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IDEALLY, THE PEDIGREE IS COMPLETE ALL THE WAY BACK TO THE FOUNDING OF THE BREED. HOWEVER, IN REALITY, MOST PEDIGREES ONLY GO BACK, MAYBE, 5 TO 10 GENERATIONS. MOST COI CALCULATORS
CALCULATING COI There are three ways to quantify the coefficient of inbreeding (COI): (1) Using a pedigree, (2) Trying a small set of polymorphic markers, or (3) Testing a genome-wide marker panel. How do you easily find out? Pedigree-Based COI are based on the relatedness of individu- als in a pedigree. 25% is 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. However, in reality, most pedigrees only go back, maybe, 5 to 10 generations. Most COI calculators assume that the original ancestors in the pedigree are unrelated. Therefore, 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 pedi- gree 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. This depends on which individuals inherit which chromosomal segments. Marker-Based Inbreeding uses dozens or hundreds of widely spaced markers to estimate inbreeding. Each marker can be hetero- zygous or homozygous (identical by state). The overall locus het- erozygosity (HL) of the panel is generally correlated with inbreed- ing. However, the absolute values of HL depend on the markers that are chosen. Because a rare marker being homozygous is stron- ger 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. Therefore, estimators do not detect most inbreeding tracts. As a result, it makes marker-based estimators poorly suited for dif- ferentiating between individuals with similar COIs (less than 5-10% different). Genome-Wide COI is the gold standard for measuring inbreed- ing. It requires at least tens of thousands of markers spread across the genome. The Embark Dog DNA kit includes Genomic-wide COI results. With this resolution, the actual inbreeding tracts can be directly observed as tracks of homozygous markers. Above a cer- tain 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 descent). 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 a breed’s 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. Inbreeding tracts are apparent using genome-wide data. Ped- igree-based and marker-based estimators often miss these tracts. Comparing an individual to the COI distribution for the breed lets you know whether a dog is more or less inbred than expect- ed for its breed. You can visualize the inbreeding tracts to see where in the genome they are found. Accurate determination of inbreeding tracts is crucial for identifying recessive disease muta- tions through homozygosity mapping. It is also crucial 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. ASSUME THAT THE ORIGINAL ANCESTORS IN THE PEDIGREE ARE UNRELATED. THEREFORE, A COI CALCULATED FROM A 5-GENERATION PEDIGREE COULD BE MUCH LOWER THAN THAT CALCULATED FROM A 10-GENERATION PEDIGREE.
58 | SHOWSIGHT MAGAZINE, JULY 2021
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