Revealing the genes for polygenic disorders

By Carol Beuchat PhD

When a genetic disorder or trait is caused by a single gene, the usual protocol is to identify it and create a test to detect it. We can now test for hundreds of single mutations, which allows us to prevent producing any affected animals by screening potential parents before mating.

But for the many disorders thought to be polygenic, we have no simple solution. Identifying multiple or even dozens of genes or loci (a region on the chromosome where a gene is located) that seem to be associated with a particular disorder is of little use to the breeder. Should dogs carrying risk alleles be removed from the gene pool? Do you breed dogs together that have some of the risk alleles? How many overlaps is safe? There are no guidelines and no way to estimate the risk. Unfortunately, many serious and common problems appear to be polygenic, and we have been able to do little to control them. So things like cancer, epilepsy, cardiac and kidney disease, immune system disorders, and more sit like subterranian explosive devices scattered across the genomic landscape of your breed undetected.

DNA tests are not useful for these complex disorders, but we do have techniques that can provide more information about risk for polygenic disorders using just a pedigree database. The analysis uses information about the genetic relationships among the dogs in a population and the identity of animals that are affected with the disorder to determine the genetic risk of a disorder based on the genetic contributions from affected ancestors. This strategy uses a statistical technique called cluster analysis, and requires no information about the genes that might be involved or mode of inheritance.

What does cluster analysis do?

Cluster analysis using pedigree data does not test marker-trait associations. Instead, it tests whether family structure based on ancestry correlates with the distribution of affected animals.
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In plain terms, it asks:

“Do dogs with this trait disproportionately descend from the same ancestors?”
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The analysis does this regardless of the complexity of the pedigree, so it can identify risk that would be undetectable by studying individual pedigrees. It uses information about the affected animals, but also their relatives, to estimate the accumulation of genetic risk in lines and individuals.

This analysis has obvious advantages over trying to identify the specific genes involved. Polygenic disorders or traits might involve dozens or even hundreds or genes, each with a small effect, but which collectively affect the expression of a trait or disease. Teasing apart the effects and interactions of many genes is difficult, and even if you could, you would still not know how to use this information to make breeding decisions. Great knowledge, but not useful to the breeder.

​With a pedigree database, however, we can determine risk of producing affected dogs, putting a valuable tool in the hands of breeders that can use this information to take some of the uncertainty out of mate selection. With the right analysis pipeline, breeders can use basic information they already have about pedigree relationships and health records to, for the first time, put these data to good use in mate selection. 

What cluster analysis can detect well:

• Lineage-associated disease risk (cancer, epilepsy, cardiac)
• Performance traits concentrated in working lines
• Fertility, longevity, and survival patterns
• Popular-sire amplification effects

These analysis are particularly useful for:

• Polygenic traits
• Founder effects
• Rare risk alleles
• Line-specific risk accumulation

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The analysis does not require:

• Knowing the causal variants
• Assuming additivity
• Detecting large effect sizes

What this technique cannot resolve alone:

• The specific causal gene
• Within-family segregation
• Environment vs genetics without controls

What you do and don't need:

• You do need a pedigree database that includes affected animals
• You need to know the Identity of affected animals
  
• You need to Identify a population of dogs for analysis that includes the current breeding stock
• You do not need to know the "unaffected" status of a dog (e.g., for problems that show up later in life)
• You do not need large numbers of affected dogs

The beauty of this technique is that you don't need DNA data, your pedigree database doesn't have to be perfect or complete, and it will produce information that is actionable for beeders immediately. It produces a map of risk superimposed on the pedigree that identifies where breeders need to avoid selecting parents that are both from within the risk population. They can, however, breed dogs with risk to dogs outside the risk population to retain genetic diversity in the breed. 

I recently analyzed a pedigree database for Yorkshire Terriers to identify dogs at risk of producing offspring with liver shunts. The database was relatively small, only about 30,000 dogs (only a fracion of the complete breed database), which included about affected 40 animals. From this, the dogs with geneticc risk in the current population were clearly identified, giving breeders the opportunity to produce litters with low risk of liver shunt while protecting the genetic diversity of the current breeding population.

If your breed is struggling to manage complex health problems for which we have no suitable tests, this analysis might provide the information you need to avoid risk and the incidence of some of the most serious health problems in dogs.

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