Tiny Genetic Differences Have Huge Consequences

A study led by McGill University researchers has demonstrated that small differences between individuals at the DNA level can lead to dramatic differences in the way genes produce proteins. These, in turn, are responsible for the vast array of differences in physical characteristics between individuals.

The study, part of the Genome Regulators in Disease (GRID) Project funded by Genome Canada and Genome Quebec, was led by Dr. Jacek Majewski of McGill University’s Department of Human Genetics and the McGill University and Genome Quebec Innovation Centre, and first-authored by his research associate Dr. Tony Kwan. It was published January 13 in the journal Nature Genetics.

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This study solves in part the mystery of how a relatively small number of differences within DNA protein coding sequences could be responsible for the enormous variety of phenotypic differences between individuals. It had previously been shown that individual differences reside in simple, relatively small variations in the DNA sequence called single nucleotide polymorphisms (SNPs, often pronounced “snips”), which exist primarily in the “junk code” of the DNA not previously known to have any profound genetic effect.

“There are many SNPs,” explained Dr. Majewski. “If you add them all together, you’d expect that two individuals would differ at more than a million of those positions. So we have a million or more small differences that distinguish you and me, and yet it would be very hard to explain all the phenotypic differences in the way we look, grow, and behave just by the handful of these protein coding differences.”

Majewski and his colleagues have demonstrated that the natural processing of messenger RNA (mRNA), via a process called splicing, is genetically controlled by these SNPs. The SNPs in certain individuals lead to changes in splicing and result in the production of drastically altered forms of the protein. These out-of-proportion consequences may lead to the development of genetic diseases such as cystic fibrosis and Type 1 diabetes.

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[Editor’s Note: “Genome-Wide Analysis Of Transcript Isoform Variation In Humans, Majewski, et al.” can be purchased or downloaded here. The abstract appears below.]

Tony Kwan1,2, David Benovoy1,2, Christel Dias1, Scott Gurd2, Cathy Provencher2, Patrick Beaulieu3, Thomas J Hudson1,2,4, Rob Sladek1,2 & Jacek Majewski1,2

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

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

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

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

Correspondence to: Jacek Majewski1,2 e-mail: jacek.majewski@mcgill.ca