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A DNA Primer for Dog Breeders. Genetic Diversity: Inbreeding (ROH)

Discussion in 'General Dog Discussions' started by Institute of Canine Biology, Jun 21, 2018.

  1. By Carol Beuchat PhD
    Inbreeding

    The Coefficient of Inbreeding (COI)
    Most breeders are familiar with Wright's Coefficient of Inbreeding (COI), which is calculated from pedigree data. The COI provides an estimate of the predicted level of inbreeding based on the simple assumptions that alleles are inherited independently and with equal probability. From this, you can predict the COI of a dog based just on the pedigree data (providing it is accurate and complete) as well as the average COI of a litter of puppies. Because COI is based on the probability of inheriting alleles across all generations of a pedigree, it cannot estimate the COI of a dog exactly. However, it usually correlates well enough with "actual" inbreeding (based on DNA homozygosity) that it remains the single most useful statistic used by animal and plant breeders to assess the level of inbreeding in an individual or the inbreeding to be expected in progeny.

    If pedigree data are incomplete, or you need a more accurate estimate of inbreeding than is computed using COI, inbreeding can be estimated directly from DNA. Of course, heterozygosity that we discussed above is related to inbreeding as

    Ho = 1- homozygosity

    Runs of Homozygosity (ROH)
    However, there are some other methods of estimating inbreeding that can also tell us about how inbreeding is distributed over the chromosomes and how long ago it occurred. This is done using "runs of homozygosity" (ROH) - regions of the chromosomes where there are many consecutive homozygoous loci (Ceballos et al. 2018; Curik et al 2014). The homozygosity produced by inbreeding is not randomly scattered all over the chromosomes. Selection, both natural and artificial, will produce "hot spots" of homozygosity in the regions of the chromosome where there are genes under selection (Sams & Boyko 2018). If the genes remain under continuous selection over generations, the blocks of homozygosity will get longer and longer each generation (Kim et al. 2015).

    Let's look at some examples.

    There are panels below for two breeds with strip identifying the chromosome identifications across the top. I've blown up the strip to show you the first 7 of 38 chromosomes since the numbers are probably too small to see on the chromosome charts. The chromosomes are lined up end to end to form a continuous strip the width of this page.

    The top chart is for Coton de Tulear, and the one below it is for Stabyhouns. Each row is a dog. SNPs that are heterozygous are pink, while homozygous SNPs are blue. You can see scattered across the chromosomes and among the individual dogs that are are blocks of blue of various sizes. These are runs of homozygosity.
    [​IMG]
    [​IMG]
    Coton de Tulear
    [​IMG]

    Stabyhoun

    [​IMG]

    We would expect to see more blue in dogs with higher levels of inbreeding. Indeed, the Stabyhoun has relatively low levels of heterozygosity, which corresponds to higher inbreeding, and there is more blue in the charts of ROH.

    Because we know that these blocks of homozygosity form as a result of inbreeding, we can use them to estimate the fraction of inbreeding across the genome by adding up the total length of runs in each dog and dividing by the total length of the chromosomes.
    Shared Homozygosity
    Something you will notice is that there are regions that are homozygous in multiple dogs, which is evident because they appear as a vertical blue line across the rows. There is an obvious one in chromosome 23 in the Stabyhoun, which shows up as a blue stripe about 25% from the right edge of the chart. There are other areas of shared homozygosity here and there in both breeds.

    New vs Older Inbreeding
    The other thing we can do with these data is detect recent versus old or even ancient inbreeding. We know that inbreeding produces longer and longer runs of homozygosity. But every generation, there is crossover during meiosis that swaps sections of chromosomes. When breaks occur in blocks of homozygosity, one larger run of homozygosity is split into two smaller one. Therefore, we would expect ROH to get shorter over the generations, with the oldest inbreeding being evidenced by the shortest blocks.


    [​IMG]
    We can see this if we visualize these shorter blocks. The two panels below are both data for Havanese, the top one showing blocks of recent inbreeding, the the lower one showing both the large blocks of recent inbreeding as well as the short blocks of older inbreeding.

    Havanese
    [​IMG]
    [​IMG]

    Recent vs Older Inbreeding

    Besides usefulness as a measure of inbreeding, runs of homozygosity are also relevant because they are enriched for deleterious mutations. That is, mutations get trapped in blocks of inbreeding and cause the genetic load of mutations to increase over the generations. If breeders can see where blocks of homozygosity are in the genome, they can select sires that do not share the same ROH, which will prevent the blocks from being passed on to offspring. The two individuals might have the same amount of inbreeding but distributed differently across the genome, and being able to visualize the actual inbreeding on the chromosomes can allow breeders to break up blocks using the heterozygosity at the same place in other parent.

    Although there seems to be general agreement that ROH is a useful tool for estimating the level of inbreeding based on homozygosity, it is still not clear blocks of homozygosity to include in the calculation (Sams & Boyko 2018). Certainly, the longest blocks represent the most recent inbreeding and should be considered, but should older inbreeding also be included? This can amount to a substantial difference in inbreeding estimates, and as yet there is no consensus on what provides the best estimate. In the meantime, comparisons should be made among individuals or between breeds using the same minimum block size, which should provide comparable estimates of the most recent inbreeding.
    You can learn more about runs of homozygosity and how to use ROH to estimate inbreeding in the two-part tutorial below.
    ROH Tutorial: part 1
    ROH Tutorial: part 2
    REFERENCES

    Curik I, M Ferencakovic, & J Solkner. 2014. Inbreeding and runs of homozygosity: a possible solution. Livestock Science 166: 26-34.

    Ceballos FC, PK Joshi, DW Clark, M Ramsay, & JF Wilson. 2018. Runs of homozygosity: windows into population history and trait architecture. Nature Reviews Genetics 19: 220-234.

    Kim E-S, TS Sonstegard, CP Van Tassell, G Wiggans, & MF Rothschild. 2015. The relationship between runs of homozygosity and inbreeding in Jersey Cattle under selection. PLoS ONE 10:e0129967. https://doi.org/10.1371/journal.pone.0129967.

    Marsden CD, D )rtega-Del Vecchyo, DP O'Brien, and others. 2016. Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs. PNAS 113: 152-157.


    Sams AJ & AR Boyko. MS. Fine-scale resolution and analysis of runs of homozygosity in domestic dogs. bioRxiv preprint (7 May 2018). doi: http://dx.doi.org/10.1101/315770.
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