Inbred shorter people

By Razib Khan | July 20, 2012 12:10 am

Evidence of Inbreeding Depression on Human Height, a paper with over 1,000 authors! (I exaggerate) It’s interesting because it seems to establish that inbreeding does have a deleterious effect on traits whose genetic architecture is presumably polygenic and additive. Why is this theoretically important? Because inbreeding depression is often assumed to be driven by the exposure of rare recessive larger effect alleles, which recombine in near relations. Using tens of thousands of individuals from across a dozen European nations the authors found that there is a consistent relationship between inbreeding and reduction in height.

As the authors note height is a convenient trait to explore. First, it’s highly heritable. 80 to 90 percent of the variation in the population is explained by variation in genes. Second, it’s easy to measure. Also, implicit in the paper is the fact that in Europe today there is far less of a environmental effect on height (that’s why the heritability value is high). Even in poor European nations most people have enough to eat, so height is highly heritable, allowing for appropriate cross-national comparison.


The simplest way to state their results is that all things being equal the offspring of two first cousins will be ~3 cm shorter than those of unrelated individuals. But there are many caveats and qualifications here. First, there are different sources of the depression. Using the most sensitive measure of recent consanguinity, a statistic of run of homozygosity pruned of markers in linkage disequilibrium, the authors did not find a strong effect of magnitude of inbreeding increasing the depression. In other words, it looks like the “bang” sharply diminishes after the first “hit.” Second, even genomewide homozygosity has some independent relationship to depression in height. The distinction here is there are genetically homogeneous populations which are nevertheless not inbred. In contrast, there are populations where inbreeding is common, where homozygosity might be lower (an example here might be a Gulf Arab community with lots of African and Persian admixture, increasing the number of heterozygous loci, but where cousin marriage is ubiquitous). The result here suggests that near inbreeding can immediately bring together recessively expressed deleterious alleles and produce a reduction in trait value, but that there is some sort of hit to having a high fraction of homozygous loci as well (I suppose one could posit some sort of genomewide heteryzogote advantage, though I’m skeptical of that).

But perhaps the biggest caveat here is population heterogeneity. There is now fair evidence that height differences between European populations are in part genetic. So naturally the magnitude of the decrease due to inbreeding depression is going to vary by the nature of the genetics of height in a given population. Additionally, I’m not quite sure that they’ve totally accounted for issues of population structure here. Those populations which are naturally very tall may also tend toward greater homozygosity or inbreeding for independent reasons, reducing the effect size of the depression. This is where focusing on Europe is a weakness in this study. I would be very curious about inbreeding depression in Arab populations, for example.

The last sentence of their abstract is obvious and intriguing:

Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

A major reason people study height is that it is a complex trait which seems to be tractable. You can measure it, and normal variation is relatively wide in realized trait value. The ultimate rationale is often to develop or test methods which can have biomedical application. The implication here is that if inbreeding between first cousins results in a ~3 cm depression in height, who knows what other ailments may be the product of these relationships? There seems a consistent result that offspring of first cousin marriage are less intelligent than similar outbred individuals (again, the magnitude seems to vary by study, but the direction of difference is consistent). But then there’s this, The Love That Dare Not Speak Its Surname:

Now a study by the National Society of Genetic Counselors says that having a child with your first cousin raises the risk of a significant birth defect from about 3-to-4 percent to about 4-to-7 percent.

I’ve seen this study being discussed on “rationalist” websites, illustrating the stupidity of religious taboos on incest. There are two issues which concern me here. First, the aggregate social cost to an increase in congenital defects from 3 to 4 percent is not trivial. Second, the focus on congenital defects ignores the impact on normal human variation. The offspring of cousin marriages may be less healthy, uglier, less intelligent, and perhaps shorter. This doesn’t mean that we should ban cousin marriages, anymore than we should ban marriages between stupid ugly people. Rather, it suggests we may need to add some extra parameters to the calculus of the wages of cousin marriage.

What about the flip side? In many species there is an equipoise of relatedness (e.g., philopatric frogs). Too close, and inbreeding depression. Too far, and outbreeding depression. Might that be an issue? In the case of height it seems unlikely. This paper indicates that the primary reason for the decrease in height are rare recessive alleles which have a large deleterious effect. The reason for outbreeding depression is most likely going to be some sort of antagonistic epistasis, deleterious gene-gene interactions. I’m skeptical that these are going to be very common (here is a rare example). But it will be an interesting question to address. Looking at long stabilized hybrid populations, such as the Uyghurs and Malagasy might be instructive.

CATEGORIZED UNDER: Genetics, Genomics
MORE ABOUT: Genomics, Height
  • Chad

    Razib, I ran across this same paper yesterday, but have yet to have the opportunity to read it.

    Do you have any thoughts on the possible contributions of epigenetics in inbreeding? There is recent evidence, primarily from Arabidopsis that there are epigenetic effects that contribute to inbreeding depression and that some of the effects of inbreeding depression are lost when epialleles revert to wild type.

  • Peter Andrews

    Perhaps this explains something I have observed — children of people of different ethnicities are often taller than one might expect from the parents. Perhaps some level of inbreeding depression on the height of the parents is being relieved?

  • http://backseatdriving.blogspot.com/ Brian Schmidt

    I didn’t know that outbreeding depression was from deleterious gene interactions, I thought it was just the dilution or loss of genes that were better adapted to local conditions.

    I’ve found it interesting that introduced populations of animals seem to do worse initially than after a number of years, whether it’s intentional introductions like lynx in Colorado and Mexican wolves in New Mexico, or unscientific introductions like starlings to the US. My assumption was that a version of outbreeding depression held the populations back for awhile until the poor-performing genes or gene assortments were removed. Maybe that’s not right.

  • Chad

    Brian, wouldn’t an introduced population have a small starting population size and thus the observed effects would be more likely due to inbreeding not outbreeding? Not to mention the fact that introduced species must adapt to a new environment, even if only subtly so, which could account for much of the initial poor performance.

    Unless you are assuming that the introduced populations are all unrelated individuals and that is the source of the outbreeding? I could understand such a scenario in the case of scientific introduction. Not so much in the case of unscientific introductions, especially the starlings which were introduced before the rediscovery of Genetics by crazy Shakespeare fans.

  • Chad

    @#2

    Peter, in this circumstance, I would instead lean towards the possibility of Heterosis, aka Hybrid Vigor.

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    I didn’t know that outbreeding depression was from deleterious gene interactions, I thought it was just the dilution or loss of genes that were better adapted to local conditions.

    can be both. for humans though i don’t think the latter applies. we’re not so well adapted to a particular ecology that there isn’t an appropriate in-between ecology. then again, i’m a genetics person :-)

    Do you have any thoughts on the possible contributions of epigenetics in inbreeding? There is recent evidence, primarily from Arabidopsis that there are epigenetic effects that contribute to inbreeding depression and that some of the effects of inbreeding depression are lost when epialleles revert to wild type.

    can i get the cite for that paper? i’m curious. i think epigenetics has a role in everything, but probably a small (though not trivial) role. if epigenetics was so powerful i don’t think that analytical genetics would have made such initial progress.

  • Chad

    Most of the evidence comes from the creation of Recombinant Inbred lines created to study epiallele inheritance using either the methyltransferase 1 (met1) or decrease in dna methylation 1 (ddm1) mutants. Both cause significant decreases in DNA methylation, but not necessarily the same changes in methylation. RILs from met1 show significant effects of inbreeding depression, while ddm1 RILs do not and it is believed that these differences may be because of differences in methylation.

    Of course this is Arabidopsis, which is typically self-pollinating and typically inbred. But it opens interesting possibilities.

    I would not expect epigenetics to supplant other traditional explanations for inbreeding depression, but complement it to a certain extent and perhaps explain some unknowns.

    Heres the papers:

    Reinders, J. et al. Compromised stability of DNA methylation and transposon immobilization in mosaic Arabidopsis epigenomes. Genes Dev. 23, 939–950 (2009).

    Johannes, F. et al. Assessing the impact of transgenerational epigenetic variation on complex traits. PLoS Genet. 5, e1000530 (2009).

    Biémont, C. Inbreeding effects in the epigenetic era. Nature Rev. Genet. 11, 234 (2010).

    Johannes, F. and Colomé-Tatché, M. Concerning epigenetics and inbreeding Nature Rev. Geneti. 12, 376 (2011).

  • Chad

    Two additional papers I forgot to paste in there:

    Kakutani, T., Jeddeloh, J. A., Flowers, S. K., Munakata, K. & Richards, E. J. Developmental abnormalities and epimutations associated with DNA hypomethylation mutations. Proc. Natl Acad. Sci. USA 93, 12406–12411 (1996).

    Mathieu, O., Reinders, J., Caikovski, M., Smathajitt, C. & Paszkowski, J. Transgenerational stability of the Arabidopsis epigenome is coordinated by CG methylation. Cell 130, 851–862 (2007).

  • http://backseatdriving.blogspot.com/ Brian Schmidt

    A simplistic example in humans of outbreeding depression might be intermarriage between two African groups, only one of which generally has adult lactose tolerance. If the resulting descendants live in the culture that herds cattle/drinks cow milk, that could be a problem.

    #4 Chad – I assume the small starting size would cause inbreeding problems as well, but that rapid expansion doesn’t solve inbreeding either. Only many generations of gradually introduced mutations solves the problems. But I don’t really know.

    Adapting to a new environment is what I’m calling outbreeding depression due to genes/gene combinations not starting off present in the right proportions for populations to grow. The alternative version that Razib outlines for outbreeding depression due to gene-gene interactions might make sense in the case you mention where individuals from very different populations are brought together to create a founding population that is genetically diverse in order to avoid inbreeding.

  • bpesta

    #5 and #2:

    Couldn’t this just be regression to the mean?

  • Ian

    I’ve long wondered why Indians and Trinidadian Indians look different. While there’s been a little non-Indian admixture, it’s relatively small – most Indo-Trinidadians are entirely Indian in their ancestry (although much of what gets passed off as ‘Kashmiri’ ancestry is probably actually Scottish (plantation managers and overseers). Obviously there’s an element of diet, and possibly medical care. Never really occurred to me that there’s probably a pretty large outbreeding effect.

    While marriage across racial and religious lines is frequently frowned upon, caste has largely been forgotten. More importantly, while the majority of the population came from what was then the United Provinces and Bihar, there was a substantial minority of Tamils, and a non-trivial scattering of others (though no one talks about it, there probably were more than a few Bengalis, given that the major port of departure was Calcutta). Given the shortage of (Indian) women in the first few decades in Trinidad, regional origin, caste and even religion was secondary to being able to find a wife at all. Even though the next generation may have been more particular about who they married, regional origin and caste were no longer meaningful – the first generation born in Trinidad was already outbred.

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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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