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Modified Penetrance of Genetic Coding Variants Affects Disease Risk in Humans

NEW YORK (GenomeWeb) – Researchers in the US and Spain have published a study today in Nature Genetics that they believe contains an explanation for the mechanism underlying the biological phenomenon of variable penetrance — why individuals carrying identical gene mutations for a disease end up having varying severity or symptoms of that disease.

"Our findings suggest that a person's disease risk is potentially determined by a combination of their regulatory and coding variants, and not just one or the other," New York Genome Center Core Faculty Member, Columbia University Department of Systems Biology Assistant Professor, and senior author Tuuli Lappalainen said in a statement.

"Most previous studies have focused on either looking for coding variants or regulatory variants that affect disease in these individuals or potentially looking at common variants that could affect disease," Lappalainen added. "We have merged these two fields into one clear hypothesis that uses data from both of them, which was fairly unheard of before."

Using genotype and RNA-sequencing data from 7,051 samples across 44 tissues from 449 individuals in the Genotype-Tissue Expression Project (GTEx) database, the researchers found that cis-regulatory variation modifies the penetrance of coding variants. They measured the regulatory haplotype of coding variants using allelic expression data, which captures cis effects of both expression and splice regulatory variation at the individual level.

"Altogether, combined with observations from functional data of allelic expression, these results suggest that joint effects between regulatory and coding variants have shaped human genetic variation in the general population through purifying selection depleting haplotype combinations, whereby cis-regulatory variants increase the penetrance of pathogenic coding variants," the authors wrote. "These patterns are significant and consistent."

Through various analyses, they observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. However, in cancer and autism patients, they conversely found an enrichment of penetrance-increasing haplotype configurations for pathogenic variants in disease-implicated genes.

They studied tumor suppressor genes that are known to harbor germline risk variants for cancer, and used transmission phased exome and imputed SNP array genotype data from the Simons Simplex Collection of 2,600 simplex families with one child with autism, their parents, and any unaffected siblings. They then applied their genetic test for regulatory modifiers of penetrance to these data sets, first separately and then jointly.

Using this approach, the researchers found that in disease-associated genes, case-specific rare pathogenic variants were significantly enriched for haplotype configurations where the major allele was on the lower-expressed haplotype, with control-specific variants showing no enrichment. When they analyzed shared variants, they found that in control individuals these were enriched for haplotype configurations where the major allele was on the higher-expressed haplotype. This suggested to the team that regulatory haplotype configuration of coding variants affects disease risk.

The researchers also experimentally validated this model by editing a Mendelian SNP using CRISPR-Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. They found that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

"A key component of our work was the integrated analysis of rare coding variants and common regulatory variants, which are too often considered as separate domains in human genetics, despite the fact that their interplay is gaining increasing interest," the authors concluded.

"Currently, rare coding variants are studied largely by exome sequencing in relatively rare diseases, and common regulatory variant analyses are focused on applications in genome-wide association studies of common diseases," they added. "Setting the stage for future studies, our work supports one of the few concrete and generalizable models of modified penetrance of genetic variants in humans, with a clear biological mechanism based on the net effect of variants on the dosage of functional gene product, and is backed by solid empirical analysis of genome-wide genetic data."