UK scientists build most complete genetic map of the brown rat

University of Kentucky scientists at the Martin-Gatton College of Agriculture, Food and Environment (CAFE) have helped create a nearly complete genetic map of the brown rat, an animal that has helped researchers study human health and disease for more than a century.

Published in Cell Genomics, a new genetic map fills in parts of rat DNA that scientists previously struggled to read. By comparing the genomes of eight different laboratory rat strains, UK researchers are giving scientists a better way to see how the animals differ genetically.

Rats are especially important because they are larger than mice and have complex behaviors that make them useful for certain types of research, including studies of aging.

“One of the most powerful mechanisms in genomic evolution is the replication of small, gene-containing regions of the genome,” said Ted Kalbfleisch, Ph.D., professor in the Department of Veterinary Science at the Maxwell H. Gluck Equine Research Center, who was a part of the study.

Until recently, though, scientists had a less complete genetic map of the rat than they had for humans or mice.

One problem was that some sections of DNA are extremely repetitive, like trying to put together a giant jigsaw puzzle in which thousands of pieces have nearly the same pattern. Older sequencing methods could identify many of the pieces but could not always determine exactly where they belonged.

Newer technology can read much longer stretches of DNA at once. Using these methods, the researchers produced what is called a telomere-to-telomere genome assembly. Telomeres are structures found at the ends of chromosomes, so the term generally means researchers are trying to read a chromosome continuously from one end to the other.

The result was a much more complete picture of the rat genome.

Sixteen of the rat’s 22 chromosomes were assembled from end to end without gaps. The new genome contained only seven remaining gaps, compared with 164 in an earlier high-quality rat genome. Researchers also added roughly 60 million DNA building blocks to the assembled chromosomes.

Seeing those previously hidden areas allowed the researchers to find genetic information that had been missed before. Using information collected from 19 different types of rat tissue, they identified dozens of possible new gene-coding sequences and previously unknown portions of genes.

“Once duplicated, either the original gene or the copy is free to change since the other copy is there to still perform its function,” Kalbfleisch said. “Several rat genomes recently developed in our lab, which are very accurate and complete, have revealed many duplication events that are present in some strains but not others. The improved genome also revealed something unusual about the rat’s X and Y chromosomes, which help determine biological sex.”

In many mammals, including humans and mice, small matching regions of the X and Y chromosomes contain genes and assist the chromosomes in pairing when sperm cells are produced. The researchers found that rats appear to accomplish this differently.

The matching region they identified contained repetitive DNA rather than protein-coding genes, providing scientists with another example of how sex chromosomes can evolve differently among species.

The researchers then went beyond studying one rat genome. They combined genome information from eight laboratory rat strains to create a pangenome — a collection of genome sequences from many individuals of the same species. By comparing these versions, scientists can see differences they might miss if they relied on only one genome.

Those comparisons revealed important differences in DNA regions linked to the immune system. Some regions varied greatly from one rat strain to another, which could help explain why different strains respond differently to disease.

That information could be valuable because of how often laboratory rats are used as models for human diseases. Knowing more precisely how one rat strain differs genetically from another may help researchers better interpret experimental results, choose the most appropriate animals for future studies and identify potential drug targets.

The researchers said the eight-strain pangenome is an important beginning, but it does not represent every brown rat. Adding genomes from a wider variety of rats could eventually provide an even more complete picture of the species’ genetic diversity and the genetic basis of many of the traits we study in rats to better understand their analogous human traits.

“These rats were selectively bred to mirror traits found in humans, such as hypertension, and the adverse effects of these traits such as stroke and organ disease,” Kalbfleisch said. “We can now take these very accurate genomes and compare them in a graph to reveal these duplication events or, as they are more commonly known, structural variants. This lets us study how these copies function differently across tissues and how they may create disease conditions or protect tissues from damage.”

Learn more about the Department of Veterinary Science at Martin-Gatton CAFE at vetsci.mgcafe.uky.edu.

Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number R01HG011252. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.