A survey of genetic and epigenetic variation affecting human gene expression

TLDR

The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. The study surveys human genes with allelic expression differences to identify cis‑acting genetic or epigenetic regulators, and presents a pipeline for efficient detection and characterization of such allele‑specific expression. Allelic transcript expression in heterozygotes is quantified by relative intragenic marker allele levels in RNA, and the authors provide a pipeline that streamlines detection and characterization of these allele‑specific expression patterns. The survey of 193 SNPs in 129 genes identified 23 genes (18%) with allele‑specific expression imbalances, with patterns ranging from Mendelian cosegregation to random monoallelic expression in IL1A, HTR2A, and FGB, and further evidence from BTN3A2 linking specific SNPs/haplotypes to differential transcript levels.

Abstract

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.