Genes on Chromosome 17 Regulating % Body Fat in the Mouse

描述(由申请人提供)：该项目的长期目标是识别和表征位于小鼠近端17号染色体(Chr17)上的数量性状基因(QTGs)，这些基因与肥胖的易感性和风险有关。我们使用C57BL/6N和129P2小鼠品系之间的小鼠杂交，确定了CHL17上体脂含量%的显著连锁。在这个基因座上，C57BL等位基因与体脂增加有关。在使用C57小鼠不同亚系的许多其他小鼠遗传杂交中，已经发现在CHR17近端的这个区域存在连锁，而C57等位基因总是增加肥胖风险的等位基因。通过基于单倍型的关联分析和生物信息学，该基因的物理位置已经显著缩小。将使用各种分子技术，包括平铺阵列、测序和表达分析，确定在最近的chr17上具有这一特征的最佳候选基因。最后，将通过在空/空小鼠中测量的表型和重组定量互补(RQC)测试来验证特定候选基因的作用。然后，将通过鉴定候选QTG的分子功能以及细胞和系统生物学，在野生型、Null/Null和rQC测试中产生的小鼠中测试经过验证的QTGs的功能作用。 公共卫生相关性：确定疾病风险的遗传基础将导致开发更好的肥胖症和肥胖症相关疾病的治疗方法，并将导致根据患者的遗传背景为个别患者量身定制治疗方法。

DESCRIPTION (provided by applicant): The long-term objective of this project is to identify and characterize the quantitative trait genes (QTGs) located on proximal mouse chromosome 17 (Chr17) that confer susceptibility and risk for the development of obesity. We have identified significant linkage for % body fat content on Chr17 using a mouse cross between C57BL/6N and 129P2 mouse strains. At this locus it is the C57BL allele that is associated with increased body fat. Linkage in this region on proximal Chr17 has been identified in numerous other mouse genetic crosses using different substrains of C57 mice, and the C57 allele is always the allele conferring increased risk for obesity. The physical location of the genes underlying this Chr17 QTL has been significantly narrowed by haplotype-based association analysis and bioinformatics. The best candidates for this trait on proximal Chr17 will be identified using a variety of molecular techniques including tiling arrays, sequencing, and expression analyses. Finally the role of specific candidates will be validated using phenotypes measured in null/null mice and the recombinant Quantitative Complementation (rQC) test. The functional role of validated QTGs will then be tested in wildtype, null/null and the mice produced in the rQC test by characterizing the molecular function, as well as the cellular and systems biology of the candidate QTG. PUBLIC HEALTH RELEVANCE: Identification of the genetic basis of disease risk will lead to the development of better treatments for obesity and obesity-related diseases and will lead to methods for tailoring treatment to individual patients based upon their genetic background.