The inbred lineage you can improve

By Razib Khan | July 18, 2013 3:34 am

Last of the Spanish Habsburgs

Thanks to the efforts of geneticists the story of the extinction of the Spanish Habsburgs is now well known. They are in short a case study in the disastrous consequences of an inbred pedigree. The downsides of inbreeding are to some extent intuitively understood by all, especially consanguineous relations between first order relatives. Though I’m willing to bet that all things equal inbred individuals are not as attractive or intelligent as outbred individuals, the literature in this area for humans is surprisingly thin. A major problem is controlling for confounds; all things are often not equal (e.g., imagine if inbreeding is more common in marginal isolated communities, which is often true in the West. See Consanguinity, Inbreeding, and Genetic Drift in Italy, where it is obvious that the less developed areas of Italy had elevated rates of marriage between relatives despite Catholic discouragement of the practice). But the case that inbreeding results in the expression of deleterious recessive diseases is more straightforward. The rarer the disease, the higher the proportion of individuals who are affected who are the consequence of inbreeding. This is due to the logical fact that very rare alleles tend not to come back together in homozygote form due to the character of the Hardy-Weinberg equilibrium. If the recessive trait is caused by a minor allele with a frequency of p, p2 can converge upon zero very rapidly as p decreases in frequency. At p = 0.1 the recessive trait will express in 1% of the population (so p/p2 = 10). At p = 0.01 the recessive trait will express in 0.01% of the population (so p/p2= 100). And so forth.

Inbreeding changes the equation, so to speak, because you are no longer dealing with random breeding. Instead you are bringing together individuals with the same rare complement of deleterious alleles which may exhibit recessive expression. To make this concrete I drew up a simple stylized pedigree where I trace the descent of one pair of chromosomes from the generation of two grandparents down to the offspring who is the product of a first cousin marriage, and so share those same two grandparents. I have illustrated the process of recombination, where two homologs break apart and are recombined to produce a  synthetic new sequence. What you see is that by the end of the process some segments from one of the four chromosomes of the shared grandparents have been passed down so that they produce two very long runs of homozyogsity (at least on the genomic scale).*  This is problematic. If there are any recessive deleterious mutations along this segment then you by definition have a homozygote at that position (barring a rare back mutation). Obviously individuals who have recent ancestors who appear in multiple positions in their pedigree have a much higher likelihood of having homozygous genotypes, which are often not optimal. In the more extreme cases this produces recessive diseases (and because inbreeding reduces effective population and increases the power of random genetic drift deleterious recessives can even fix within a population rather quickly). Even in cases where individuals are healthy there is likely a fitness drag due to elevated homozygosity across the genome.

And this problem varies quite a bit by locale. Some populations are much more inbred than others, because of cultural practices. In the Arab Muslim world marriages between the offspring of brothers are a common way to cement relations between branches of a lineage. In some South Indian castes marriages between uncles and nieces are common, while in other cases marriages between the offspring of a brother and a sister are preferred. Finally, even though familial exogamy is enforced among many North Indian Hindus, a population bottleneck during the founding of the groups, and subsequent intra-caste endogamy, have resulted in a likely higher load of recessive diseases among these populations, despite their aversion to consanguinity.

But there is hope. Generations of inbreeding, resulting in near pedigree collapse, can be abolished by one generation of outbreeding! How is this possible? Think back to the example of the chromosome with long homozygous stretches. Imagine a magical individual who is 100% homozygous, but alive and fertile. Likely they are a repulsive nincompoop due to the enormous disease burden, but in this fanciful world they find someone who mates with them who is not related to them. Most of the deleterious recessive traits will immediately become masked in the offspring, because at the locations where the inbred individual carries functionally defective alleles their mate will carry the wild type variant.

What does this mean in the “news you can use” department? If your partner comes from an inbred lineage then don’t worry about your offspring (at least for genetic reasons). The outbreeding event will result in a genotype unburdened by deleterious recessive expression. People are always looking for ways to be socially productive and altruistic, and marrying someone from an inbred lineage is one way to guarantee that the world is filled with healthier and more beautiful people.

* A friend who is the product of a first cousin marriage has many 30-50 megabase homozygote segments.

CATEGORIZED UNDER: Genetics
  • razibkhan

    not sure that variance in copy number is that significant compared what i’m talking about

    http://en.wikipedia.org/wiki/Copy-number_variation#Prevalence_in_humans

    obviously something like huntington’s though does show up in inbred lineages. but that’s because of the drift in those lineages, not something specific to the duplicatons.

  • Chad

    Such a outcross with a heavily inbred individual, or even better, two heavily inbred individuals from two separate pedigrees would be fascinating to observe the effects of heterosis……somebody needs to play matchmaker with the Amish and some other inbred population…..just saying.

  • QnsGambit

    I always thought it odd to omit in these discussion of inbreeding that just as defective traits are enhanced is such populations so are beneficial ones. The idea being that natural selection would select out those that are too maladapted to breed (e.g from just a shade too ugly or too crippled by whatever local standard…that is, unmarriageable, to downright unable to survive childhood). There is a fine line where the population is too inbred. But having too much diversity would slow adaptation.

    Of course, one must define what it is a population is supposed to be adapting to in the environment to draw any such conclusions. Anyway, the topic of inbreeding and fitness just seems unable to shake its cultural frames of reference.

    • razibkhan

      hybrid breakdown seems to be the exception, not the rule, for humans. very common in other lineages, and of course plants can ‘purge load’ through selfing…humans probably would not be able to sustain the selection differentials because the pop size would shrink so quick.

  • RogerB

    The most inbred Western family besides royals I’m aware of is the Randolphs of colonial Virginia. The founder, William Randolph, arrived in the late 17th Cent. and in generations 3 to 5 there were many cousin marriages. One motive was that they had large tobacco plantations and wanted to conserve property. When the tobacco business declined many of them left VA.

    They appear to have gotten away with it. There was one marriage in which both parties were products of Randolph cousin marriages. One child of that marriage had congenital deaf-mutism, but the parents were cousins of the Bolling family as well, and there is a similar case in a marriage of Bolling cousins.

    The eccentric congressman John Randolph was the product of a Randolph cousin marrige and was hypo-androgenic (high pitched voice, slender build, rarely or never shaved). But this can be an acquired state.

    It would be interesting to calculate the odds that a recessive gene for a genetic disease would show up in the descendants of William Randolph (or his wife).
    It should be 1/32 for an individual child of a first cousin marriage. For the Randolph example, it should be well over 0.5.

  • razibkhan

    There is a reason after all, that animal breeds are inbred for desirable traits. Unfortunately, the bad traits sometimes ride with and can be hard to separate.

    if you want a trait VERY FAST this is how you do it. unfortunately that has many side effects. this is a problem with breeding for aesthetic traits in dogs and cats by inbreeding. you get the right look, but the animals are often fragile, and there is a high infant mortality. this what you’d expect though as a way to ‘purge load.’ in practice it doesn’t seem to work too well with mammals like it does with plants.

    , the human population has 5x as many genetic mutations than expected,

    what’s your citation for this? i have an idea where, but i’m curious as to the specific.

  • MrJones

    If regional scale inbreeding was the norm in a lot of countries until recently then urbanization might have this effect.

  • Kate Williams

    This is why I have been saying that an outcross to a street dog, or its equivalent, would fix all the genetic problems in one generation. Then, as in the interesting part of Cattanbach’s experiment, it won’t take more than 4 generations to get excellent typiness back in the breed. I think it would be much faster then breeding to a similar (and inbred) breed trying to keep the type close. Those Mexican street dogs are very handsome beasts, not far from the original wolfy archetype, the “dogwolf”.

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This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!

About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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