Decoding Brown Rat Pangenomes Provides Accurate Blueprints for Human Illness

Researchers have created the most complete genetic profile of the brown rat to date, according to a UTHealth Houston-led team, paving the way for scientists to more accurately research the genetic links to conditions like heart disease, kidney disease, high blood pressure, and stroke. 

The research was published today in Cell Genomics and led by corresponding author Peter Doris, PhD, director of the Center for Human Genetics at The Brown Foundation Institute of Molecular Medicine within McGovern Medical School at UTHealth Houston.

The assembly of the brown rat's genome provides a complete genetic fingerprint and reveals that the brown rat's DNA is more complex than scientists previously understood. In addition to uncovering more than 60 new genes, many of which were previously difficult to sequence and are thought to play a role in immunity and other biological processes, the team discovered that brown rat sex chromosomes differ in a significant way from those in humans.

In humans, the X and Y chromosomes contain a region known as the pseudoautosomal region, or PAR, which plays a unique role in allowing the two dissimilar chromosomes to pair up and replicate. In most mammals, this region contains about 20 genes shared by both the X and Y chromosomes. This shared sequence is what allows these dissimilar chromosomes to match up and replicate. 

Doris and his team found that these PAR genes have been lost from the X and Y chromosomes in the brown rat, indicating rats use a different mechanism to reproduce. The team found that the PAR genes have moved to the regular chromosomes and uncovered new sequences that cause the X and Y chromosomes to pair head to tail, rather than head to head as in most other mammals.

Sexual reproduction in the rat can take place, but it's not taking place in exactly the same way that it is in humans. We wouldn't have been able to discern that if we hadn't had this complete, high-quality, and accurate sequencing of the genome."

Peter Doris, Director of the Center for Human Genetics, UTHealth Houston

The findings have important implications for healthcare research, as scientists will now have a more accurate starting point during preclinical studies that use the brown rat. 

"We know that there are genetic causes of diseases, but when we try to find out where in the genome they're coming from, we kind of get lost," Doris said. "Until now, it has been extremely difficult to recognize genetic differences because the assemblies that we were working with had missing pieces."

Many of these pieces were regions in which genes have duplicated. The nearly identical copies could not be seen independently of each other prior to Doris' work. Gene duplication is a key mechanism by which individual genomes, and the functions they encode, can differ.

The rat genome, or genetic fingerprint, is made up of 22 pairs of chromosomes, at each end of which is a sequence called a telomere. Doris' research represents the first telomere-to-telomere assembly of the brown rat's genome, providing complete, unbroken descriptions of each chromosome's sequence.

Prior to this research, scientists were essentially trying to put together a complicated jigsaw puzzle without the photo you find on the puzzle box, Doris said. 

"If the puzzle doesn't come with a picture on the box, and if there are a lot of pieces in there that just look like pieces of blue sky, it's very hard to know where to put those pieces," he said.

Using the long-read assembly method, Doris and his team were able to create eight different reference-quality genome assemblies, allowing scientists to better understand genetic variations among different brown rats and to track down the genetic variation contributing to disease. Like in humans, individual rat genomes are unique. That means that one rat's genome, or jigsaw puzzle, will have pieces that another rat's "puzzle" does not have.

The eight reference strains allowed the team to create what's known as a pangenome, which allows scientists to compare the genomes of multiple rats simultaneously. This pangenome adds 7% more sequence to the genome of the rat species.

"You can go into any particular place around any particular gene that you're interested in, say, the protease gene that's involved in digesting your steak dinner. Is that gene going to be the same in all of these animals, or could it be different?" Doris said. "Turns out, in some rats, the gene is specialized to do one job in digestion and another one in the immune system. Each function resides in the original and a recently duplicated copy of the gene. The pangenome gives you one place to go where you can capture all of the major differences that you're likely to encounter. That's a very, very valuable tool to have."

Yaming Zhu, a research assistant in the Center for Human Genetics at The Brown Foundation Institute of Molecular Medicine with McGovern Medical School, also served as an author on the study.