Identification of genes and quantitative trait loci (QTL) that control hematopoietic stem cell functioning

We have combined large-scale mRNA expression and gene mapping methods to identify genes and loci that control hematopoietic stem cell (HSC) functioning. mRNA expression levels were measured in purified HSC isolated from a panel of densely genotyped recombinant inbred mouse strains. Quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts were mapped. Comparison of the physical transcript position with the location of the controlling QTL identified polymorphic cis-acting stem cell genes. In addition, multiple trans-acting control loci were highlighted that modify expression of large numbers of genes. These groups of co-regulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of strong candidate genes involved with HSC turnover. We compared expression QTLs in HSC and brain from the same animals, and document both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of co-regulated transcripts. Keywords: other本研究结合大规模mRNA表达谱与基因定位方法，旨在鉴定调控造血干细胞（hematopoietic stem cell, HSC）功能的基因与基因座。研究人员从一组经高密度基因分型的重组近交小鼠品系分离的纯化造血干细胞中，测定了其mRNA表达水平。本研究定位了与数千条转录本的表达变异相关的数量性状位点（quantitative trait loci, QTLs）。通过比对转录本的物理位置与调控性QTL的定位区域，研究鉴定出了携带多态性的顺式作用（cis-acting）干细胞基因。此外，本研究还筛选出多个可调控大量基因表达的反式作用（trans-acting）调控基因座。这些共调控转录本群组可揭示调控干细胞变异的通路。我们通过鉴定与造血干细胞更新相关的强效候选基因，阐释了这一研究思路。我们对比了同一批动物中造血干细胞与脑组织的表达QTL，证实了既存在共享的QTL，也存在组织特异性QTL。本研究的数据可通过WebQTL获取——该工具为基于网页的交互界面，支持自定义遗传连锁分析与共调控转录本的鉴定。关键词：其他