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8.16: Why do harmful alleles persist?

At this point, you might well ask yourself, given the effectiveness of natural selection, why do alleles that produce severe diseases exist at all? There are a number of possible scenarios. One is that a new mutation arose spontaneously, either in the germ line of the organism’s parents or early in the development of the organism itself, and that it will disappear from the population with the death of the organism. The prevalence of the disease will then reflect the rate at which such pathogenic mutations occur together with the rate at which individuals carrying them are eliminated (before they have off-spring). The second, more complex reason involves the fact that many organisms carry two copies of each gene (they are diploid), and that carrying a single copy of the allele might either have no discernible effect on the organism’s reproductive success or, in some cases, might even lead to an increase in reproductive success. In this case, the allele will be subject to positive selection, that is, it will increase in frequency. This increase will continue until the number of individuals carrying the allele reaches a point where the number of offspring with two copies of the mutant (pathogenic) allele becomes significant. These homozygous individuals (and the alleles they carry) then become subject to strong negative selection. We therefore arrive at a steady state population where the effects of positive selection (on individuals carrying one copy of the allele) will be balanced by effects of negative selection on individuals that carry two copies of the allele. You could model this behavior in an attempt to predict the steady state allele frequency by considering the sizes of the positive and negative effects and the probability that a mating will produce an organism with one (a heterozygote) or two (a homozygote) copies of the allele.

Generally the process of selection occurs gradually, over many (hundreds to thousands) of generations, but (of course) the rate depends on the strength of the positive and negative effects of a particular allele on reproductive success. As selection acts, and the population changes, the degree to which a particular trait influences reproductive success can also change. The effects of selection are themselves not static, but evolve. For example, a trait that is beneficial when rare may be less beneficial when common. New mutations that appear in the same or different genes can further influence the trait, and so how the population will change over time. For example, alleles that were “neutral” or without effect in the presence of certain alleles at other genes (known as the genetic background) can have effects when moved into another genetic background. A (now) classic example of this effect emerged from studies on the evolution of the bacterium Escherichia coli. A mutation with little apparent effect occurred in one lineage and its presence made possible the emergence of a new trait (the ability to use citrate for food) ~20,000 generations later253. We will return to how this works exactly toward the end of the next chapter, but what is important here is that it is the organism (and its traits and all its alleles) that is “selected”. Only in cases of strong positive or negative selection, does it make sense to say that specific alleles are selected.

Questions to answer & to ponder

  • How does the presence of PrPsc lead to the change in the structure of PrPc?
  • Why is it, do you think, that FFI and CJD are late onset diseases?
  • Which do you think would be more susceptible to proteolytic degradation, a compact or an extended polypeptide?


253 Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli:


  • Michael W. Klymkowsky (University of Colorado Boulder) and Melanie M. Cooper (Michigan State University) with significant contributions by Emina Begovic & some editorial assistance of Rebecca Klymkowsky.