One component of the reombination hotspot model presented on Friday was fertility selection. If hotspots are not present to cause crossovers between homologous chromosomes at meiosis, the chromosomes segregate randomly into the two daughter cells, so that half of the time one cell gets both homologs and the other gets neither, creating a defective gamete. This 50% reduction in fertility creates very strong selection for active hotspots
In our original model, this selection acted directly on the hotspot alleles, but wasn't quite strong enough to preserve the active alleles in the face of their self-destructive mode of action (Boulton et al, 1997, Pineda-Krch and Redfield 2005). In the new model presented at the seminar, this selection instead acts on a modifier locus which determines which hotspot alleles are active. The hotspot alleles undergo mutation that changes their sequence, and mutations at the modifier locus change its specificity so that formerly inactive hotspot alleles sometimes become active. If this occurs when the previously active hotspot has self-destructively converted itself into an inactive allele that's now activated by the mutant modifier, this creates fertility selection for the new modifier allele.
This model is supported by the recent discovery that the activity of real hotspots is modified by another locus, PRDM9 (Drive Against Hotspot Motifs in Primates Implicates the PRDM9 Gene in Meiotic Recombination.) This gene was first identified because the alleles present in different species of mice cause infertility in hybrids, and this is now thought to occur because of failure to recognize the other species' hotspot alleles at meiosis. The PRDM9 locus does evolve rapidly, especially at certain amino acids in its DNA-binding zinc-finger repeats (Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa).
The model presented on Friday was able to reproduce the key features of hotspot evolution - rapid turnover of individual hotspots (replacement of active alleles by inactive ones) and preservation of a reasonable recombination rate. (But I can't remember how high this recombination rate was...). But it depended on fertility selection acting on the modifier.
In the talk I raised one issue that I think is very important, the strength of fertility selection, but I'm not sure how coherently I explained it. Many models of natural selection incorporate a step that restores the population size in each generation, after selection has removed some individuals. In a deterministic model this can be done simply by normalizing the numbers, but in a model that follows individuals stochastically, new individuals must be added to the population in each generation to replace those that have died or failed to reproduce. This implicitly assumes that population size is not limited by selection. This is a dangerous assumption because it eliminates the risk that the population will go extinct if selection is too severe. In most models this is only a theoretical concern, because selection is relatively weak. We usually think of strong selection as a positive force for evolutionary change, but it can also be a negative force causing extinction. In fact, extinction might be the usual outcome, with only those lucky populations that happen to have the right alleles escaping it.
Models of hotspot-dependent recombination can incorporate very severe selection, as we discussed in our two hotspot papers. If even a single chromosome loses enough active hotspots that it usually has no crossovers, the population's fertility will be reduced by 50%; if several chromosomes have this problem, fertility will be so low that extinction becomes likely.
Two aspects of the model presented on Friday raised red flags about the strength of fitness selection. First, the modifier locus was assigned a very high rate of mutations that changed its sequence specificity (I think 10^-2 per generation), but never suffered mutations that reduced its activity. This is very unrealistic; everything we know about gene function predicts that loss-of-function mutations will be much more common than change-of-specificity mutations, and nothing about the PRDM9 gene suggests that it should be exempt from this principle. Loss-of-function mutations at the modifier locus would be expected to cause sterility, as is well established for PRDM9. Second, only a single chromosome was modeled, but I think the fertility cost will increase dramatically (exponentially?) as the number of chromosomes increases.
I still think the model is very important, because it incorporates the same features implicated by the PRDM9 work. But it won't be realistic until it considers the real cost of the fertility selection it depends on. It should be easy to modify the model to monitor the fraction of the population that fails to reproduce in each generation. If this fraction is substantial (I'm being deliberately vague here because I don't know how large would be too large), then introduction of a modifier locus hasn't really resolved the paradox.
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