Scientists untangle how inbreeding has led to disease in dogs

May 4, 2021

We love our dogs, but our love for specific breeds is damaging them. (Pixabay/Rebecca Schönbrodt-Rühl)

Researchers have uncovered the basis for a range of undesirable genetic variations in dogs, from golden and Labrador retrievers to Yorkshire terriers, pointing to the preservation of recessive mutations fostered over hundreds of years of inbreeding.

Modern dog breeds descended from a relatively small and widely inbred starter population, so they can easily continue passing undesirable traits, because offspring receive very similar genetic material from both parents. A new study published April 14 in PNAS presents an analysis of genomic data that helps describe this mechanism.

"If you have a population that had a small number of founders, or, like in a dog breed, then a lot of the individuals today will tend to be more similar to each other because their genomes are sort of scrambled-up versions of those founders," said senior author Kirk Lohmueller, an associate professor of evolutionary biology at the University of California, Los Angeles. "And if there's a small number of founders, then the scrambled-up parts of the individuals today are going to be more similar to each other."

Such scrambling has led to greater identity by descent, as well as runs of homozygosity in dogs. These terms refer to segments of chromosomes that came from the same ancestral source. A run of homozygosity, for example, is also a form of identity by descent, just in the same individual. An organism develops a run of homozygosity when it receives the same haplotypes, or groups of alleles, from both of its parents.

The lead author on the paper, Jazlyn A. Mooney, a postdoctoral researcher in human genetics at Stanford University, had been working on runs of homozygosity and identity by descent in humans, while Lohmueller had previously investigated deleterious genetic variation in flies, mice and other species. 

Dogs offered Lohmueller and his colleagues a unique opportunity to study the effects of limited genetic diversity using Mooney's approach. Unlike other species, dogs have experienced multiple population bottlenecks, or sharp declines in population, over time. The first bottleneck occurred with the first domestication, and another happened around 200 years ago, with the formation of new breeds during the Victorian era, according to the study. 

To understand how runs of homozygosity and identity by descent manifest in dog genotypes, Lohmueller and his colleagues gathered a large dataset of 4,414 breed dogs; 327 village dogs, or strays; and 380 wolves from publicly available sources. More than a dozen breeds were represented in the study.

Compared with wolves and village dogs, breeds burdened by greater runs of homozygosity showed greater association with five different traits. In golden retrievers, for example, this burden equaled a greater association with lymphoma when more of their genome was inside a run of homozygosity. 

Further, all breeds showed greater disposition to elbow dysplasia, a condition stemming from growth abnormalities in the elbow joint that can lead to arthritis, due to runs of homozygosity. Each breed also showed significant association with mast-cell tumors under runs of homozygosity. These tumors, composed of a type of white blood cell, usually appear on the skin but can also manifest in internal organs or bone marrow.  

Poor genetics also link Bernese mountain dogs, Rottweilers and golden retrievers to a rare form of cancer, histiocytic sarcoma, that afflicts a range of tissues, including lung, skin and bone — and sometimes manifests in humans. 

The runs of homozygosity appeared to have a protective effect in some instances, with Yorkshire terriers having less risk of developing portosystemic vascular anomalies, a defect involving the circulatory system and liver typically found in purebred dogs, with an enriched burden of runs of homozygosity. 

The new study could help inspire future research in different species to see how various recessive and deleterious mutations pass down through generations, according to Lohmueller. To do that, researchers could create more detailed evolutionary models of the processes that give rise to such mutations. 

Doing so could help scientists better understand the genetic risk of conditions governed by complex traits, such as diabetes or cancer. So far, the bulk of research in human genetics has focused on specific genetic variants, such as those that might be common among a population. 

"What our study is pointing to is, maybe some of these lower-frequency variant mutations, or variants that maybe are recessive and individually rare, might have bigger effects that might be important in the trait," Lohmueller said. "Maybe now we have more of a biological basis for thinking about how they may be important in other systems and other traits, like in humans."

The study, "The impact of identity by descent on fitness and disease in dogs," published April 14 in PNAS, was authored by Jazlyn A. Mooney, University of California, Los Angeles and Stanford University; and Abigail Yohannes and Kirk E. Lohmueller, University of California, Los Angeles.

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