In Case of Mutation, Many of Our Genes Have a Backup Plan

A rare form of gene regulation—found previously in only a handful of genes in fish, worms, and mice—is widespread in the human and mouse genomes, according to a new study by researchers at Columbia University Vagelos College of Physicians and Surgeons and Northwestern University.

It is the first time that this form of gene regulation—called transcriptional adaptation—has been found in the human genome. Genes affected by transcriptional adaptation, when disabled by a mutation, can turn on related genes to compensate for lost functions.

The researchers found evidence that related genes are activated for 22% of the 74 human and mouse genes examined in the study. Some of these genes are among the most widely studied in biomedical research, including Myc, which can lead to cancer when mutated, and TLR4, which plays a central role in the immune system.

“If we can understand the rules better, this form of gene regulation could eventually lead to a new style of genetic engineering to boost the activity of beneficial genes,” says Ian Mellis, a fellow in transfusion medicine who led the study with Yogesh Goyal, a quantitative biologist at Northwestern University.

The discovery also reveals an aspect of the human genome that has remain hidden until now. “It suggests a level of information-sensing by the genome that I didn’t realize could exist, especially in mammalian genomes,” says Mellis.

“Fundamentally, this changes our understanding of how human genes respond to mutations,” says Goyal.

Fish, worms, and people

Transcriptional adaptation was discovered only five years ago and has only been observed in a few genes in fish, nematodes, and cultured mouse cells.

Mellis and Goyal, who as a graduate student and postdoc, respectively, worked together in the same lab at the University of Pennsylvania, were captivated by the first reportsof the phenomenon. Those studies found that compensatory genes are turned on by pieces of dysfunctional mRNA transcribed from the mutated gene.

“It seemed like such a clever and unexplored area of gene regulation that could have implications for gene therapy—if it existed in the human genome,” says Mellis,

Mellis realized that an analysis of published genetic engineering data could answer that critical question and, if the answer was yes, determine how frequently transcriptional adaptation occurs across the human genome.

Widespread adaptation 

The two researchers looked for studies that used CRISPR-Cas9 engineering to completely disable, or “knock out” a specific gene in human or mouse cells. Such engineering should eliminate the gene’s activity and disrupt the cell’s function, but researchers sometimes find little biological change.

By analyzing the activity of other genes, the researchers found that related genes seemed to be activated to compensate for the loss of the CRISPR’d gene in 16 out of 74 genes with enough available data.

No common feature distinguished genes with potential for transcriptional adaptation and those without. “Based on the genes we tested, it can happen to any type of gene and in any biological context,” Mellis says.

Going forward, Mellis adds, it will be important for the field to learn more about the specific molecular mechanisms that regulate transcriptional adaptation, the rules that govern which genes can be called on to compensate for a mutated gene, and for which genes and their networks is this process most important.