Identification of common genetic variants that account for transcript isoform variation between human populations

Abstract

In addition to the differences between populations in transcriptional and translational regulation of genes, alternative pre-mRNA splicing (AS) is also likely to play an important role in regulating gene expression and generating variation in mRNA and protein isoforms. Recently, the genetic contribution to transcript isoform variation has been reported in individuals of recent European descent. We report here results of an investigation of the differences in AS patterns between human populations. AS patterns in 176 HapMap lymphoblastoid cell lines derived from individuals of European and African ancestry were evaluated using the Affymetrix GeneChip® Human Exon 1.0 ST Array. A variety of biological processes such as response to stimulus and transcription were found to be enriched among the differentially spliced genes. The differentially spliced genes also include some involved in human diseases that have different prevalence or susceptibility between populations. The genetic contribution to the population differences in transcript isoform variation was then evaluated by a genome-wide association using the HapMap genotypic data on single nucleotide polymorphisms (SNPs). The results suggest that local and distant genetic variants account for a substantial fraction of the observed transcript isoform variation between human populations. Our findings provide new insights into the complexity of the human genome as well as the health disparities between the two populations.

Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts

“…Earlier studies have shown that common genetic variants contribute significantly to the individual differences in proteincoding gene expression variation (Cheung et al 2003(Cheung et al , 2005Morley et al 2004;Deutsch et al 2005;Stranger et al 2005Stranger et al , 2007Spielman et al 2007;Storey et al 2007) and transcript isoform variation (Hull et al 2007;Kwan et al 2007Kwan et al , 2008Zhang et al 2009). Our study adds a level of complexity to cellular gene expression regulation by revealing that cis-and trans-eQTLs can affect the expression of miRNAs that are themselves regulatory molecules.…”

Pharmacogenomic Discovery Using Cell-Based Models

“…1000genomes.org), with the most detailed catalog of human genetic variation, are emerging on the 270 HapMap LCLs. In addition, basal gene expression data are available for a portion of the 270 LCLs from Affymetrix Focus array (Spielman et al, 2007;Storey et al, 2007), Affymetrix Human Exon 1.0 ST array (exon array) Zhang et al, 2009), and Illumina BeadChips (Stranger et al, 2007a,b). Thus, with genotypic and expression data, the HapMap LCLs are a rich resource that requires only pharmacological phenotyping to evaluate genotype-phenotype, expression-phenotype, or genotype-expression-phenotype relationships.…”

Association of TCF7L2 Gene Polymorphisms with T2DM in the Population of Juana Koslay, San Luis Province, Argentina

“…All exons of TCF7L2 were sequenced in multiple patients and controls but no coding variation was identified [6] suggesting that T2DM risk is associated with a non-coding variation. Genetic variations may affect levels of expression and splicing architecture of mRNA transcripts [21] [22] thus several studies have tested the relationships between TCF7L2 mRNA expression and genotypes of rs7903146 and rs12255372 in human tissues [23] [24].…”