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1 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada
2 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
3 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Pediatrics, University of Montreal, Hopital Sainte Justine Research Centre, Montreal, Quebec, Canada
4 Pediatrics, University of Montreal, Hopital Sainte Justine Research Centre, Montreal, Quebec, Canada
5 Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; Research Instititute of the McGill University Health Centre, Montreal, Quebec, Canada
6 Lipid Research Centre and Department of Food Science and Nutrition, Laval University, Quebec, Canada
7 Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; Research Instititute of the McGill University Health Centre, Montreal, Quebec, Canada; Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
8 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; Research Instititute of the McGill University Health Centre, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: tom.hudson{at}mcgill.ca.
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 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 pedigrees, and demonstrate a spectrum of patterns of transmission, including co-segregation 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.
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