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Oedipus Rex: Dog Inbreeding, its consequences, and its quantification

Oedipus Rex: Dog Inbreeding, its consequences, and its quantification

March 1, 2018

For millenia, dog breeders have intentionally mated relatives as a way to fix traits in a lineage, recognizing that there is a reduction of fitness in offspring of close relatives. However, this certainly wasn’t always intentional as one can see from this post on the Hapsburg lip. A century ago, Sewall Wright devised the coefficient of inbreeding (COI) as a way to measure inbreeding, a statistic still popular today. Conveniently, with Embark’s dog DNA test, we automatically reports the COI for every dog, so let’s explore what it means!

Inbreeding 101

Like humans, dogs tend to be 99.8-99.9% genetically similar to other members of their species. Even other species can exhibit similarities—dogs and humans are 64% similar at the base pair level. But genetic variation is the spice of life, and the 0.1-0.2% of the genome that differs encodes a myriad of variation. Some of these we have intentionally perpetuated like body shape, coat color, or behavior. Unfortunately, other less desirable variants confer potentially harmful effects on health, longevity, and reproductive success.

Harmful mutations come in three main varieties: recessive, dominant, and additive. In large outbred populations like humans, harmful dominant and additive mutations are quickly weeded out because the individual carrying these mutations has a reduced fitness. Recessive mutations, on the other hand, are different. A harmful recessive mutation might “break” a gene, which has little or no consequence if an individual has a working copy of the gene from his or her other parent; however, it can have disastrous consequences when an individual inherits two broken copies. Because outbred individuals almost never inherit two broken copies, they cannot be effectively selected against by natural selection or by breeders unless there is a genetic test for the mutation. For example, if a mutation is at 1% frequency in an outbred population, any given dog has a 0.01% chance of inheriting two copies of the mutation—clearly a very small chance.

As such, every dog population—or in the context of purebred dogs, every dog breed—contains an abundance of rare recessive mutations that were either present in a founder individual or arose spontaneously in the dog population sometime afterwards. These rare mutations are hardly ever problematic for outbred individuals because they almost always inherit at least one working copy; however, they can cause real problems for inbred individuals—animals that arise from the mating of closely related parents.

Let’s consider what happens with dogs in a mother-son mating. A mother passes along 50% of her genome to each pup, so each rare (<1% frequency) recessive mutation carried by the mother has a 50% chance of being transmitted to a son. Offspring from a mother-son mating would, therefore, have a 25% chance of inheriting two bad copies of the mutations that have been passed down to the son. This is a greater than 100-fold risk compared to an outbred dog!

Inbreeding in dogs has real consequences. Research in the Boyko Lab has shown that a 10% increase in inbreeding can lead to a 6% reduction in adult size (poor growth) and a six- to ten-month reduction in lifespan. Reduced litter size and fertility are also likely. These risks occur from both classical inbreeding and from drift in small populations where every individual is a not-so-distant relative. Assessing these risks depends on accurately quantifying the likelihood that mutations will be identical-by-descent, or inherited from the same ancestor.

Calculating COI

There are three ways to quantify the coefficient of inbreeding (COI): (1) Using a pedigree, (2) Using a small set of polymorphic markers, or (3) Using a genome-wide marker panel. How do you easily find out?

Pedigree-based COI estimates are based on the relatedness of individuals in a pedigree, with 25% being the value from a mother-son or full-sibling mating; 12.5% being the value from a grandparent-grandchild or half-sibling mating; and 6.25% being the value from a first cousin mating. These values accumulate. Logically, all individuals have COIs between 0% (completely outbred) and 100% (completely inbred). So three generations of full-sibling matings would lead to a COI of 50%.

Ideally, the pedigree is complete all the way back to the founding of the breed, but in reality, most pedigrees only go back maybe 5 to 10 generations. For most COI calculators, the original ancestors in the pedigree are assumed to be unrelated, so a COI calculated from a 5-generation pedigree could be much lower than that calculated from a 10-generation pedigree. This is likely much lower than the true COI if the complete pedigree back to the breed founders was known. For this reason, there’s no one answer for what a “good” COI is: It all depends on how complete the pedigree is. Furthermore, because of the principle of segregation, two individuals with identical expected COIs from a pedigree may have very different levels of inbreeding depending on which chromosomal segments happened to be inherited by each individual.

Marker-based inbreeding estimates use dozens or hundreds of widely spaced markers to estimate inbreeding. Each marker can be heterozygous or homozygous (identical by state). The overall locus heterozygosity (HL) of the panel is generally correlated with inbreeding, but the absolute values of HL depend on the markers that are chosen. Because a rare marker being homozygous is stronger evidence of inbreeding (identity by descent) than a common marker being homozygous, different weightings may be used to calculate statistics like internal relatedness (IR). This varies from -1 to 1. Nevertheless, most of the genome is not linked to any marker, so most inbreeding tracts are undetected by these estimators. As a result, it makes marker-based estimators poorly suited for differentiating between individuals with similar COIs (less than 5-10% different).

Genome-wide COI estimation is the gold standard for measuring inbreeding. It requires at least tens of thousands of markers spread across the genome. This is what we do here at Embark. With this resolution, the actual inbreeding tracts can be directly observed as tracks of homozygous markers. Above a certain size, these runs almost always represent identity-by-descent, and thus we can easily calculate the coefficient of inbreeding (the proportion of the genome that is identical by decent). At Embark, we use about 1 million basepairs, known as 1 centimorgan, as the minimum size of each track. This is because we are interested in inbreeding all the way back to breed founding: Remember, for most domestic dog breeds, this is usually 50-100 generations ago.

Calculating COI directly using genome-wide data has several advantages. It doesn’t require a pedigree. Also it doesn’t depend on marker frequencies or require complicated statistics to correct for rare/common markers. And finally, it is directly comparable across studies because it doesn’t depend on the specifics of the markers used or the populations being studied. Consider the two situations in the figure below: While the two pedigrees have the same pedigree calculated COI (inset), the genome-wide calculation gives two drastically different COIs.

Inbreeding tracts that are shared by all individuals in a breed are apparent using genome-wide data, as you can see in the figure below. These tracts are often missed by pedigree-based and marker-based estimators. Comparing an individual to the COI distribution for the breed lets you know whether a dog is more or less inbred than expected for its breed. In addition you can visualize the inbreeding tracts to see where in the genome they are found.

Next steps

Accurate determination of inbreeding tracts is crucial for identifying recessive disease mutations through homozygosity mapping and for more precisely understanding the risks of inbreeding within and across breeds. Although some level of inbreeding cannot be avoided for most purebred dog breeds, and inbreeding risk shouldn’t be the only consideration when selecting mates, reducing the inbreeding load in a population is a valuable goal. In our next blog, we’ll discuss how Embark helps breeders evaluate potential breeding pairs, and how this can contribute to the long-term health of the breeding population.

To find out your dog’s COI, take Embark’s dog DNA test while also learning important breed and health information.

This is the first installment of a blog series on inbreeding, authored by Embark’s own Adam Boyko, PhD, Chief Science Officer, and Aaron Sams, PhD, Research Scientist.

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Founder & Chief Science Officer