Gene mutations not random, but clustered

Newswise — A discovery more than 20 years in the making has turned the dogma that gene mutations occur randomly on its head.

An international team of researchers found that the distribution of mutations is skewed toward areas of the genome that are less likely to cause harm and more likely to benefit the organism. “Our results have massive implications for how genetic variation is created by mutations and how genomes evolve,” said South Dakota State University professor and Oak Lake Field Station Director Charles Fenster.

“Mutations are rare and infrequent, so it is a challenge to study them,” he explained. Mutations are changes in the DNA such that offspring differ from either parent or, as in the case of cancers, for instance, the cells acquire DNA differences through mutations that lead to uncontrolled cell growth, or tumors.

The research teams compiled large datasets of new, naturally occurring mutations in Arabidopsis thaliana, a small flowering annual plant from the mustard family, that has been extensively examined as a model organism. The teams then determined where within the genome those mutations occurred.

This required years of developing the genetic resources to study mutations and teaming with collaborators that had the laboratory know-how to generate DNA sequence data efficiently and inexpensively, Fenster said. “The research teams sequenced and analyzed more than 2.5 trillion base pairs of DNA to make this discovery.”

 An article detailing the findings was published online in Nature, one of the world’s leading science journals. 

Collaboration key to discovery

“The nice thing about a good collaboration is that is where ideas begin and the end result becomes blurred across the team,” said Fenster. He helped assemble the group in 2004 and articulate the basic research questions through National Science Foundation funding in which Fenster was lead principal investigator from 2002 to 2019, first at the University of Maryland and then at SDSU beginning in 2016.

The United States side of the research included a series of Research for Undergraduate Institutions grants awarded to Fenster’s former postdoc, Matt Rutter, now a professor at College of Charleston, who provided more than 1,000 undergraduate students across 10 institutions the opportunity to be part of the cutting-edge research. NSF funded most of the sequencing work in Germany and additional funding from the German Max Planck Society facilitated the data analyses.

Mutations not random

“We kept finding patterns that were not random,” Fenster said, comparing what they were seeing to rolling a loaded dice. Analyses by the lead author, Grey Monroe, now an assistant professor at University of California Davis, showed that mutations are much less likely to occur in housekeeping genes, which are like the foundation or framework of a building, essentially protecting the organism’s basic functions.

“Mutations that are likely to be deleterious are suppressed, while mutations that are more likely to be beneficial are enhanced,” Fenster explained.

The Nature paper also describes a mechanism for the non-random pattern of mutations showing that different types of proteins that bind to the plant’s DNA either elevate or decrease mutation rates. “It appears that Darwin’s force of natural selection can act even at the most minute molecular level where mutations occur,” he pointed out.

“This provides the molecular mechanisms for the beneficial mutations described in our publications based on extensive field studies from 2010 through 2021 and also gives us hope that organisms can evolve in place in response to climate change because genes associated with a plant’s response to the environment have higher mutation rates” Fenster said. That’s also good news for plant scientists because it suggests mutations may be used as a breeding tool to increase crop yields under stressful conditions.

Fenster concluded, “The next big question is whether other labs can replicate our results with other organisms, including humans.” That work is already underway.