Molecular evolution

Molecular evolution is the process of evolution at the scale of DNA, RNA, and proteins. Molecular evolution emerged as a scientific field in the 1960's as researchers from molecular biology, evolutionary biology and population genetics sought to understand recent discoveries on the structure and function of nucleic acids and protein. Some of the key topics that spurred development of the field have been the evolution of enzyme function, the use of nucleic acid divergence as a "molecular clock" to study species divergence, and the origin of non-functional or junk DNA. Recent advances in genomics, including whole-genome sequencing, high-throughput protein characterization, and bioinformatics have led to a dramatic increase in studies on the topic. In the 2000s, some of the active topics have been the role of gene duplication in the emergence of novel gene function, the extent of adaptive molecular evolution versus neutral drift, and the identification of molecular changes responsible for various human characteristics especially those pertaining to infection, disease, and cognition.

Mutations
Main article: Mutation

Mutations are permanent, transmissible changes to the genetic material (usually DNA or RNA) of a cell. Mutations can be caused by copying errors in the genetic material during cell division and by exposure to radiation, chemicals, or viruses, or can occur deliberately under cellular control during the processes such as meiosis or hypermutation. Mutations are considered the driving force of evolution, where less favorable (or deleterious) mutations are removed from the gene pool by natural selection, while more favorable (or beneficial) ones tend to accumulate. Neutral mutations do not affect the organism's chances of survival in its natural environment and can accumulate over time, which might result in what is known as punctuated equilibrium; the modern interpretation of classic evolutionary theory.

Causes of change in allele frequency
Main article: Population genetics

There are four known processes that affect the survival of a characteristic; or, more specifically, the frequency of an allele (variant of a gene):


 * Mutation detailed above.
 * Genetic drift describes changes in gene frequency that cannot be ascribed to selective pressures, but are due instead to events that are unrelated to inherited traits. This is especially important in small mating populations, which simply cannot have enough offspring to maintain the same gene distribution as the parental generation.
 * Gene flow: or gene admixture is the only one of the agents that makes populations closer genetically while building larger gene pools.
 * Selection, in particular natural selection produced by differential mortality and fertility. Differential mortality is the survival rate of individuals before their reproductive age. If they survive, they are then selected further by differential fertility – that is, their total genetic contribution to the next generation. In this way, the alleles that these surviving individuals contribute to the gene pool will increase the frequency of those alleles. Sexual selection, the attraction between mates that results from two genes, one for a feature and the other determining a preference for that feature, is also very important.

The production and redistribution of variation is produced mostly by three of the four agents of evolution: mutation, genetic drift, and gene flow. Natural selection, in turn, acts on the variation produced by these agents. One important goal is to understand, using both data from molecular biology and theory from population genetics, the main force driving molecular evolution. Currently, three main positions are defended. Neutralism and near-neutralism (Kimura, 1983; Ohta, 2002), where neutral and nearly-neutral mutations, along with random genetic drift and purifying selection, explain most of evolution. Selectionism (Gillespie, 1991), where balancing selection is considered the main force, and finally, mutationism (Nei, 2005), where mutational input and random genetic drift are thought to be more important.

Molecular study of phylogeny
Main articles: Molecular systematics, Phylogenetics

Molecular systematics is a product of the traditional field of systematics and molecular genetics. It is the process of using data on the molecular constitution of biological organisms' DNA, RNA, or both, in order to resolve questions in systematics, i.e. about their correct scientific classification or taxonomy from the point of view of evolutionary biology.

Molecular systematics has been made possible by the availability of techniques for DNA sequencing, which allow the determination of the exact sequence of nucleotides or bases in either DNA or RNA. At present it is still a long and expensive process to sequence the entire genome of an organism, and this has been done for only a few species. However it is quite feasible to determine the sequence of a defined area of a particular chromosome. Typical molecular systematic analyses require the sequencing of around 1000 base pairs.

The neutral theory
Main article: Neutral theory of molecular evolution

One of the questions concerning molecular evolution is what proportion of mutations are neutral with respect to natural selection, meaning mutations that do not convey a selective advantage or disadvantage to the individual that inherits them. Neutralists believe the driving forces of molecular evolution are random genetic drift and mutations, while selectionists explain molecular evolution with advantageous mutations and balancing selection. The Neutral theory was developed by Motoo Kimura, while John H. Gillespie a leading proponent of selectionism. Resolving this controversy is an aim of population genetics.

Rare spontaneous errors in DNA replication cause the mutations that drive molecular evolution. The molecular clock technique, which researchers use to date when two species diverged by comparing their DNA, deduces elapsed time from the number of differences. The technique was inspired by the once common assumption that the DNA replication error rate is constant--not just over time, but across all species and every part of a genome that you might want to compare. Because the enzymes that replicate DNA differ only very slightly between species, the assumption seemed reasonable a priori. But as molecular evidence has accumulated, the constant-rate assumption has proven false--or at least overly general. Molecular clock users are developing workaround solutions.

Infinite alleles model
The Japanese geneticist Motoo Kimura and American geneticist James F. Crow (1964) introduced the infinite alleles model, an attempt to determine for a finite diploid population what proportion of loci would be homozygous. This was, in part, motivated by assertions by other geneticists that more than 50 percent of Drosophila loci were heterozygous, a claim they initially doubted. In order to answer this question they assumed first, that there were a large enough number of alleles so that any mutation would lead to a different allele (that is the probability of back mutation to the original allele would be low enough to be negligible); and second, that the mutations would result in a number of different outcomes from neutral to deleterious.

They determined that in the neutral case, the probability that an individual would be homozygous, F, was:


 * $$F = {1 \over 4 N_e u + 1}$$

where u is the mutation rate, and Ne is the effective population size. From this it is possible to determine an upper limit to the number of possible alleles in a population, n as the inverse of the homozygosity:


 * $$n = {1 \over F} = 4N_e u + 1$$

If the effective population is large, then a large number of alleles can be maintained. However, this result only holds for the neutral case, and is not necessarily true for the case when some alleles are more or less fit than others, for example when the fittest genotype is a heterozygote (a situation often referred to as overdominance or heterosis).

In the case of overdominance, because Mendel's second law (the law of segregation) necessarily results in the production of homozygotes (which are by definition in this case, less fit), this means that population will always harbor a number of less fit individuals, which leads to a decrease in the average fitness of the population. This is sometimes referred to as genetic load, in this case it is a special kind of load known as segregational load. Crow and Kimura showed that at equilibrium conditions, for a given strength of selection (s), that there would be an upper limit to the number of fitter alleles (polymorphisms) that a population could harbor for a particular locus. Beyond this number of alleles, the selective advantage of presence of those alleles in heterozygous genotypes would be cancelled out by continual generation of less fit homozygous genotypes.

These results became important in the formation of the neutral theory, because neutral (or nearly neutral) alleles create no such segregational load, and allow for the accumulation of a great deal of polymorphism. When Richard Lewontin and J. Hubby published their groundbreaking results in 1966 which showed high levels of genetic variation in Drosophila via protein electrophoresis, the theoretical results from the infinite alleles model were used by Kimura and others to support the idea that this variation would have to be neutral (or result in excess segregational load).

Related fields
An important area within the study of molecular evolution is the use of molecular data to determine the correct scientific classification of organisms. This is called molecular systematics or molecular phylogenetics.

Tools and concepts developed in the study of molecular evolution are now commonly used for comparative genomics and molecular genetics, while the influx of new data from these fields has been spurring advancement in molecular evolution.

Key researchers in Molecular Evolution
Some researchers who have made key contributions to the development of the field:
 * Motoo Kimura — Neutral theory
 * Masatoshi Nei — Adaptive evolution
 * Walter M. Fitch — Phylogenetic reconstruction
 * Walter Gilbert — RNA world
 * Joe Felsenstein — Phylogenetic methods
 * Susumu Ohno — Gene duplication

Journals and Societies
Journals dedicated to molecular evolution include Molecular Biology and Evolution, Journal of Molecular Evolution, and Molecular Phylogenetics and Evolution. Research in molecular evolution is also published in journals of genetics, molecular biology, genomics, systematics, or evolutionary biology.

The Society for Molecular Biology and Evolution publishes the journal "Molecular Biology and Evolution" and holds an annual international meeting.