Inbreeding depression in man

July 3, 2015 • 12:22 pm

by Greg Mayer

In a paper soon to appear in Nature, Peter K. Joshi and a cast of thousands show that inbreeding can make you shorter, ‘dumber’, and less likely to succeed in school, but not a blowhard. In a study of hundreds of thousands of people from dozens of populations from all over the globe, they found that height, educational attainment, g (‘general intelligence’, derived from various cognitive tests), and expiratory volume (the amount of air you expel while breathing) are all negatively correlated with the degree of inbreeding. An original aspect of their study is that they did not estimate inbreeding from pedigrees, but by directly examining large swathes of the genome for homozygosity, thus allowing the scope of their study to be considerably enlarged.

The slopes (beta) of the regressions of 16 phenotypic characters on the estimated inbreeding coefficient, F. Note that all slopes are near 0, except for those for educational attainment, cognitive ability, height, and FEV1+ (a measure of how much air the lungs expel when you breathe out), which are all negative. negative slope
The slopes (beta) of the regressions of 16 phenotypic characters on the estimated inbreeding coefficient, F. Note that all slopes are near 0, except for those for educational attainment, cognitive ability, height, and FEV1+ (a measure of how much air the lungs expel when you breathe out), which are all negative.

This is an interesting, but expected, result. It has long been known that matings between close relatives, in both plants and animals, can lead to reduced viability, reduced vigor, reduced fertility, and phenotypic abnormality: inbreeding depression. Though long known to breeders, the phenomenon was first quantitatively investigated by Darwin (who fretted over the possible effects on his children of his own consanguineous marriage– Emma was his first cousin); he studied the effects of inbreeding and outcrossing in a number of plants, many of which have adaptations that limit the extent of inbreeding and insure outcrossing. Inbreeding is also often said to have afflicted the royal families of Europe, who repeatedly married within a small group of families. A historically famous case often attributed to inbreeding, that of the ‘Habsburg jaw‘, however, is not due to inbreeding, as the allele causing prognathism is apparently dominant (see below on why this is relevant), although inbreeding may well have contributed to the family’s physical and mental decline.

Charles V , Holy Roman Emperor, ca. 1515 (reigned 1519-1556).
Charles V , Holy Roman Emperor, ca. 1515 (reigned 1519-1556).

The converse of inbreeding depression, hybrid vigor, has also long been known: the offspring of crosses between unrelated individuals or different strains of the same species often show increased vigor, increased viability, and increased fertility. Almost all of the corn grown on farms in the United States comes from seeds produced by crossing disparate varieties. So-called ‘hybrid corn’ has higher yield than the parental varieties (and also insures that the seed companies get paid every year, as the high-yielding variety cannot be regenerated by the farmer the next season by reserving some of his yield for seed). A similar phenomenon can occur in interspecies crosses, but offspring of such crosses, despite being large and vigorous, may well be sterile (e.g., mules, a cross between horses and donkeys), so such sterile crosses are said to show somatic luxuriance.

There is a longstanding debate in genetics over the cause of hybrid vigor/inbreeding depression. There are two main possibilities. First, inbred individuals may have reduced vigor because they are more likely to be homozygous (i.e. possess two copies) for deleterious recessive mutations. In a heterozygote, the deleterious effects of a recessive allele are masked by the dominant allele, while in a homozygote such deleterious effects can now be expressed. And, the chief genetic effect of inbreeding is to increase homozygosity, and hence the phenotypic effects of deleterious recessives. The second possibility is that inbred individuals are less likely to be heterozygous at loci that show overdominance for fitness, and thus will express the less fit phenotypes associated with the homozygous genotypes. In overdominance for fitness, heterozygotes have the highest viability and/or fertility, while both homozygotes are lower. Perhaps the best known example of overdominance for fitness is the sickle cell allele of human hemoglobin in malarial environments: heterozygotes don’t get sickle cell anemia, plus they are resistant to malaria, and thus have higher fitness than either homozygote. (In a non-malarial environment, the fitness of heterozygotes is essentially the same as that of wild type homozygotes.) Both of these genetic phenomena– deleterious recessives and overdominance for fitness– can lead to inbreeding depression. In an extensive literature review a few years ago, Deborah Charlesworth and John Willis showed that the predominant cause is deleterious recessives, and that overdominance is a minor contributor.

The relationship between dominance and fitness also figured in another longstanding debate in evolutionary genetics: the debate between R.A. Fisher and Sewall Wright, two of the founders of theoretical population genetics, over whether new, deleterious mutations are recessive ab initio (fide Wright), or whether selection on modifying alleles causes initially dominant or additive effects of deleterious mutations to become recessive (fide Fisher). Wright showed that the selective effect of such modifiers would be very small (of about the same strength as mutation rates, which are very small), and he doubted that such modest selection could prevail over other factors (including selection on other phenotypic effects of the modifying alleles) in natural populations. Fisher, who thought that natural populations were large, thought they could. The fact that newly observed mutations were generally recessive, and some rather clever work by Jerry’s student Allen Orr using a normally haploid alga to show that recessivity was the rule even when there had been no opportunity for selection of modifying alleles in a diploid state, has finally convinced most people “that recessive phenotypic effects of rare mutations do not result from selection on dominance modifiers.” (Charlesworth and Charlesworth, 2010:183).

Joshi’s study focused on the relationship of the phenotypic traits and inbreeding within populations, so it says nothing directly about the effects of intermarriage between ethnic and national groups. For largely additive, polygenic traits like height, children of such marriages would be expected to be intermediate between their parents in height (not taller than both), but hybrid vigor in other traits cannot be ruled out.


Alvarez, G., F.C. Ceballos and C. Quintero. 2009. The role of inbreeding in the extinction of a European royal dynasty. Plosone 4(4): e5174, 7 pp. pdf

Charlesworth, B. and D. Charlesworth. 2010. Elements of Evolutionary Genetics. Roberts, Greenwood Village, Colorado. (pp. 170-183)

Charlesworth, D. and J.H. Willis. 2009. The genetics of inbreeding depression. Nature Reviews Genetics 10:783-796. pdf

Darwin, C. 1876. The Effects of Cross and Self Fertilisation in the Vegetable Kingdom. John Murray, London. (Darwin Online)

Joshi, P.K. et al. 2015. Directional dominance on stature and cognition in diverse human populations. Nature in press. html

Orr, H. A. 1991. A test of Fisher’s theory of dominance. Proceedings of the National Academy of Sciences USA 88: 11413-11415. pdf

Provine, W.B. 1986. Sewall Wright and Evolutionary Biology. University of Chicago Press, Chicago. (pp. 243-260)

Thompson, E.M. and R.M. Winter. 1988. Another family with the ‘Habsburg jaw’. Journal of Medical Genetics 25: 838-842. pdf

39 thoughts on “Inbreeding depression in man

  1. Although that may be the case in some (and not all) of the European monarchies, it certainly isn’t the case in the Russian monarchy – the Romanov dynasty – as any genealogical research will clearly show. The hemophilia of Tsarevich Alexei was the unfortunate consequence of his being a descendant of his great-grandmother Queen Victoria via her daughter, his grandmother, and her daughter, his mother.

  2. Inbreeding is also often said to have afflicted the royal families of Europe, who repeatedly married within a small group of families.

    About ten years ago the King and Queen of Spain visited Seattle to introduce a show of Spanish art at the Seattle Art Museum. During a Q&A session with a group of schoolchildren they were asked if they ever got together to party with other kings and queens. “We have to,” said the King, “they’re our relatives.”

  3. Would hemophilia be a good example of “inbreeding depression” in european royal families? There is clearly reduced viability caused by recessive genes in that case.

    1. Hemophilia (or at least the common kinds) are X-linked recessive mutations. This means that for a female to have the disease, she must be homozygous for the mutation, and inbreeding would increase the probability of homozygosity. For males, however, since the mutation is on the X chromosome (of which males have only one copy), the disease can be expressed via a single copy of the mutation. For X-linked traits, males are neither homozygous or heterozygous, but hemizygous, and recessive traits are expressed in hemizygous males. (In species with ZW sex determination, females can be hemizygous.) Thus Tsarevich Alexei, mentioned by Vierotchka above, who had hemophilia, was not homozygous, but hemizygous (i.e. not inbred at that locus).

      GCM

      1. There’s an excellent mystery novel about the genetics of hemophilia called The Blood Doctor by Barbara Vine (aka Ruth Rendell).

  4. A question of cause and effect: might it be that people who are not as smart, shorties, or get short of breath are more likely to stick around home and strike up a relation with a relative?

  5. A point not widely realized about the “decline of royal families due to inbreeding” is that even one generation of outbreeding reverses it. Your mother could be the descendant of 10 generations of inbreeding, but if your father were unrelated to her, you wouldn’t be inbred.

      1. Well strictly speaking Charles and Diana were also an outcross (their closest known common ancestor was back in the 1700s, 7th cousins) and the current Queen’s parents were also an outcross (closest known common ancestor back in the 1500s, 13th cousin). The current Queen did marry her second cousin once removed (and also third cousin, etc.); this might explain Charles.

          1. No idiot? Please don’t tempt me. He is a walking talking archetype of Dunning-Kruger: pro-woo in medicine, anti-GMO, anti-Enlightenment (it is “old-fashioned”, this from a hypocrite who has a kneejerk reaction anything modern), religious, arrogant, failed to complete a modest degree, and actually crashed a four-engined jet because he overestimated his ability to land it.

            Long live the Queen!

            1. Yep, he’s a clear picture of what a very average person can achieve with the right environment. He lives in a bubble of sycophants, in which he is never contradicted, and encouraged to think he’s wonderful. He is delusional.

              1. Who on earth is Vieorathka? Or did you mean me? In that case, misspelling my name this way can only mean one of two things – you deliberately insulted me, or you are the progeny of first cousins who both carried a degenerative gene.

  6. Ah, fascinating post! Thanks Greg! I’m hoping there are now a few hypotheses as to why the 4 traits that were significantly different are…well, what they are. There seems to be a notable difference in type between “cognitive difference and education attained” and all the other traits measured. One wonders why other traits that reflect life history as greatly as the first two were not included.

    Also–jest at the title–good thing none of this affects women.

  7. Does beg the question as to whether middle eastern religious traditions of marrying close relatives had had a deleterious impact on the cognitive abilities of whole swathes of humans.

  8. Does beg the question as to whether religious/cultural traditions of marrying cousins has had a persistent deleterious impact on the cognitive abilities of generation after generation.

  9. very interest series going now on PBS on Wednesdays call First Peoples. Modern genetics is finding the homosapiens that walked out of Africa to Europe and to Asia had sex with earlier species and many of the genes picked up by this breeding was very important to our survival.

    1. I was thinking about that too. It is a good series, though I missed much of the 1st episode. They emphasize that different populations of humans in Africa encountered each other and the resulting interbreeding produced new varieties of humans.
      What I did not take to was their repeated depiction of these encounters between human populations as being friendly and curious. Like two tribes meet and they all start singing kumbaya. If written history is a guide the encounters would be anything but that.

  10. Other high achievers married to cousins were composers Stravinsky and Rachmaninoff and scientist Albert Einstein whose 2nd wife was BOTH his first cousin from one set of grandparents AND his second cousin from the other set of grandparents.

    See https://en.wikipedia.org/wiki/List_of_coupled_cousins
    for a large list.

    One wonders if the fact that some cultures allow this more amongst the aristocracy than among commons is a belief that nobility are less vulnerable to inbreeding.

    1. One wonders if the fact that some cultures allow this more amongst the aristocracy than among commons is a belief that nobility are less vulnerable to inbreeding.

      I imagine its because they want to concentrate power and wealth and keep themselves “pure”.

    2. You’ll be surprised how widespread and legal it is. For example, just in the USA, see: http://www.ncsl.org/research/human-services/state-laws-regarding-marriages-between-first-cousi.aspx

      “No European country prohibits marriage between first cousins. It is also legal throughout Canada and Mexico to marry your cousin. The U.S. is the only western country with cousin marriage restrictions.”

      More interesting facts at http://www.cousincouples.com/?page=facts

  11. Thanks. This is very interesting.
    But (please forgive me if this is an idiotic question) what is overdominance? I tried to read about it, but I don’t think that I got the idea.

    1. Overdominance is when the heterozygote (the Aa genotype) has a greater phenotype than either homozygote does (the AA and aa genotypes). For the trait ‘fitness’ (i.e. viability and fertility), a sickle cell heterozygote (in a malarial environment) has a (relative) fitness of 1.00 (because heterozygotes are resistant to malaria, and don’t get sickle cell disease), a normal heterozygote has a fitness of .85 (because while they can’t have sickle cell disease, they get malaria), while sickle cell homozygotes have a fitness of .20 (because they get sickle cell disease, which is debilitating and life shortening; the fitness of sickle cell homozygotes can be raised greatly by proper medical care, so the .20 is just illustrative of their lower fitness, the exact value of which would vary greatly depending on the level of medical care available).

      GCM

      1. Thanks 🙂
        This definitely made it clearer, which is remarkable, considering that the closer I got to biology was at high school.

  12. Golan– I don’t think your question is idiotic at all. I’m a (plant) geneticist and I was also confused by use of “overdominant”. In my experience, and with specific regard to sickle cell anemia/malaria, the scenario is typically described as “heterozygote advantage”– and it’s no more complicated than that.

      1. I’d already forgotten what overdominant and underdominant meant and I just took Mohammed Noor’s excellent Genetics course. Those terms are certainly NOT self-descriptive.

  13. GCM:

    Thank you for everything, especially posting something relevant to evolutionary biology!

    In terms of the evolution of species (or, for that matter, the shift of a population toward a genome more in tune with a changing environment), do you think this phenomenon gets lost in the noise, or does it have some crucial, nay, meaningful effect?

    Is this phenomenon primarily a cultural one, or does it happen to an equally significant degree in Nature? Is it just a “fad” that, in an evolutionary sense, just come and go by chance?

  14. Nifty. If only my friend Raven was here to read it. She always used to say things like (in Inuit tradition of being optimistic and pessimistic at the same time) that: “hm, I’m inbred, so I have both long beautiful legs AND blood diseases …”

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