Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies.
Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies.
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DOI：
10.1371/journal.pgen.1010234
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发表时间：
2022-05
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
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Sprague道利（SD）大鼠是最广泛使用的远系繁殖实验室大鼠群体之一。尽管如此，SD大鼠的遗传特征尚未得到明确描述，并且SD大鼠很少用于旨在探索基因型-表型关系的实验。为了使用SD大鼠进行全基因组关联研究（GWAS），我们收集了4，625只SD大鼠的行为数据，这些大鼠主要来自两个商业供应商Charles River Laboratories和哈兰斯普拉格道利公司。使用双消化测序基因分型（ddGBS），我们在4，061只大鼠中获得了291，438个SNP的高质量基因型。该遗传数据使我们能够表征Charles River与哈兰SD大鼠中存在的变异。我们发现，这两个群体是高度分化（FST > 0.4）。此外，即使对于从同一供应商处获得的大鼠，整个饲养设施甚至同一设施的房间之间也存在强烈的种群结构。我们通过拟合线性混合模型进行了多个单独的GWAS，该模型考虑了人群结构，并使用荟萃分析来联合分析所有队列。我们的研究考察了巴甫洛夫条件接近（PavCA）的行为，评估大鼠的倾向，奖励相关的线索属性的激励显着性。我们确定了46个用于定义PavCA的各种指标的重要关联。来自不同来源的SD大鼠之间令人惊讶的种群结构程度对于它们在遗传和非遗传研究中的应用具有重要意义。远交Sprague道利大鼠是神经科学、生理学和药理学研究中最常用的大鼠之一;于二零二零年，4，188篇出版物包含关键词“Sprague道利”。识别为“Sprague道利”的大鼠由几个商业供应商出售，包括Charles River Laboratories和哈兰Sprague道利Inc.。(now Envigo）。尽管它们被广泛使用，但人们对SD的遗传多样性知之甚少。我们对4,000多只SD大鼠进行了基因分型，并将其用于全基因组关联研究（GWAS），以表征来自Charles River实验室和哈兰的SD大鼠之间的遗传差异。我们的分析揭示了供应商之间和供应商内部的广泛人口结构。巴甫洛夫条件反射方法（PavCA）的GWAS确定了许多复杂行为特征的全基因组显著位点。我们的研究结果表明，尽管有相同的名称，但从不同供应商获得的SD大鼠是非常不同的。未来的研究应仔细确定SD大鼠的确切来源，并可能利用其遗传多样性进行复杂性状的遗传研究。
Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted for population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies. Outbred Sprague Dawley rats are among the most commonly used rats for neuroscience, physiology and pharmacological research; in the year 2020, 4,188 publications contained the keyword “Sprague Dawley”. Rats identified as “Sprague Dawley” are sold by several commercial vendors, including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their widespread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 SD rats, which we used for a genome-wide association study (GWAS) and to characterize genetic differences between SD rats from Charles River Laboratories and Harlan. Our analysis revealed extensive population structure both between and within vendors. The GWAS for Pavlovian conditioned approach (PavCA) identified a number of genome-wide significant loci for that complex behavioral trait. Our results demonstrate that, despite sharing an identical name, SD rats that are obtained from different vendors are very different. Future studies should carefully define the exact source of SD rats being used and may exploit their genetic diversity for genetic studies of complex traits.
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影响因子：
30.8
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