Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'

Abstract

We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified 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 coregulated transcripts.

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

“…If the expression of Kras2 was solely under the control of trans-acting factors (trans-QTL) 26,27 at different genomic locations, this would not be compatible with the model proposed. To examine these alternative possibilities, we generated an additional independent population of untreated, wild-type (FVBSPRETF1)FVB backcross mice, and measured the expression levels of Kras2 in the normal lungs of a total of 47 animals.…”

Multiple sclerosis genetics: leaving no stone unturned

“…Using this approach, a gene expression pattern strongly associated with murine obesity was identified leading to the identification of four new QTL linked to this complex phenotype. 110 More recently, genetical genomics yielded the identification of regulatory networks affecting stem cell function, 111 blood pressure, 112 and some neural phenotypes. 113 In humans, analysis of genomically controlled variation in gene expression has also been reported 114 opening a promising venue for unraveling biological pathways in complex diseases.…”

Evolutionary conservation of metabolism explains howDrosophila nutrigenomics can help us understand human nutrigenomics

“…This approach has been called "genetical genomics" because it merges classical QTL genetics studies with whole-genome microarray analyses (Bystrykh et al, 2005;Carlborg et al, 2005;Jansen and Nap, 2001;Li et al, 2005;PerezEnciso and Misztal, 2004). We have described approaches to utilize genetical genomics approaches to nutrigenomic studies in Drosophila (Page and Ruden, 2005).…”

“…In addition to pioneering studies in yeast and Arabidopsis, genetical genomics studies were also recently conducted with several isolated cell types in mice (Bystrykh et al, 2005;Carlborg et al, 2005;Jansen and Nap, 2001;Li et al, 2005;Perez-Enciso and Misztal, 2004). In yeast and Arabidopsis genetical genomics studies, it was found that the great majority of QTLs identified are "cis-QTL," which are polymorphisms in the promoter and enhancer regions that alter the expression levels.…”

“…Interestingly, studies with mouse cells, such as fluorescentactivated cell sorter (FACS)-purified hematopoetic stem cells, identified large-effect trans-QTLs that the authors called "master regulatory genes" because they can alter the expression of over 1,000 genes (Bystrykh et al, 2005). Different tissues, such as purified brain cells or immune cells have large-effect trans-QTLs in different regions of the genome, suggesting that "master regulatory genes" are numerous and tissue specific (Bystrykh et al, 2005).…”