INRA, UMR598, Génétique Animale, IFR140 GFAS, 35000 Rennes, France.
BMC Genomics. 2011 Nov 21;12:567. doi: 10.1186/1471-2164-12-567.
Integrative genomics approaches that combine genotyping and transcriptome profiling in segregating populations have been developed to dissect complex traits. The most common approach is to identify genes whose eQTL colocalize with QTL of interest, providing new functional hypothesis about the causative mutation. Another approach includes defining subtypes for a complex trait using transcriptome profiles and then performing QTL mapping using some of these subtypes. This approach can refine some QTL and reveal new ones.In this paper we introduce Factor Analysis for Multiple Testing (FAMT) to define subtypes more accurately and reveal interaction between QTL affecting the same trait. The data used concern hepatic transcriptome profiles for 45 half sib male chicken of a sire known to be heterozygous for a QTL affecting abdominal fatness (AF) on chromosome 5 distal region around 168 cM.
Using this methodology which accounts for hidden dependence structure among phenotypes, we identified 688 genes that are significantly correlated to the AF trait and we distinguished 5 subtypes for AF trait, which are not observed with gene lists obtained by classical approaches. After exclusion of one of the two lean bird subtypes, linkage analysis revealed a previously undetected QTL on chromosome 5 around 100 cM. Interestingly, the animals of this subtype presented the same q paternal haplotype at the 168 cM QTL. This result strongly suggests that the two QTL are in interaction. In other words, the "q configuration" at the 168 cM QTL could hide the QTL existence in the proximal region at 100 cM. We further show that the proximal QTL interacts with the previous one detected on the chromosome 5 distal region.
Our results demonstrate that stratifying genetic population by molecular phenotypes followed by QTL analysis on various subtypes can lead to identification of novel and interacting QTL.
将分离群体中的基因分型和转录组谱分析相结合的综合基因组学方法已被开发用于剖析复杂性状。最常见的方法是鉴定与感兴趣的 QTL 共定位的基因，为致病突变提供新的功能假说。另一种方法包括使用转录组谱定义复杂性状的亚型，然后使用其中一些亚型进行 QTL 映射。这种方法可以细化一些 QTL 并揭示新的 QTL。在本文中，我们引入了多重测试因子分析 (FAMT)，以更准确地定义亚型并揭示影响同一性状的 QTL 之间的相互作用。所使用的数据涉及 45 只半同胞雄性鸡的肝转录组谱，这些鸡的父本已知在染色体 5 远端区域约 168 cM 处存在影响腹部肥胖 (AF) 的 QTL 杂合。
使用这种方法可以解释表型之间隐藏的依赖结构，我们鉴定了与 AF 性状显著相关的 688 个基因，并区分了 5 种 AF 性状亚型，这些亚型不能通过经典方法获得的基因列表来观察到。在排除两种瘦禽亚型之一后，连锁分析显示在染色体 5 约 100 cM 处存在一个先前未检测到的 QTL。有趣的是，该亚型的动物在 168 cM QTL 处具有相同的 q 父系单倍型。这一结果强烈表明这两个 QTL 存在相互作用。换句话说，168 cM QTL 处的“q 构型”可能隐藏了在 100 cM 近侧区域存在的 QTL。我们进一步表明，近端 QTL 与先前在染色体 5 远端区域检测到的 QTL 相互作用。
我们的结果表明，通过分子表型对遗传群体进行分层，然后对各种亚型进行 QTL 分析，可以识别出新的和相互作用的 QTL。
