Letter | Published:

Genome-wide analysis of transcript isoform variation in humans

Nature Genetics 40, 225–231 (2008) | Download Citation

Subjects

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

    , , & Estimating rates of alternative splicing in mammals and invertebrates. Nat. Genet. 36, 915–917 (2004).

  2. 2.

    Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72, 291–336 (2003).

  3. 3.

    & Pre-mRNA splicing and human disease. Genes Dev. 17, 419–437 (2003).

  4. 4.

    & The splicing machinery is a genetic modifier of disease severity. Trends Genet. 21, 480–483 (2005).

  5. 5.

    Genotype and phenotype in cystic fibrosis. Respiration 67, 117–133 (2000).

  6. 6.

    et al. OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. Diabetes 54, 1588–1591 (2005).

  7. 7.

    et al. Genetic control of alternative splicing in the TAP2 gene: possible implication in the genetics of type 1 diabetes. Diabetes 56, 270–275 (2007).

  8. 8.

    et al. Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Hum. Mol. Genet. 16, 579–591 (2007).

  9. 9.

    et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl. Acad. Sci. USA 104, 6758–6763 (2007).

  10. 10.

    et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).

  11. 11.

    et al. Common genetic variants account for differences in gene expression among ethnic groups. Nat. Genet. 39, 226–231 (2007).

  12. 12.

    et al. Genome-wide associations of gene expression variation in humans. PLoS Genet 1, e78 (2005).

  13. 13.

    et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

  14. 14.

    et al. Discovery of tissue-specific exons using comprehensive human exon microarrays. Genome Biol. 8, R64 (2007).

  15. 15.

    et al. Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array. BMC Genomics 7, 325 (2006).

  16. 16.

    et al. Heritability of alternative splicing in the human genome. Genome Res. 17, 1210–1218 (2007).

  17. 17.

    International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  18. 18.

    & Empirical threshold values for quantitative trait mapping. Genetics 138, 963–971 (1994).

  19. 19.

    et al. Sequence polymorphisms cause many false cis eQTLs. PLoS ONE 2, e622 (2007).

  20. 20.

    , , , & Allele-specific transcript isoforms in human. FEBS Lett. 577, 233–238 (2004).

  21. 21.

    et al. Identification of common genetic variation that modulates alternative splicing. PLoS Genet 3, e99 (2007).

  22. 22.

    & Large scale study of protein domain distribution in the context of alternative splicing. Nucleic Acids Res. 31, 4828–4835 (2003).

  23. 23.

    , & Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl. Acad. Sci. USA 100, 189–192 (2003).

  24. 24.

    , , & A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res. 33, 201–212 (2005).

  25. 25.

    & Computational analysis of 3′-ends of ESTs shows four classes of alternative polyadenylation in human, mouse, and rat. Genome Res. 15, 369–375 (2005).

  26. 26.

    , , & Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

  27. 27.

    , & MicroRNAs direct rapid deadenylation of mRNA. Proc. Natl. Acad. Sci. USA 103, 4034–4039 (2006).

  28. 28.

    & Solving the riddle of the bright mismatches: labeling and effective binding in oligonucleotide arrays. Phys. Rev. E 68, 011906 (2003).

  29. 29.

    & Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Methodol. 57, 289–300 (1995).

  30. 30.

    & Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–386 (2000).

Download references

Acknowledgements

The authors would like to thank D. Serre, T. Pastinen, E. Harmsen and H. Zuzan for helpful discussions and D. Sinnett for technical assistance. This work is supported by Genome Canada, Genome Québec and the Canadian Institutes of Health Research (CIHR). T.J.H. is the recipient of a Clinician-Scientist Award in Translational Research by the Burroughs Wellcome Fund and an Investigator Award from CIHR. J.M. is a recipient of a Canada Research Chair.

Author information

Affiliations

  1. Department of Human Genetics, McGill University, 740 Dr. Penfield, Room 7210, Montréal, Québec H3A 1A4, Canada.

    • Tony Kwan
    • , David Benovoy
    • , Christel Dias
    • , Thomas J Hudson
    • , Rob Sladek
    •  & Jacek Majewski

  2. McGill University and Génome Québec Innovation Centre, 740 Dr. Penfield, Room 7210, Montréal, Québec H3A 1A4, Canada.

    • Tony Kwan
    • , David Benovoy
    • , Scott Gurd
    • , Cathy Provencher
    • , Thomas J Hudson
    • , Rob Sladek
    •  & Jacek Majewski

  3. Division of Hematology-Oncology, Research Centre, Sainte-Justine Hospital, Montréal, Québec H3T 1C5, Canada.

    • Patrick Beaulieu

  4. Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, Ontario M5G 1L7, Canada.

    • Thomas J Hudson

Authors

  1. Search for Tony Kwan in:

  2. Search for David Benovoy in:

  3. Search for Christel Dias in:

  4. Search for Scott Gurd in:

  5. Search for Cathy Provencher in:

  6. Search for Patrick Beaulieu in:

  7. Search for Thomas J Hudson in:

  8. Search for Rob Sladek in:

  9. Search for Jacek Majewski in:

Corresponding author

Correspondence to Jacek Majewski.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1,2 and Supplementary Tables 1–3

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2007.57

Further reading Further reading