Natural selection deleterious mutations

A breakthrough was achieved by recognizing that the process of natural selection can be harnessed to evolve effective enzymes in artificial circumstances. In directed evolution the processes of natural evolution are accelerated in a test tube in order to select proteins with the desired properties. The realization that one could screen or select beneficial point mutations or recombinations and discard deleterious ones, thus mimicking sexual recombination, spawned the field of directed evolution. 

Because a recessive mutation so rarely becomes homozygous, it is eliminated by natural selection primarily because of its deleterious heterozygous effects, ttiis can occur even if the heterozygous effect reduces survival and fertility by only 2-5%. 

Neutral mutations are neutral with respect to fitness. This does not mean they are neutral with respect to all enzyme behaviors. In fact, many neutral mutations will be deleterious to stability, catalytic ability, or any other property that does not contribute directly to fitness. Properties not protected by the purifying effects of natural selection can change as mutations accumulate, but the process is random and contains litde information that can be used to elucidate mechanisms (Benner and Ellington, 1990 Benner, 1989). 

In natural evolution mutations are often deleterious. While they provide the variability that drives natural selection, they frequently result in loss of function and genetic instability. As a result, a variety of enzymes have evolved to repair DNA damages that can cause mutations and to synthesize DNA during cell replication with exquisite fidelity. The enzymes responsible for DNA repair and replication are in general highly conserved across diverse domains of life as befitting their unique roles in the cell, i.e. the maintenance of genetic stability. 

Endler J A 1986 Natural selection in the wild. Princeton University Press, Princeton, N J Eyre-Walker A, Keightley PD 1999 High genomic deleterious mutation rates in hominids. Nature 397 344-347... 

Nesse You say that on average we each carry 30 deleterious mutations. This means that some people are going to carry 28, and some people are going to carry 32 the question then becomes how much variance there is, and whether that s sufficient to allow natural selection to discriminate effectively between those people carrying more or fewer mutations. 

Casanova Most of the Mendehan mutations discovered in the field of primary immunodeficiencies have been recessive. It could take quite some time before they would be counter selected by natural selection. The few but increasingly recognized dominant mutations that I did not discuss today can be counter-selected in populations at a higher rate, but there are still de novo mutations. There are even a few multiplex kindreds, with patients in multiple generations. In most cases the children have died before bearing their own children. Theoretically what you say is possible, but I don t have examples in mind of infectious disease-predisposing human mutations for which we know a factor that has acted as a positive selection factor. On the other hand, we know deleterious mutations that have been selected because they protect from some infectious diseases, such as the sickle cell trait and malaria. 

The genetic code is degenerate. Of the 20 amino acids, 18 are specified by more than one codon. Hence, many nucleotide changes (especially in the third base of a codon) do not alter the nature of the encoded amino acid. Mutations leading to an altered amino acid are usually more deleterious than those that do not and hence are subject to more stringent selection. 

---