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.

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.

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