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Genetic rescue and rehabilitation: III. Genetic assessment from pedigree data

Discussion in 'Dog Discussion' started by Institute of Canine Biology, Mar 27, 2019.

  1. By Carol Beuchat PhD

    III. Genetic Assessment From Pedigree Data

    Central to the development of a plan for genetic rescue is information about the current genetic status of the breed. The pedigree database is a primary source of historical genetic information, and DNA analysis can now be used to supplement this with much detail about actual genetic diversity, gene frequencies, inbreeding, relatedness, etc.

    Population Statistics
    The information from pedigree analysis for Lundehunds was produced by the scientists at NordGen and presented in a study by Kettunen et al. (2017) (download a copy below). They used pedigree data for 1930-2015, which included 5433 dogs. Of these, 1230 dogs were noted as alive, and 617 (50.4%) of these were living in Norway. The next largest populations were in other Nordic countries (i.e., Sweden and Finland).


    Founder Dogs

    There were 49 founder dogs in the pedigree dataset, where founders are defined as dogs without known parents (so again, these founder dogs will all be assumed to be unrelated and not inbred, i.e., COI = 0%). After accounting for founder dogs with one missing parent ("half-founder"), the actual founder population numbered 43.5 dogs (a missing parent counts as a "half-founder"). Eight of these had a single contributing offspring, one male founder had three offspring (two of which contributed to the population), and one male contributed 10 offspring.

    Population Genetics
    The pedigree database can provide a significant amount of critical data, including:

    1. level of inbreeding (coefficient of inbreeding, F, or "COI")
    2. genetic relatedness (mean kinship, mK, and average mK for the population)
    3. effective number of founders (fe)
    4. effective number of ancestors (fa)
    5. founder genome equivalent (fg)
    6. effective population size (Ne)

    For the population genetic analyses, the earliest dogs in the pedigree database were considered to be unrelated. This is a standard assumption for these kinds of analyses. In most cases, and in the case of the Lundehund, this assumption is not true, but the actual relatedness and inbreeding of the founder dogs is usually unknown. In effect, this assumption sets these founder dogs as the "base" population, and analyses of inbreeding and relatedness will reflect the cumulative effects of breeding since then. As a consequence, these genetic analyses will underestimate the true values by an unknown degree. MIssing data will result in underestimation of inbreeding and relatedness, and it will also inflate the effective population size (Ne).

    Dogs born between 2007 and 2014 were taken to be the current potential breeding population. For these, diversity was estimated as fe (effective number of founders), which reflects the genetic population size in terms of the number of "equally-contributing founders that would be expected to result in the same genetic diversity" as the breeding population. Kettunen et al. also computed fa (effective number of ancestors), which accounts for genetic diversity lost due to bottlenecks, and fg (founder genome equivalents), which reflects alleles lost due to both bottlenecks and genetic drift. The fg is especially useful because it "describes how many alleles and in which frequencies they have been maintained in a given locus".

    Inbreeding and Relatedness
    The most recent fully registered cohort of Lundehunds had an average pedigree COI of 33.9% and mean kinship (also called "coancestry") of 35.6%. This graph shows the rise in the average COI since 1964, and also the average inbreeding expected if the population was breeding randomly ("Exp. F"), which is the same as the mean kinship.

    "Alpha" on this graph is the difference between observed and expected inbreeding. When alpha = 0, the two lines are the same, and ordinarily this would indicate that breeding of the population was effectively random. When alpha > 0, it indicates selective inbreeding; and alpha < 0 indicates selective outcrossing.

    From this graph, you can see that the value of alpha hovers around zero for most of the history. However, over this time breeders were trying to avoid matings between close relatives, and this graph shows that the relatedness of individuals is so high that this had no significant effect.

    They computed the COI of all of the dogs in the pedigree back to founding and found that 33 had a COI equal or greater than 50%. A COI of 50% results from three generations of full-sib matings. Remember that this assumes the founder dogs were unrelated and not inbred, so this is the inbreeding that has accumulated only over the generations represented by the pedigree. There are two "blips" in the chart of inbreeding over time- one in 2004 that reflects an importation, and one in 2014 that reflects a cross-breeding.

    Genetic Diversity
    Kettunen et al. computed the measures of genetic diversity for Lundehunds from pedigree data as:

    fe = 6
    fa = 3
    fg = 1.3

    The value of fg = 1.3 indicates that the current population contains less diversity than would be accounted for by 2 dogs.

    The ratio of effective founders (fe) to effective ancestors (fa) reflects the loss of genetic diversity due to bottlenecks. If fa and fe are equal, there have been no bottlenecks. For Lundehunds, fa/fe = 3/6 = 0.5, indicating a significant loss of diversity because of bottlenecks over the period of the pedigree records.

    These data show that of the 49 founder dogs (which again, were assumed to be not inbred and not related), only about 12% (6 out of 49) contributed genes to the current population. This means that much of the genetic diversity in the earliest dogs in the pedigree database failed to get passed on to subsequent generations. This is because about 8% of the initial variation was lost through unequal genetic contributions of the founders, and 30.5% was lost just by chance through genetic drift. So a total of about 39% of the original diversity in the founder dogs has been lost from the breed and is not represented in the current reproductive dogs.In fact, if we consider that the dogs in the first generation of the pedigree data were unrelated and not inbred, their COI would be 0%. The loss of genetic diversity over the period of the pedigree information is reflected in the current mK, which is also 39%.
    Effective Population Size
    Effective population size (Ne) is a way of quantifying the genetic characteristics of a population. Specifically, Ne "translates census sizes of a real population into the size of an idealized population showing the same rate of loss of genetic diversity as the real population under study" (Husemann et al, 2016). This allows us to assess the genetic status of a population against a theoretical population with known properties.

    There are a variety of different ways to determine Ne that will result in different estimates (Table 5 in Kettunen et al 2017). The one they used estimated Ne at about 16, with a range of 8-16 over the generations represented by the pedigree data.

    Origin of genetic variation
    A statistical technique called "gene dropping", simulates inheritance of a founder allele thousands of times to determine the likely origin of an allele in the current generation. From this, Kettunen et al. estimated that 76% of the genetic variation in the current population came from only two ancestors. In fact, 38.8% of the genetic diversity in the base population had been lost. Part of this (78%) was attributed to random genetic drift, and the remainder (22%) to unequal contributions of the founder dogs.

    Genetic Contributions of Ancestors
    The dog making the largest genetic contribution (41%) to the current reproductive population was a female born in the 1980s that produced 18 offspring. Her pedigree traces back to the base founder dogs through three rounds of full-sib mating, so her inbreeding coefficient was 50%. The next greatest genetic contribution (35%) to the current population was a male from the 1960s that produced 10 offspring. These two dogs, a male and a female, account for 76% of the genetic variation present in dogs born in the first half of 2015.

    Assessment of Current Genetic Status
    The extreme level of inbreeding (> 80%), low Ne (8-16), and extremely small gene pool (fe = 1.3) all point to the urgent necessity of a rehabilitation or rescue program to improve genetic health.

    Rehabilitation vs Rescue
    To determine if there was adequate genetic diversity remaining in the breed to improve genetic status without introduction of new diversity, Kettunen et al. evaluated a breeding strategy called "optimal contribution selection" (OCS). This is a statistical technique designed to retain as much genetic diversity as possible while also balancing the genetic contributions of the founders across the population. As part of the analyses, they explored the effects of variation in the number of matings allowed per sire. When their simulations included only Lundehunds, the use of OCS had no effect on the genetics of the population because of the very high relatedness of the dogs in the breed. This indicates that a genetic rescue, with the addition of new genetic variation, will be necessary to improve the genetic health of the breed.

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