Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
BMC Genomics. 2014 Mar 14;15(1):197. doi: 10.1186/1471-2164-15-197.
The metabolic syndrome (MetS), a complex disorder involving hypertension, obesity, dyslipidemia and insulin resistance, is a major risk factor for heart disease, stroke, and diabetes. The Lyon Hypertensive (LH), Lyon Normotensive (LN) and Lyon Low-pressure (LL) rats are inbred strains simultaneously derived from a common outbred Sprague Dawley colony by selection for high, normal, and low blood pressure, respectively. Further studies found that LH is a MetS susceptible strain, while LN is resistant and LL has an intermediate phenotype. Whole genome sequencing determined that, while the strains are phenotypically divergent, they are nearly 98% similar at the nucleotide level. Using the sequence of the three strains, we applied an approach that harnesses the distribution of Observed Strain Differences (OSD), or nucleotide diversity, to distinguish genomic regions of identity-by-descent (IBD) from those with divergent ancestry between the three strains. This information was then used to fine-map QTL identified in a cross between LH and LN rats in order to identify candidate genes causing the phenotypes.
We identified haplotypes that, in total, contain at least 95% of the identifiable polymorphisms between the Lyon strains that are likely of differing ancestral origin. By intersecting the identified haplotype blocks with Quantitative Trait Loci (QTL) previously identified in a cross between LH and LN strains, the candidate QTL regions have been narrowed by 78%. Because the genome sequence has been determined, we were further able to identify putative functional variants in genes that are candidates for causing the QTL.
Whole genome sequence analysis between the LH, LN, and LL strains identified the haplotype structure of these three strains and identified candidate genes with sequence variants predicted to affect gene function. This approach, merged with additional integrative genetics approaches, will likely lead to novel mechanisms underlying complex disease and provide new drug targets and therapies.
代谢综合征（MetS）是一种涉及高血压、肥胖、血脂异常和胰岛素抵抗的复杂疾病，是心脏病、中风和糖尿病的主要危险因素。里昂高血压（LH）、里昂正常血压（LN）和里昂低血压（LL）大鼠是通过选择高、正常和低血压分别从一个共同的远交 Sprague Dawley 群体中同时衍生的近交系。进一步的研究发现，LH 是一种易患代谢综合征的品系，而 LN 是抗性的，LL 则具有中间表型。全基因组测序确定，虽然这些品系在表型上存在差异，但在核苷酸水平上几乎有 98%的相似性。使用这三个品系的序列，我们应用了一种利用观察到的品系差异（OSD）或核苷酸多样性的分布来区分三个品系之间具有同源关系的基因组区域和具有不同祖先的基因组区域的方法。然后，我们将此信息用于精细映射 LH 和 LN 大鼠杂交中鉴定的 QTL，以鉴定导致表型的候选基因。
我们鉴定了单倍型，它们总共包含了里昂品系之间至少 95%的可识别的多态性，这些多态性可能来自不同的祖先。通过将鉴定的单倍型块与 LH 和 LN 大鼠杂交中先前鉴定的数量性状基因座（QTL）相交，候选 QTL 区域缩小了 78%。由于基因组序列已经确定，我们还能够在候选基因中鉴定出可能导致 QTL 的功能变异。
LH、LN 和 LL 品系之间的全基因组序列分析确定了这三个品系的单倍型结构，并鉴定了候选基因，这些候选基因的序列变异预测会影响基因功能。这种方法与其他综合遗传学方法相结合，可能会导致复杂疾病的新机制，并为新的药物靶点和疗法提供依据。
