Gerrits Alice, Li Yang, Tesson Bruno M, Bystrykh Leonid V, Weersing Ellen, Ausema Albertina, Dontje Bert, Wang Xusheng, Breitling Rainer, Jansen Ritsert C, de Haan Gerald
Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
PLoS Genet. 2009 Oct;5(10):e1000692. doi: 10.1371/journal.pgen.1000692. Epub 2009 Oct 16.
Genetical genomics is a strategy for mapping gene expression variation to expression quantitative trait loci (eQTLs). We performed a genetical genomics experiment in four functionally distinct but developmentally closely related hematopoietic cell populations isolated from the BXD panel of recombinant inbred mouse strains. This analysis allowed us to analyze eQTL robustness/sensitivity across different cellular differentiation states. Although we identified a large number (365) of "static" eQTLs that were consistently active in all four cell types, we found a much larger number (1,283) of "dynamic" eQTLs showing cell-type-dependence. Of these, 140, 45, 531, and 295 were preferentially active in stem, progenitor, erythroid, and myeloid cells, respectively. A detailed investigation of those dynamic eQTLs showed that in many cases the eQTL specificity was associated with expression changes in the target gene. We found no evidence for target genes that were regulated by distinct eQTLs in different cell types, suggesting that large-scale changes within functional regulatory networks are uncommon. Our results demonstrate that heritable differences in gene expression are highly sensitive to the developmental stage of the cell population under study. Therefore, future genetical genomics studies should aim at studying multiple well-defined and highly purified cell types in order to construct as comprehensive a picture of the changing functional regulatory relationships as possible.
遗传基因组学是一种将基因表达变异映射到表达数量性状位点（eQTLs）的策略。我们在从重组近交系小鼠品系的BXD面板中分离出的四个功能不同但发育密切相关的造血细胞群体中进行了一项遗传基因组学实验。该分析使我们能够分析不同细胞分化状态下eQTL的稳健性/敏感性。虽然我们鉴定出大量（365个）在所有四种细胞类型中均持续活跃的“静态”eQTL，但我们发现了更多（1283个）显示细胞类型依赖性的“动态”eQTL。其中，分别有140、45、531和295个在干细胞、祖细胞、红细胞和髓细胞中优先活跃。对这些动态eQTL的详细研究表明，在许多情况下，eQTL特异性与靶基因的表达变化相关。我们没有发现不同细胞类型中由不同eQTL调控的靶基因的证据，这表明功能调控网络内的大规模变化并不常见。我们的结果表明，基因表达中的遗传差异对所研究细胞群体的发育阶段高度敏感。因此，未来的遗传基因组学研究应旨在研究多种定义明确且高度纯化的细胞类型，以便尽可能全面地描绘不断变化的功能调控关系。
