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1 McGill University and Genome Quebec Innovation Centre H3A 1A4, Canada
2 Departments of Human Genetics and Medicine, McGill University H3A 1B1, Canada
3 Hopital Sainte Justine Research Centre, Department of Pediatrics, University of Montreal H3T 1C5, Canada
4 Research Institute of the McGill University Health Centre, Montreal H3G 1A4, Canada
5 Lipid Research Centre and Department of Food Science and Nutrition, Laval University, Quebec G1K 7P4, Canada
6 Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada
The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or "allelic imbalances," can be observed in multiple samples derived from reference CEPH ("Centre d’Etude du Polymorphisme Humain") pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes (IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.
transcription; polymorphism
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