Togawa Katsuhiko, Moritani Maki, Yaguchi Hiroshi, Itakura Mitsuo
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Japan.
Hum Mol Genet. 2006 Jan 1;15(1):113-28. doi: 10.1093/hmg/ddi433. Epub 2005 Dec 1.
Most quantitative trait loci (QTL) studies have focused on detecting the genetic effects of individual QTLs. This study thoroughly dissected the genetic components of type 2 diabetic mice, including a search for epistatic interactions and multi-locus additive effects that result in variation in diabetes-related phenotypes. F2 population was generated from BKS.Cg-Leprdb+/+m and DBA/2 intercross and separated into six subpopulations by sex and the db-dependent diabetes severity. Single-locus and pairwise genome scans first identified the QTLs in these F2 subpopulations, and next covariate-dependent scans confirmed their sex-, db- and sex-by-db-specific effects in the combined populations. Single-locus genome scans detected four QTLs (QBIS1, QBIS2, QBIS3 and QBIS4) that presented their genetic effects beyond sex, but most QTLs showed their effects specifically in limited conditions. This highly conditional feature of the QTLs was accentuated in the pairwise analysis. The pairwise genome scans uncovered a total of 27 significantly interacting or additively acting pairs of loci, showing a better fit to explain the total phenotypic variation of the traits. These significant pairs affected the traits under constantly varying combinations of loci in a time series or in both sexes. In addition, pairwise analysis indicated the appropriate genetic background in constructing congenic strains to obtain the maximum power in the replication of phenotypes. Our study showed high degree of complexity in the genetics of type 2 diabetes in mice, and it suggested that a comprehensive understanding of the multi-locus effects was essential to disentangle the complex genetics of diabetes and obesity in humans.
大多数数量性状基因座（QTL）研究都集中于检测单个QTL的遗传效应。本研究深入剖析了2型糖尿病小鼠的遗传成分，包括寻找上位性相互作用和多位点加性效应，这些效应导致了糖尿病相关表型的变异。F2群体由BKS.Cg-Leprdb+/+m和DBA/2杂交产生，并根据性别和db依赖性糖尿病严重程度分为六个亚群。单基因座和双基因座基因组扫描首先在这些F2亚群中鉴定出QTL，然后协变量依赖性扫描在合并群体中确认了它们的性别、db和性别-by-db特异性效应。单基因座基因组扫描检测到四个QTL（QBIS1、QBIS2、QBIS3和QBIS4），其遗传效应不受性别影响，但大多数QTL仅在有限条件下表现出效应。QTL的这种高度条件性特征在双基因座分析中更为突出。双基因座基因组扫描共发现27对显著相互作用或具有加性作用的基因座，能更好地解释性状的总表型变异。这些显著的基因座对在时间序列或两性中以不断变化的基因座组合影响性状。此外，双基因座分析表明，在构建同源近交系时，合适的遗传背景有助于在表型复制中获得最大功效。我们的研究表明小鼠2型糖尿病的遗传具有高度复杂性，这表明全面了解多位点效应对于理清人类糖尿病和肥胖的复杂遗传学至关重要。
