Genome-wide analysis of transcript isoform variation in humans

We have performed a genome-wide analysis of common genetic variation controlling differential expression of transcript isoforms in the CEU HapMap population using a comprehensive exon tiling microarray covering 17,897 genes. We detected 324 genes with significant associations between flanking SNPs and transcript levels. Of these, 39% reflected changes in whole gene expression and 55% reflected transcript isoform changes such as splicing variants (exon skipping, alternative splice site use, intron retention), differential 5′ UTR (initiation of transcription) use, and differential 3′ UTR (alternative polyadenylation) use. These results demonstrate that the regulatory effects of genetic variation in a normal human population are far more complex than previously observed. This extra layer of molecular diversity may account for natural phenotypic variation and disease susceptibility.

[1]  S. Hunt,et al.  Genome-Wide Associations of Gene Expression Variation in Humans , 2005, PLoS genetics.

[2]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[3]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[4]  Tyson A. Clark,et al.  Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array , 2006, BMC Genomics.

[5]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[6]  J. Ott,et al.  Estimating rates of alternative splicing in mammals and invertebrates , 2004, Nature Genetics.

[7]  Constantin Polychronakos,et al.  Genetic Control of Alternative Splicing in the TAP2 Gene , 2007, Diabetes.

[8]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[9]  J. Kelso,et al.  Allele‐specific transcript isoforms in human , 2004, FEBS letters.

[10]  F. Pociot,et al.  OAS 1 Splice Site Polymorphism Controlling Antiviral Enzyme Activity Influences Susceptibility to Type 1 Diabetes , 2005 .

[11]  Tyson A. Clark,et al.  Discovery of tissue-specific exons using comprehensive human exon microarrays , 2007, Genome Biology.

[12]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[13]  T. Cooper,et al.  Pre-mRNA splicing and human disease. , 2003, Genes & development.

[14]  Bin Tian,et al.  A large-scale analysis of mRNA polyadenylation of human and mouse genes , 2005, Nucleic acids research.

[15]  Joshua T. Burdick,et al.  Common genetic variants account for differences in gene expression among ethnic groups , 2007, Nature Genetics.

[16]  Felix Naef,et al.  Solving the riddle of the bright mismatches: labeling and effective binding in oligonucleotide arrays. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[17]  G. Hannon,et al.  Control of translation and mRNA degradation by miRNAs and siRNAs. , 2006, Genes & development.

[18]  D. Black.  Mechanisms of alternative pre-messenger RNA splicing. , 2003, Annual review of biochemistry.

[19]  Harry Zuzan,et al.  Heritability of alternative splicing in the human genome. , 2007, Genome research.

[20]  F. Pociot,et al.  OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. , 2005, Diabetes.

[21]  Geoffrey Hom,et al.  Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus , 2007, Proceedings of the National Academy of Sciences.

[22]  S. Brenner,et al.  Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Alberts,et al.  Sequence Polymorphisms Cause Many False cis eQTLs , 2007, PloS one.

[24]  T. Marr,et al.  alternative polyadenylation in human , mouse , and rat Computational analysis of 3 '-ends of ESTs shows four classes of data , 2005 .

[25]  A. Gutin,et al.  Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. , 2007, Human molecular genetics.

[26]  J. Zieleński.  Genotype and Phenotype in Cystic Fibrosis , 2000, Respiration.

[27]  Ligang Wu,et al.  MicroRNAs direct rapid deadenylation of mRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Kerem,et al.  The splicing machinery is a genetic modifier of disease severity. , 2005, Trends in genetics : TIG.

[29]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[30]  Martin S. Taylor,et al.  Identification of Common Genetic Variation That Modulates Alternative Splicing , 2007, PLoS genetics.

[31]  Russ B Altman,et al.  Large scale study of protein domain distribution in the context of alternative splicing. , 2003, Nucleic acids research.

[32]  Joshua T. Burdick,et al.  Mapping determinants of human gene expression by regional and genome-wide association , 2005, Nature.