Allele-Specific Gene Expression Is Widespread Across the Genome and Biological Processes

Allelic specific gene expression (ASGE) appears to be an important factor in human phenotypic variability and as a consequence, for the development of complex traits and diseases. In order to study ASGE across the human genome, we have performed a study in which genotyping was coupled with an analysis of ASGE by screening 11,500 SNPs using the Mapping 10 K Array to identify differential allelic expression. We found that from the 5,133 SNPs that were suitable for analysis (heterozygous in our sample and expressed in peripheral blood mononuclear cells), 2,934 (57%) SNPs had differential allelic expression. Such SNPs were equally distributed along human chromosomes and biological processes. We validated the presence or absence of ASGE in 18 out 20 SNPs (90%) randomly selected by real time PCR in 48 human subjects. In addition, we observed that SNPs close to -but not included in- segmental duplications had increased levels of ASGE. Finally, we found that transcripts of unknown function or non-coding RNAs, also display ASGE: from a total of 2,308 intronic SNPs, 1510 (65%) SNPs underwent differential allelic expression. In summary, ASGE is a widespread mechanism in the human genome whose regulation seems to be far more complex than expected.

[1]  Joaquín Dopazo,et al.  FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes , 2004, Bioinform..

[2]  E. Lander,et al.  Detection of regulatory variation in mouse genes , 2002, Nature Genetics.

[3]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[4]  B. Weinshenker,et al.  Interferon gamma allelic variants: sex-biased multiple sclerosis susceptibility and gene expression. , 2008, Archives of neurology.

[5]  Thomas E. Royce,et al.  Global Identification of Human Transcribed Sequences with Genome Tiling Arrays , 2004, Science.

[6]  Michael C O'Donovan,et al.  A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. , 2003, American journal of human genetics.

[7]  R. Spielman,et al.  Natural variation in human gene expression assessed in lymphoblastoid cells , 2003, Nature Genetics.

[8]  G. Churchill,et al.  Variation in gene expression within and among natural populations , 2002, Nature Genetics.

[9]  T. Hudson,et al.  Mapping common regulatory variants to human haplotypes. , 2005, Human molecular genetics.

[10]  B Pickard,et al.  Imprinting mechanisms. , 1998, Genome research.

[11]  Thomas J. Hudson,et al.  Cis-Acting Regulatory Variation in the Human Genome , 2004, Science.

[12]  Pablo Villoslada,et al.  European Population Substructure: Clustering of Northern and Southern Populations , 2006, PLoS genetics.

[13]  G. Helt,et al.  Transcriptional Maps of 10 Human Chromosomes at 5-Nucleotide Resolution , 2005, Science.

[14]  I. Craig,et al.  The Genetic Basis for Sex Differences in Human Behaviour: Role of the Sex Chromosomes , 2004, Annals of human genetics.

[15]  Jun Kawai,et al.  Pseudo–Messenger RNA: Phantoms of the Transcriptome , 2006, PLoS genetics.

[16]  K. Buetow,et al.  Allelic variation in gene expression is common in the human genome. , 2003, Genome research.

[17]  Joshua M. Korn,et al.  Mapping and sequencing of structural variation from eight human genomes , 2008, Nature.

[18]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[19]  Enrico Petretto,et al.  Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans , 2006, Nature.

[20]  Bert Vogelstein,et al.  Allelic Variation in Human Gene Expression , 2002, Science.

[21]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[22]  Maciej Szymanski,et al.  Non-coding, mRNA-like RNAs database Y2K , 2000, Nucleic Acids Res..

[23]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[24]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[25]  Douglas Grove,et al.  Denoising array-based comparative genomic hybridization data using wavelets. , 2005, Biostatistics.

[26]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  L. Almasy,et al.  Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes , 2007, Nature Genetics.

[28]  S. Pääbo,et al.  Intra- and Interspecific Variation in Primate Gene Expression Patterns , 2002, Science.

[29]  K. Kinzler,et al.  Small changes in expression affect predisposition to tumorigenesis , 2002, Nature Genetics.

[30]  Pablo Villoslada,et al.  Analysis and Application of European Genetic Substructure Using 300 K SNP Information , 2008, PLoS genetics.