A survey of genetic and epigenetic variation affecting human gene expression.
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.
Pastinen
Tomi
T
McGill University and Genome Quebec Innovation Centre H3A 1A4, Canada.
Sladek
Robert
R
Gurd
Scott
S
Sammak
Alya'a
A
Ge
Bing
B
Lepage
Pierre
P
Lavergne
Karine
K
Villeneuve
Amelie
A
Gaudin
Tiffany
T
Brändström
Helena
H
Beck
Allon
A
Verner
Andrei
A
Kingsley
Jade
J
Harmsen
Eef
E
Labuda
Damian
D
Morgan
Kenneth
K
Vohl
Marie-Claude
MC
Naumova
Anna K
AK
Sinnett
Daniel
D
Hudson
Thomas J
TJ
D022981:Allelic Imbalance; D002460:Cell Line; D004303:Dosage Compensation, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic