A team of researchers from Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard has developed a groundbreaking strategy to determine whether two mutations in a specific gene are present in the same copy of the gene (in cis) or different copies of the gene (in trans). This innovative approach will help to interpret results from clinical genetic testing, particularly for recessive diseases where both copies of the gene are affected by a damaging genetic variant.
The study, published in Nature Genetics, involved the analysis of sequencing data from 125,748 individuals in the Genome Aggregation Database (gnomAD), a global open-access human genome resource that focuses on protein coding regions of the genome. Using a statistical method known as an expectation-maximization algorithm, the team estimated whether pairs of rare variants were found in cis or in trans.
According to senior author Kaitlin E. Samocha, Ph.D., the success rate of the method in estimating the phase of rare variants was 96% in two independent datasets, including a group of patients with recessive Mendelian conditions. The accuracy of the approach remained high even for very rare variants and across different genetic ancestry groups.
Interestingly, the researchers discovered that only a small number of genes were affected by loss-of-function variants predicted to be in trans, which leads to the complete loss of the associated protein. In most cases, when two rare loss-of-function variants were found in the same gene, they were in cis. Therefore, when such variant pairs are observed in the same gene in an individual in the general population, it is more likely that these variants are carried on the same copy of the gene rather than on different copies.
Samocha explains that the team has publicly released phasing predictions for over five billion pairs of rare variants found in the gnomAD dataset, as well as the counts per gene of variant pairs predicted to be in trans. These findings are available at gnomad.broadinstitute.org.
While the focus of this work was on estimating the phase of rare coding variants in expressed genes, the researchers intend to include noncoding and other variant types in their phasing estimates in the future. Moreover, as more genome sequencing data becomes available, they plan to compare their approach with more advanced phasing algorithms and evaluate its utility in a clinical genetic setting.
Overall, this novel approach developed by the research team offers significant potential in understanding the contributions of rare gene variant pairs to disease and improving the accuracy of clinical genetic testing.
Source: Coherent Market Insights, Public sources, Desk research
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