Cat Genetics 101 – Part 3

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Coefficient of Inbreeding (COI) and the Future of Genetic Testing

Lucy Drury, MT(ASCP)SC, and Roger Brown, DVM

If you have read and understood our last two articles on feline genetics, you should now have a fundamental understanding of basic genetics and genetic testing as it applies to our furry feline friends. You are ready to graduate from Cat Genetics 101 and enroll in Cat Genetics 201 for this next semester. If you haven’t read those articles, please take the time to review them before embarking on this journey, as they will be helpful in understanding the concepts we cover in this installment.

The Pros and Cons of Inbreeding

Every serious breeder of pedigreed animals will, at some point, need to weigh the pros and cons of breeding those which are closely related. But, how close is too close?  Animal breeders in the early 20th century began asking that question. They noted that there were definitely some advantages to breeding close relatives, as it produced desirable, inherited traits more consistently. But it had its downside – they also noted that fertility was lower, offspring were smaller, early mortality was higher, and lifespan was shorter.1  With inbreeding, you might be improving your current generation, but you were risking the viability of future generations. (Table 1)

Table 1. Advantages and Disadvantages of Inbreeding2

Advantages Disadvantages
Increased Uniformity Lower fertility
Increased prepotency (ability to pass traits on to offspring) Lower “vigor”
“fixing” of desired traits and breed type Birth defects
Smaller size
Fewer offspring
Slower growth
Higher offspring mortality
Shorter lifespan
Increased genetic diseases
Reduced “genetic potential” (ability to improve a trait)

 

Enough was understood at this time about genetics and inheritance to know that inbreeding increases homozygosity; i.e., that the probability  of inheriting identical alleles for any given gene from both parents increases with inbreeding. When both parents carry the same allele, then the child must inherit that allele. So, inbreeding was useful for setting type and desired traits, but the increased risk of health issues was problematic. Particularly puzzling was the decreased vigor and vitality of the inbred offspring, often referred to as “inbreeding depression”.3 It was easy to understand how the probability of single allele genetic diseases was increased, but in the absence of that, what was causing the overall decline in health?

Geneticists theorized that an animal population – any animal – contains within that population many recessive mutations. The detrimental effects of any one of these mutations are usually unnoticed; however, inbreeding increases the probability of more than a few of these recessive mutations pairing up.  They further theorized that while, individually, these mutations did not create any discernible problem, the cumulative effects of multiple mutations produced the population health issues noted in Table 1.

Wright’s Coefficient of Inbreeding

Sewell Wright, an evolutionary geneticist, tackled the challenge of reliably calculating the level of inbreeding and determining at what statistical point the problems of inbreeding overshadowed the benefits. In 1921, while working for the USDA, he wrote a seminal paper on inbreeding called “Coefficients of Inbreeding and Relationships.”1, 7  In this short paper, he describes the derivation of his formula and the rationale behind it. While a detailed discussion of the formula and how to calculate the coefficient using his formula is beyond the scope of this article, the rationale and the interpretation of the coefficient is not too difficult for most breeders to understand. Wright was simply trying to quantify the probable percentage of homozygous alleles passed on by related parents to their offspring. Putting it very simply, if a COI equals 10%, it means that statistically, 1 in 10 alleles will be homozygous because of the inbreeding – over and above the homozygosity present in randomly chosen parents within a given population. By correlating the calculated coefficient to the observed advantages and disadvantages, breeders could then use the coefficient to make intelligent decisions regarding their breeding pairs.

The COI, for a possible match where there is not a history of inbreeding in the population, is roughly one-half of the Coefficient of Relationship (COR). The COR for full, non-identical siblings is 50%, so the COI would be roughly 25%. This is only a rough estimate, because the COI takes into consideration all relationships in the pedigree, not just the relationship between the parents. If there has been a lot of inbreeding in generations prior, it could push the COI to percentages approaching or exceeding the COR. In some small, controlled populations (such as laboratory mice), the COI has been known to approach 100%.

Because of the potential influence of prior generations, a complete pedigree – including as many generations possible – is essential for correctly calculating the COI. So now you have such a pedigree: Now what? How do you calculate this coefficient?

There are two ways: by pencil and paper, using the formula below (Figure 1) and working through the calculations for each relationship (Figure 2), or by using a computer application designed for breeders that lets you enter your animals and their pedigrees, then calculates the COI for the proposed breeding pair’s offspring.

In the formula below, Fx is the COI for the individual x, n is the number of connecting links between two parents, and FA is the COI of the common ancestor of the parents, so one must calculate the COI for the common ancestor before calculating  for individual x. For the scenario in Figure 2, the parents (O and P) of offspring Q (who is our individual x in this example), have common ancestors, I and J, making them single first cousins. However, I is also the offspring of parents G and H, who are first cousins as well and have common ancestors A and B. So we must calculate the COI for I before we complete our calculation for Q. Figure 3 (for those of you who had college algebra) shows the calculations to achieve our COI for I, which is 6.25%—one-half the COR for single first cousins, and the COI for Q, which is slightly higher, 6.45%. This demonstrates the impact of multiple generations of inbreeding. It’s relatively minor if there are not many inbred ancestors  but quickly climbs if a parent has many inbred ancestors

 

 

 

 

 

 

 

 

 

 

Figure 36

Find FQ

The only inbred common ancestor of the two parents (O and P) is I (his parents are single first cousins).

  1. a) First Find FI
Common Ancestors
(of parents G and H)		 Paths (1/2)n+1 (1 + FA)
A G_1_D_2_A_3_E_4_H 1/32 x 1.0 = 1/32
B G_1_D_2_B_3_E_4_H 1/32 x 1.0 = 1/32
Therefore FI = Σ [(1/2)n+1(1 + FA)] = 1/16

i.e. FI = 0.0625 = 6.25%

  1. b)Main Calculation(To find FQ)
Common Ancestors
(of parents O and P)		 Paths (1/2)n+1 (1 + FA)
I O_1_L_2_I_3_M_4_P 0.03125 x 1.0625 = 0.03220
J O_1_L_2_J_3_M_4_P 0.03125 x 1.0 = 0.03125
Therefore FQ = Σ[(1/2)n+1 (1 + FA)] = 0.06445

i.e. FQ = 0.06445 = 6.45%

 

 

Most people of modest mathematical ability can calculate COI with a little practice for four or five generations, depending on how many instances of inbreeding occur in the pedigree. For more than five  generations (or if college algebra was not your thing), breeder software is recommended. While several applications were reviewed in preparation for this article, no recommendations are being provided as breeders’ needs vary widely,  and there was insufficient time to test them all thoroughly. However, a few general observations can be made. Most of the software programs were not new – some had been around ten  years or longer. Consequently, they may not run well on newer devices. Many did offer internet hosted alternatives that you run on your browser. Keep in mind, though, that the calculations become increasingly  complex with each additional generation. Most applications should be able to calculate a COI for up to ten  generations, after that, the calculation may require more horsepower than a home computer or web-based application can muster. Most of us probably don’t have pedigrees going back more than ten  generations, but a few of you may, so keep that in mind. If you would like to check out some of these options, do an internet search for “cat breeder software,” which will populate a number of leads.

Using the COI

Okay, so now you have your COI—what do you do with this? In our example above, parents O and P (who are single first cousins) are predicted to have offspring with a COI of 6.45%. Is this okay, or should you think about another match?

Things to consider: this number is estimating that 6.45% of all the alleles are going to be “identical by descent,” meaning that both alleles at a particular locus on a gene are identical because they came from the same common relative.1 Those alleles would not normally be homozygous in a random mating. When one considers that there are approximately 20,000 genes in a cat, there are a lot of opportunities  for recessive mutations to manifest themselves, even at what appears to be a relatively low COI percentage at face value.

Researchers have observed that the detrimental effects of inbreeding begin to manifest themselves above 5%. At 10% or higher, there begins to emerge an “extinction vortex,” where the combination of smaller litters, higher mortality, and higher expression of genetic defects has a negative effect on the size of the population. The smaller size of the population causes the rate of inbreeding to go up, resulting in a negative feedback loop that drives a population towards extinction.1

Let’s return to the example COI that we calculated for O and P. Should this pair be bred? Do the advantages of inbreeding justify the elevated risk of lower vigor and vitality and genetic defect? Only you as the breeder can answer that question. If your goal is to produce the healthiest kitten possible and lower the risk of possible birth defects, the answer is obviously NO. You would not want to breed this pair. You would want to find yourself a nice outcross to introduce into your breeding program.

However, the answer is not always that simple. There are a number of breeds that have limited options. They are already approaching or have reached that extinction vortex. Or maybe a breed has drifted away from its standard in certain features, and it’s hard to find an outcross that can help restore those features. In these cases, the breeder would want to examine the pedigree for health issues. If the cats are known to the breeder to have been robust, healthy cats, then the breeder may decide to take the risk and breed the pair. There is still the likelihood that the offspring would have some minor health issues, but if the breeder avoids any more inbreeding using these offspring, they may achieve their goal improving or stabilizing the breed. Each case will likely be different.

One may ask, “If I run genetic screening tests on the pair and no mutations are identified, does that decrease the risk of health issues? Can I breed cats with higher COIs?”

You can breed any pair you want as long as they are fertile, but testing for specific mutations only decreases the risk for the defects you are testing for. It will have no impact on the COI. Do the math: If there are approximately 20,000 genes carried in a cat’s chromosomes, and if the COI is 10%, that means 2,000 of those genes are identical by descent. If you test for the two or three defects that are significant for your breed, and the pair is homozygous for the good allele, 1998 ÷ 20,000 is 9.99% that you still don’t know about. You haven’t significantly impacted the COI, but 9.99% is still a really bad COI. “But what if I test for all known defects? Will that help?”

The Online Mendelian Inheritance in Animals (OMIA) catalogue4 lists 339 identified genetic traits and disorders in cats, and the list is growing. It would take a tremendous amount of financial commitment to complete these tests, and it still would not make much of a difference. 339 is less than 2% of 20,000 plus genes in a cat; statistically, only about 34 of those would be identical by descent in a cat with a COI of 10%. Testing for them is not going to stop the decline of the population if inbreeding continues, because statistically, the defects will still be there – whether you can test for them or not. Unless you can fix them, you can’t change the outcome just by knowing what causes it.

Like it or not, a breeder must be prepared to deal with and accept the risks inherent with inbreeding. Having stillborn or defective kittens is something no breeder enjoys, and something that many breeders find heart-wrenching . If a breeder wants to maintain a healthy population in their breed, they should keep the COI of their offspring under 5%.1

The Future of Genetic Testing

If genetic testing cannot help improve the health of inbred lines, why is there such an emphasis on genetic testing? One of the main reasons for a breeder to test (even when they only select breeding pairs who have a low COR) is that they can improve the overall health of a population by identifying carriers of a single allele, high-impact defect and eliminating those carriers from their breeding stock. In the past, genetic testing was quite expensive and only a few breeders were willing and able to pay for even the most basic testing. Some companies offer breeders tests such as:

  • Polycystic Kidney Disease (PKD)
  • GM Gangliosidosis (Types I and II)
  • Spinal Muscular Atrophy
  • Hypertrophic Cardiomyopathy (HCM)
  • Progressive Retinal Atrophy (PRA)

There are many more, and as companies continue working to validate other health concerns in a large number of cat breeds, so expect to see this test menu grow over time as genetic causes for other diseases are identified.

Can We Ever Fix These Problems?

Being able to test for a genetic defect is not much consolation to a breeder whose population has a high COI throughout the breed, and it is difficult to find suitable breeding animals without significant genetic defects. What then? Are there cures for genetic diseases?

Genetic diseases are of such a nature that you can’t fix them, at least not yet. You can only treat the symptoms, or try to delay the onset of the disease. There may be hope in the future, however. There is an emerging technology – gene editing – that may one day be the solution to genetic defects. Clinical trials are already underway using this technology as a therapy for blood diseases, cancers, and viral diseases.5 It will be some time before these therapies are available to the public … human or animal. Changing DNA at the molecular level is not without potential side effects, and the safety of the procedure is far from established. Cost will most certainly be an issue if this technology ever emerges from the research laboratory. But there is hope on the horizon, and one day we may see today’s science fiction become tomorrow’s cure.

 

 

References

  1. Beuchat, C. 2015,June 4. COI FAQS: Understanding the Coefficient of Inbreeding. The Institute of Canine Biology. Retrieved from http://www.instituteofcaninebiology.org/blog/coi-faqs-understanding-the-coefficient-of-inbreeding.
  2. Beuchat, C. 2014,Sept 19. The Costs and Benefits of Inbreeding. The Institute of Canine Biology. Retrieved from http://www.instituteofcaninebiology.org/blog/the-costs-and-benefits-of-inbreeding.
  3. Inbreeding Depression. Wikipedia. (2017, Dec 15). Retrieved from https://en.wikipedia.org/wiki/Inbreeding_depression.
  4. Nichols,F. (curator) (2017,Dec 14) OMIA – Online Medelian Inheritance in Animals. University of Sydney School of Veterinary Medicine. Retrieved from http://omia.org/home/.
  5. Shim, G., Kim, D., Park, G. Jin, H.,Suh,S., Oh, Y. Therapeutic Gene Editing: Delivery and Regulatory Perspectives. Acta Pharmologica Sinica. 2017 Jun; 38(6): 738–753. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520188/.
  6. The Coefficient of Inbreeding and Its Application. Genetic and Qualitative Aspects of Geneology. (2017, Dec 15). Retrieved from http://www.genetic-genealogy.co.uk/Toc115570144.html.
  7. Wright S, 1922. Coefficients of inbreeding and relationship. Am Nat 56: 330-338. Retrieved from https://www.ars.usda.gov/ARSUserFiles/80420530/Publications/contributed/wright1922.pdf

 

This article originally appeared in Cat Talk Magazine


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