European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
BMC Genomics. 2017 Dec 22;18(1):986. doi: 10.1186/s12864-017-4351-9.
The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems.
We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver-associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain-specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity-one of the metabolic symptoms shown by the Lyon strains-amongst the genes assigned to promoters with strain-specific variation.
Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems.
实验室大鼠品系的基因组具有独特的遗传历史导致的镶嵌单倍型结构。这些镶嵌单倍型最近通过对关键品系的广泛测序进行了映射。比较具有不同表型的两个密切相关的大鼠品系之间的基因组变异已被提出作为发现与表型差异相关的候选品系特异性区域的有效策略。我们开发了一种通过整合预测与特定表型相关的基因组变异和基因组调控数据来对品系特异性单倍型进行优先级排序的方法。具体来说，我们旨在识别与代谢综合征（MetS）相关的基因组区域，代谢综合征是一种影响多个器官系统的能量利用和储存障碍的疾病。
我们比较了两种 Lyon 大鼠品系，即易患代谢综合征的 Lyon 高血压（LH）和易患肥胖症作为中间代谢综合征表型的 Lyon 低血压（LL），以及第三种对代谢综合征和肥胖均有抗性的 Lyon 正常血压（LN）品系。应用一种新的度量标准，我们使用在包括大鼠在内的五种啮齿动物中肝脏特异性转录因子（HNF4A、CEBPA 和 FOXA1）的占有率的进化保守性对鉴定出的品系特异性单倍型进行了排序。考虑调控信息可以有效地识别与肝脏相关的基因和与肥胖和代谢特征相关的人类 GWAS 变体的大鼠同源物的区域。我们试图找到可能的致病变体，并将它们与之前研究提出的候选基因进行比较。在具有保守调控的品系特异性区域中，我们发现与肥胖相关的基因在具有品系特异性变异的启动子中分配的基因中存在与发表的证据显著富集，肥胖是 Lyon 大鼠表现出的代谢症状之一。
我们的研究结果表明，使用功能调控保守性是一种潜在有效的方法，可以选择与 Lyon 大鼠之间表型差异相关的品系特异性基因组区域，并且可以扩展到其他系统。
