In a study published in the journal Genetics in Medicine, researchers at the University of Miami Miller School of Medicine have developed powerful new insights into unique, highly constrained genes, including their biological pathways and potential impacts on health and disease. The study showed, based on large-scale data from healthy people, that these genes do not tolerate mutations, suggesting the critical roles they play in many cellular functions.

This is the first time these constrained genes have been studied so comprehensively, said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School’s Department of Pediatrics and Jackson Health System. We used large datasets to really understand them and we found these genes translate into proteins that are critical to cellular function. Some have not yet been linked to human disease, but they need more study.

Constrained Genes and Health
Dr. Agrawal and colleagues wanted to understand constrained genes because they, and the biological processes they govern, are often essential to good health. The team focused on two types of genetic variations: loss of function and missense. Loss of function mutations eliminate a protein’s ability to do its biological job, which can have grave consequences. Missense mutations change one of the amino acids that make up a protein, which can also seriously impact its function.
To better understand these genes, the team drew data from the Genome Aggregation Database (gnomAD), which has collected results from multiple genomic sequencing projects. At the time it was accessed, the database had information from more than 76,000 whole genome and 730,000 whole exome sequences.

The team cross-referenced this information with results from other databases, such as ClinVar and Online Mendelian Inheritance in Man (OMIM), to make the connections between constrained genes and disease.

Missense Variations and Loss of Function
The study found that many genes are vulnerable to missense variations, loss of function or both. Those vulnerabilities largely depend on the protein’s role in human biology. Actin proteins, for example, link together to form cellular skeletons (cytoskeletons). Missense variations change an important protein component and can interfere with an actin molecules’ ability to connect and form these all-important cytoskeletons.

Some genes can tolerate loss of function, but they cannot tolerate missense, said Dr. Agrawal. Others tolerate missense but not loss of function. And then there are a group of genes which cannot tolerate either loss of function or missense. The fact that there are some genes which are very tolerant for one or the other, but not both, is truly fascinating.

Having investigated these genes’ various vulnerabilities, the team will soon leverage that information to better understand how they might match up with various diseases.

We found 76 constrained genes that have not been linked to human diseases, said Dr. Agrawal. We are now looking into our own datasets of people with rare diseases to see if we can find patients with any of these mutations. We want to look at the genes and the patients’ symptoms to see if we can put this story together.

Source: https://news.med.miami.edu/the-role-of-constrained-genes-in-cellular-function/