Gene that shapes mutation rate found in mice

image: Authors of a nature article from May 11, 2022, A natural mutator allele shapes the variation of the mutation spectrum in mice, go via Zoom. They are: Abraham Palmer, Kelley Harris, Thomas Sasani, Robert Williams, Annabel Beichman, David Ashbrook, Lu Lu and Jonathan Pritchard.
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Credit: Kelley Harris Lab

Every organism is born with a few mutations in its genome that differ genetically from its two parents. Such changes in an individual’s genetic code create the diversity that allows nature to select for advantageous traits that drive the evolution of a species.

The type of mutations and the rate at which they appear vary between individuals and species. Some researchers suspect that environmental factors are responsible for most of this variation. Others suspect that some of this variation has a genetic basis that could also affect susceptibility to cancer, as cancer can be caused by mutations in cells in affected organs.

A collaborative team led by researchers at the University of Washington School of Medicine in Seattle now reports having located an area of ​​the mouse genome where genetic variation is associated with differences in mutation rates between individuals. The genetic variants associated with a particular trait are called alleles, therefore the variants affecting the rate of mutation are called mutator alleles.

“Our results show that at least one mutator allele exists in nature, and that’s something we’ve been trying to demonstrate for some time,” said Kelley Harris, assistant professor of genome science at the UW School of Science. Medical.

Harris and his research colleagues report their findings today, May 11, in the journal Nature.

To locate the mutator allele, the researchers sequenced the genomes of inbred mice. Scientists create such populations by mating siblings over many generations. The resulting mice have highly standardized genomes that make it easier to study genetic associations with complex traits.

For this study, the researchers sequenced inbred lines that had been created by crossing two lines, called “B” and “D” strains. Many of these BXD offspring had 50% B and 50% D genomes but with these alleles randomly mixed in different combinations.

The oldest inbred lines of BXD have been kept in captivity for almost 50 years. Although the genome of each line remained relatively stable, all acquired mutations and some lines acquired mutations faster than others. This difference in mutation rate allowed researchers to recognize the alleles associated with a higher or lower mutation rate. In particular, they discovered a region of the mouse genome that affects the rate of a specific mutation in which the DNA nucleotide cytosine (C) is replaced by the DNA molecule adenine (A), a so-called “C-to-A”. ” mutation.

The researchers found that mice whose genomes accumulated C-to-A mutations at a higher rate tended to have a segment of DNA on the fourth chromosome inherited from the D line.

“Mice that had an allele from parent D at this location on chromosome four accumulated C to A mutations at a 50% higher rate than those that inherited this locus from parent B,” Harris said.

The region associated with the higher mutation rate is known to contain 76 genes, Harris said. Further analysis to see which gene might be causing the higher mutation rate led them to a gene called Mutyh.

Mutyh encodes a protein that plays a role in DNA replication and repair and is associated with colorectal cancer syndrome in humans. Harris said they couldn’t rule out the possibility that other nearby genes don’t play a role in the rate of increase of C-to-A mutations in these mice, but Mutyh’s link to cancer in l man makes him the prime suspect.

“Our results add weight to the theory that naturally occurring mutator alleles underline variations in mutations seen in humans and show that they can be mapped to model organisms such as the mouse using our approach,” said Harris. .

The first author of the paper is Thomas A. Sasani, who was a postdoctoral student in genome science at the UW School of Medicine when he did the research. Sasani is now at Recursion Pharmaceuticals in Utah. Other authors include David G. Ashbrook, Lu Lu, and Robert W. Williams of the University of Tennessee Health Sciences Center; Annabel Beichman at UW; Abraham A. Palmer of the University of California, San Diego; and Jonathan K. Pritchard of Stanford University.

This press release was written by Michael McCarthy.

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