Errors in the fidelity of DNA replication along with physical and chemical agents all potentially induce mutations in the DNA sequence. If they affect coding sequences, this may influence the function of any expressed protein. That is, the "phenotype" may alter. The types of mutation include missense, nonsense, and frameshift mutations. All are classified as point mutations. The latter two point mutations have the most serious consequences for the expressed proteins function.
As living organisms are exposed to so many mutagens, life has evolved elaborate DNA repair mechanisms as a counter-measure. The mechanisms include excision-, direct-, and mismatch repair, and they are discussed at length later. This is one area where as an example, antioxidant nutrients prove useful, although they are only one form of defense in this cellular war that is continuously waged within every one of us.
Not all mutations are necessarily bad. A gene that has, for example, an A where previously there was a G, may, under the influence of evolution, become more frequent in successive generations. That is, it is advantageous to possess this mutation in a given environment because it improves reproductive efficiency. Perhaps the protein change provides a selective advantage. As a hypothetical example, maybe the mutated protein in question leads to a more efficient form of an intestinal binding protein specific for a trace nutrient that is important in sperm motility. This provides an easy visualization of how a beneficial trait will be selected for by nature.
Many people use the term mutation, but as I have said, not all mutations are deleterious, so the term polymorphism is more appropriate to use and simply means variant.
If you examine the genetic code within any population, you will find an enormous amount of variation. This stems from mutations and provides the fodder for the process of natural selection first described by Charles Darwin. Of course, although Darwin made his deductions from an examination of whole organisms, we are examining the same phenomenon, but from a molecular perspective. Maintaining population variation by natural selection alone is unlikely, because much of the variation within a population is selectively neutral, and subject to random change or what evolutionary biologists refer to as "drift." Drift is interesting because it can promote or eradicate extremely rare traits, particularly in small populations, which relates to the founder effect described earlier. In North America, the Anabaptist Amish and Hutterite communities give recent human examples of small culturally isolated populations that grew in size, and that now have a unique genetic signature with unrepresentative gene frequencies. The Amish grew from a founder population of around 200 and the Hutterites from 443 people. Both communities were closed to immigration. As a further example, Dutch immigrants arrived in South Africa during the seventeenth century, and although they were a small group, they were interesting in that they carried several rare genetic disorders that were not representative of the parent population from which they were drawn. The Dutch Afrikaner population grew rapidly and maintained the high frequency of these abnormal genetic traits. For example, a single couple of emigres from Holland in the 1680s is now responsible for around 30,000 Afrikaners carrying the trait for porphyria variegata.
In the new synthesis of neo-Darwinian evolution, selection is examined in the context of how it acts on the fundamental genetic unit—the allele. We inherit a copy of any given gene from each of our parents. If neither copy (allele) contains, for example, an A where there is normally a G, then the genotype is wildtype. If one allele contains an A and the other allele a G, the genotype is referred to as heterozygous. If both alleles contain the abnormal (mutant) A, the genotype is homozygous recessive. By considering the frequency of polymorphic alleles, we can look at genetic evolution in a quantitative manner. For example, it is possible to work out how many generations it would take for a given level of selection pressure to substitute one allele for another. This is different to the view many people have of natural selection, because we are looking at the selection of molecular rather than phenotypic traits. As a consequence, scientists are now very interested in the relatively new idea of "selfish genes." Selfish genes and not phenotypes or genotypes span the generations. Consider that phenotypes senesce and die, whereas genotypes are determined as a function of meiosis— only the allele is immortal.
There is considerable debate as to the relative contribution of the following three phenomena as drivers of human evolution: (1) mutational induction of new alleles, (2) drift leading to selectively neutral random changes in allele frequency, and (3) natural selection forcing directional allele change. To put the importance of these evolutionary mechanisms into perspective, what makes us unique as individuals is the subtle, yet extensive variation in our genetic codes. There are in fact several alleles for any given gene in the human genome, emphasizing the seemingly infinite number of possibilities for individuality.
When wildtype and homozygous recessive genotypes are less fit than heterozygotes, then both wildtype and mutant alleles will be maintained in a population. This is known as a heterozygote advantage or balanced selection. The example that is always given to demonstrate this phenomenon describes how a valine substitution for glutamic acid in the hemoglobin molecule can protect individuals from sickle cell anemia. The "mutant" HbS allele is particularly common where malaria is endemic because heterozygosity (HbAHbS) for this trait protects against this life-threatening parasitic infection. Although wildtype (Hb AHb A) individuals are less able to contend with falcoparium malaria, homozygous recessive individuals (HbSHbS) suffer from overt sickle cell anemia, a debilitating and often lethal condition. Despite this awful condition, the frequency of HbSHbS individuals in parts of Africa within the malaria belt can reach 4% of the population. Clearly, the advantages of maintaining heterozygosity for this trait within the population are high. Another example of the heterozygote advantage is given by Tay-Sachs disease in which heterozygosity may confer a degree of protection against tuberculosis despite the recessive genotype being fatal by age 4. However, one of the most interesting and perhaps bizarre examples of a putative heterozygote advantage is given later in a discussion of human prion disease and cannibalism (see Chapter 7).
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