In good archetypal practice, the prince from one kingdom marries the princess from another, bringing two distinct families together to "invigorate the bloodline", and achieve what geneticists call hybrid vigor, or heterosis. On the other hand, royal families sometimes inbreed, either on purpose, as in ancient Egypt, or by accident, as among the fusty houses of Europe. Such inbreeding leads to genetic decline, as recessive traits become exposed. Better to have Princess Diana running through the china shop than be saddled with hemophilia! Or better yet, have the king litter the land with bastards who, in another archetype, are more robust and vigorous than the proper, and sickly, royals.
In the first approximation, the underlying explanation for these outcomes is deleterious recessive alleles, which are common and arise through mutation. The effect of any individual one may be small, especially in the heterozygotic state, thus they accumulate over time in a normal population, and survive in direct proportion to how deleterious they are. If genetically similar people have children, the likelihood is higher that such alleles that are normally hidden by a complementary wild-type allele will come together and show their defect. If A is the wild-type allele, and a is the recessive, defective allele, then the cross Aa X Aa ==yields==> AA, Aa, and aa, of which the latter offspring is defective or dead, assuming that the a allele is important enough to affect survival. That is the simple story of inbreeding depression, and understandable enough. But why are some hybrids even better off than either parent? Corn is notorious for benefiting from hybridization. The genetics of that are a bit more complicated.
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| Inbreeding or outbreeding? |
A great paper from 1934 laid the groundwork of this field. Sewall Wright stated that this effect was going to be explained not by genetics, but by the biochemistry of the individual loci. The hybrid effect is going to be the net sum over many thousands of genes whose variants, whether good or bad, work out their effects in the development and maintenance of the resulting organism. Some researchers have invoked "overdominance", for instance, where a hybrid at a particular locus is better adapted than either parent. The most famous example is sickle cell anemia, where the hybrid or heterzygote is somewhat protected from malaria. But overdominance is not going to be the general explanation, since such finely tuned allele relationships are rare, and because this tuning is naturally specific to a given population and environment. The likelihood of cross-breeding to an outside genome, adapted to other conditions, benefiting this kind of locus is going to be slim.
No, the more general explanation recognizes that the overwhelming majority of recessive and otherwise deleterious alleles are mechanistically missing function- either partially or wholly. And that they are selectively deficient as well, representing not an advantage to heterozygote, but a slight disadvantage, due to reduced amounts of whatever it is they encode and do. For most enzymes and other functions, half the normal amount is far, far better than none (especially when regarded as enzymes, which are often produced in excess). So, assuming that either population has drifted into a condition where they are homozygous for some minor function, mating with an outside group instantly remediates all those fully defective loci, bringing in 50% molecular function and likely much more than 50% selective function. It also works in both directions- making up deficiencies from both partners of the cross.
But such homozygous recessive/defective loci will be rare, if they have significant functions. More common will be a large pool of heterozygotic recessive alleles. The hybrid cross, between partners that are complementary wild-type at such loci, guarantees some function (at least 50%) at each of those loci, and provides a 50% chance of 100% function. Both are significantly higher rates than for an inbreeding cross, where the chances at each locus of this type are 50% (for 50% function) and 25% (for 100% function), respectively. Summed over numerous loci with complementary character, or just a few key ones, this can have dramatic effects on the resulting offspring. This is the fundamental origin of "heterosis", another name for hybrid vigor. The figure below from one of the reading papers shows this effect constituted in the test tube with enzymes.
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| An experiment hybridizing enzymes in test tubes. A set of four enzymes from glycolysis was set in various "parental" solutions at some arbitrary concentration value (blues and yellows). Then such parents were "mated" into "hybrid" solutions (one per row here) and assayed for enzymatic flux. The midline denotes the flux of the hybridized (mixed) enzymes, while the blue and yellow balls represent the respective parental values. One can easily see that across the collection, the hybrid value on average exceeds the mean parental value, and never falls below that of the worst parent. And the hybrid value often surpasses even the best parental value, exhibiting strong heterosis. The explanation offered for this is that each parent may have had a different limiting step/enzyme that was complemented by that supplied by its "mate". |
How distant can such crosses be? There is a limit, clearly, since with greater distance, genetic incompatibilities begin to arise, (incipient speciation), which begin to strongly impair fitness, usually affecting fertility first, before other traits. So hybrid vigor arrives at a sweet spot of ... distant enough to have a significant number of distinctive recessive and wild-type alleles, but not so distant that the genomes are no longer compatible at those loci which are evolving most rapidly, which tend to be those involved in immunological functions and those involved in reproduction, which are scenes of notorious arms races of pathogenic and sexual selection, respectively.
Hybrid vigor is complemented by a much more insidious process, the concentration and disposal, via the lottery of sex, of bad alleles into unfortunate offspring that either die before birth (miscarriages) or suffer from their deficiencies through life. While outcrossing hides such recessive alleles, the next cross (F2, in the parlance) brings them back, all mixed and matched with each other, some of which are likely to be dead. That is why farmers using seeds from their hybrid corn crop are bound to be disappointed with a motley field of scarecrows. Inbreeding likewise brings out recessive loci, and the more advanced the inbreeding program, the more "pure-bred" a strain is, the more every locus is homozygous, for good or for ill.
Hybrid vigor is thus an evanescent affair, delaying the inevitable reckoning of bad alleles with their grim reaper- natural selection. Some populations (Mennonites, Ashkanazi Jews) are more inbred, and stricken with more dramatic genetic defects that appear for that reason at higher frequency, but all deficiencies are time bombs that, even if they are well-hidden by their recessiveness and rarity, can eventually meet up to form homozygotes and bode ill for their host.
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| Human heterozygosity decreases with distance from Southern Africa, as predicted by the Out-Of -Africa hypothesis. As populations move, they leave some of their genetic patrimony/matrimony of variation behind (called a bottleneck effect). |
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| Conversely, the rate of predicted deleterious alleles goes up with distance from Southern Africa. This is thought to arise from the relaxation of selection which is the definition of rapid range edge expansion. Genetic bottlenecks with small populations can also fix deleterious mutations, (i.e. bring them to 100% of the population), overwhelming selective effects, and bequeathing them to succeeding populations, no matter how large. |
Reading:
- Sewall Wright, 1934 - describing hybrid vigor in enzymatic terms.
- Julie Fievet et al. 2018 - performing the experiments to validate Wright's theory.
- Brenna Henn, et al, 2016 - human genetics vs geography and prehistoric migration.
- Francois Vasseur et al. 2019 - more studies of heterosis in plants, focusing on nonlinear phenotypic effects.
- Trump before the raving gun nuts ... next week one shoots up a synagogue. Does this resemble a well-regulated militia or mind?
- A pervasive lack of character.
- First, the elite lost control of religion, then art. What is next? The economy?
- Where do good jobs come from? From policy, not accidents.
- Losing Afghanistan.. now, we just don't want to know.
- Bill Mitchell on May Day, veils and myths.
