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Genetic analysis of genome-wide variation in human gene expression - PubMed

  • ️Thu Jan 01 2004

. 2004 Aug 12;430(7001):743-7.

doi: 10.1038/nature02797. Epub 2004 Jul 21.

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Genetic analysis of genome-wide variation in human gene expression

Michael Morley et al. Nature. 2004.

Abstract

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.

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Figures

Figure 1
Figure 1

Genome scans for ten expression phenotypes. Chromosomal location of the regulated (target) gene is given in parentheses. The top eight panels show examples of linkage with cis- or trans-acting transcriptional regulators. The bottom two panels show examples of phenotypes regulated by several unlinked genetic determinants.

Figure 2
Figure 2

Master transcriptional regulators. a, Distribution of significant linkage peaks (P < 3.7 × 10−5) in 5-Mb windows across the autosomal genome. Arrowheads indicate the two windows (located on chromosomes 14 and 20) that contain regulators for the most expression phenotypes. b, Dendrogram representing hierarchical clustering of genes whose transcriptional regulators map to one 5-Mb window. Target genes for the hotspot of regulation on chromosome 14q32 are shown. Expression levels of genes with branches connected to the right of the dotted line are correlated at P < 0.001 (see text).

Figure 3
Figure 3

Regression of expression phenotype of LOC64167 and HSD17B12 on nearby SNPs. For LOC64167, the distance between SNP markers rs4869311 and rs1230381 is 30 kb. For HSD17B12, the distance between hCV289210 and rs1061810 is 172 kb.

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