‘Dose sensitivity map’ predicts active ingredients in copy number variants | Domain

A new map catalogs hundreds of rare copy number variants (CNVs) — duplications, deletions or insertions of large portions of DNA — associated with 54 conditions, including autism. It also identifies individual genes within CNVs that are likely to drive traits of different conditions, the researchers explain in a new study. study.

The study investigator says the reference can inform statistical models to predict which CNVs are likely to be more or less abundant among people with certain conditions. Ryan Collinsa graduate student in Michael TalkowskiLaboratory at Massachusetts General Hospital in Boston. “This is especially true for neurodevelopmental phenotypes such as autism spectrum disorder, and others.”

Rare CNVs – those seen in less than 1 percent of the population – can predispose people to a combination of traits and neurodevelopmental conditions, including autism And some of the syndromes associated with autism. Scientists suspect that doubling or missing certain genes within CNVs leads to neurodevelopmental states, but they have historically struggled to identify these “driver genes,” Collins says.

“We saw this problem: the need for a better interpretation of these copy number variants,” Collins says. “We set out to create new and larger catalogs of these copy number variants in as many people as possible that we could pool into one research study.”

TThe analysis was based on current CNV data from 17 different institutions and 950,278 people, about half of whom had at least one of 54 different physical or neurological traits or conditions. The team systematically reviewed strips of 200,000 nucleotides long from each chromosome at a time, shifting the focus by just 10,000 nucleotides from one strand to another.

They identified a total of 558,113 rare CNVs of 100,000 or more nucleotides in size, which is a “relatively coarse solution,” says lead researcher Talkosky, director of the Center for Genomic Medicine at Massachusetts General Hospital.

The team found that 163 of these people were more common among people with health conditions than controls, and another 15 had lower trust ties. These 178 CNVs were significantly more likely than other CNVs to contain genes previously associated with any of the 95 cases.

All but 12 CNVs overlapped with protein-coding genes. More than half contain at least one driver gene, identified by an algorithm that combs through each variant of “dose-sensitive” genes: those that are rarely mutated in the general population and that have previously been linked to health or neurodevelopmental conditions. They identified 121 genes in total, including top candidates for autism such as Majel 2And the RAI1And the SHNK3 And the UBE3A.

The machine-learning model created by the team recorded a dose-sensitivity of 18,641 protein-coding genes throughout the genome, of which 2,987 were marked sensitive to deletion and 1,559 were sensitive to duplication.

The paper describing the algorithm and its “dose sensitivity map” appeared in August in cell.

THe says the procedures and algorithm the team used could help other researchers analyze additional genetic data sets David Ledbetter, an assistant professor of psychiatry at the University of Florida at Gainesville, was not involved in the work. A similar set of tools was used for Predict effect sizes CNVs are based on autism scores and IQ, and it would be interesting to compare the results of the two approaches, he adds.

This work can help clarify the relationship between CNV size and its effect — two very different, and often intertwined, measures, he says. Krista Liz Martin, chief scientific officer of Geisinger Health System in Danville, Pennsylvania, who was not involved in the work. “You can have [10 million nucleotide base-pair] A deletion with no insufficient genes in that region, versus a [100,000 base-pair] Deleting a gene causes significant phenotypic effects.”

The map can also help researchers understand the effects of variables in non-coding geneswhich do not encode proteins, he says Sarah Elsie, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, who was not involved in the work. “Non-coding variation may have significant effects on gene expression but may be excluded or prioritized differently if a nearby gene is not known to be dose sensitive.”

The team is pursuing this study by mapping CNVs at a higher resolution — 10,000 or even 1,000 nucleotides at a time, instead of 100,000, Collins says.

Cite this article: https://doi.org/10.53053/WBFT2950

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