It’s abundantly clear by now that the sequence of our genes can be very important to our health. Mutations in some key areas can lead to the development of diseases such as cancer. However, gene sequence isn’t everything. It’s necessary to know when and at what levels that mutated gene is expressed in the body’s cells and tissues.
This analysis is complicated by the fact that most of us have two copies of every gene - one from our father and one from our mother (the sex chromosomes X and Y would be an exception; people with conditions like Down syndrome that are caused by abnormal chromosomal copy numbers, another). The two copies, called alleles, are not always expressed in the same way (a phenomenon called allele-specific expression). In particular, structural changes or other modifications to the alleles, or the RNA that is made from them, can significantly affect levels of expression. This matters when one copy has a mutation that could cause a disease like cancer. That mutation could be very important if that allele is preferentially expressed, or less important if its partner is favored.
Understanding relative levels of allele expression is therefore critical to determining the effect of particular mutations in our genome. But it’s been very difficult to accomplish - in part because allele-specific expression can vary among our body’s tissues.
Recently, Stanford researchers Stephen Montgomery, PhD, an assistant professor of pathology and genetics, and Jin Billy Li, PhD, an assistant professor of genetics, devised a way to use microfluidic and deep-sequencing technology to measure the relative levels of expression of each allele in various tissues. (The research was published - subscription required - in January in Nature Methods.) Now they’ve taken the research one step further to look at the varying expression of potentially damaging alleles across ten tissues from a single individual. As Montgomery explained in an e-mail to me:
We were able to learn that as many as one-third of personal genome variants (that is, potentially damaging mutations that would be detected by genome sequencing within an individual) can be modified by allele-specific expression in ways that could influence individual outcomes. Therefore, just knowing a variant exists is only one step towards predicting clinical outcome in an individual. It is also necessary to know the context of that variant. Is the damaging allele in a gene that is abundantly expressed within and across an individual’s tissues?
Montgomery and Li published their most recent findings in today’s issue of PLOS Genetics. They were recently awarded a grant from the National Human Genome Research Institute to study allele-specific expression in thousands of tissues from 100 donors during the next three years. The grant is part of the institute’s Genotype-Tissue Expression effort, or GTEx.