
]}

Sarkis, Allison ^{[5
]}

Rotival, Maxime ^{[3
]}

Game, Laurence ^{[4
]}

Tschannen, Michael R. ^{[5
]}

Kaisaki, Pamela J. ^{[6
]}

Otto, Georg W. ^{[6
]}

Ma, Man Chun John ^{[7
]}

Keane, Thomas M. ^{[8
]}

Hummel, Oliver ^{[9
]}

Saar, Kathrin ^{[9
]}

Chen, Wei ^{[9
]}

Guryev, Victor ^{[10
,11
,12
]}

Gopalakrishnan, Kathirvel ^{[13
]}

Garrett, Michael R. ^{[14
]}

Joe, Bina ^{[13
]}

Citterio, Lorena ^{[15
]}

Bianchi, Giuseppe ^{[15
]}

McBride, Martin ^{[16
]}

Dominiczak, Anna ^{[16
]}

Adams, David J. ^{[8
]}

Serikawa, Tadao ^{[17
]}

Flicek, Paul ^{[18
]}

Cuppen, Edwin ^{[10
,11
]}

Hubner, Norbert ^{[9
,19
]}

Petretto, Enrico ^{[3
]}

Gauguier, Dominique ^{[6
,20
]}

Kwitek, Anne ^{[7
]}

Jacob, Howard ^{[5
]}

Aitman, Timothy J. ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, Physiol Genom & Med Grp, London W12 0NN, England

[2] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England

[3] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, Integrat Genom & Med Grp, London W12 0NN, England

[4] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, Genom Core Lab, London W12 0NN, England

[5] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA

[6] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[7] Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA

[8] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[9] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany

[10] Hubrecht Inst KNAW, NL-3584 Utrecht, Netherlands

[11] Univ Med Ctr Utrecht, NL-3584 Utrecht, Netherlands

[12] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, NL-9700 AD Groningen, Netherlands

[13] Univ Toledo, Coll Med, Dept Physiol & Pharmacol, Ctr Hypertens & Personalized Med, Toledo, OH 43606 USA

[14] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA

[15] Univ Vita Salute San Raffaele, Chair Nephrol, San Raffaele Sci Inst, OU Nephrol, I-20132 Milan, Italy

[16] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland

[17] Kyoto Univ, Grad Sch Med, Inst Lab Anim, Kyoto 6068501, Japan

[18] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England

[19] DZHK German Ctr Cardiovasc Res, D-13092 Berlin, Germany

[20] INSERM, Cordeliers Res Ctr, UMR S872, F-75006 Paris, France

来源：

CELL | 2013年 / 154卷 / 03期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

OXIDATIVE STRESS; CARDIAC-HYPERTROPHY; GENETIC-ANALYSIS; ANGIOTENSIN-II; HYPERTENSION; GENERATION; PRESSURE; MUTATION; MECHANISMS; PHYSIOLOGY;

D O I：

10.1016/j.cell.2013.06.040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Large 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.

引用

页码：691 / 703

页数：13

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