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NY Genome Center Team Wins $1.7M NIH Grant to Study Penetrance

NEW YORK (GenomeWeb) – A research team from the New York Genome Center (NYGC) has been awarded a five-year, $1.7 million grant from the National Institute of General Medical Sciences to study penetrance, a phenomenon where the severity of effects of a particular genetic mutation differs among individuals who carry it.

"Our goal is to explore new ways to look at how genetic variants function together with each other, and what kind of effect that interaction has on human traits and disease," NYGC's Tuuli Lappalainen, the study's principal investigator, said in a statement. "What we are focusing on in our research is to describe the basic paradigms and concepts of what is happening on a cellular level. We propose to demonstrate that these interactions actually do exist in the human genome and to determine their significance."

With the grant funding, Lappalainen and her collaborators will focus on haplotype epistasis, a type of modified penetrance caused by a genetic interaction wherein a cis-regulatory variant modifies the penetrance of coding variants of the target gene.

Using various datasets covering the general human population and diseases with different genetic architecture, the scientists plan to first study signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant epistatic effects, according to the grant's abstract. "This will shed light on the modes and prevalence of haplotype epistasis, and the role of epistatic selection in shaping the spectrum of genetic variation in humans."

Because haplotype epistasis has been shown to influence genetic disease risk in certain instances but is rarely considered in genetic studies analyzing individual variants, Lappalainen and her team further aim to characterize haplotype epistasis in autism, which is caused by rare genetic mutations, as well as in more common diseases including cancer. They also hope to be able to validate examples of epistasis by using CRISPR to introduce specific gene mutations human cell lines, followed by cellular phenotyping.

The grant began on May 1 and runs until April 30, 2022.