Saturday, 17 August 2013

Molecular Clocks- Timing the Gene Pool

It certainly doesn't tick. And it has no hands either. But the molecular clock is more than a faceless clock. It is a fairly new technique, employing a relatively constant rate of evolution to date almost anything from the divergence of taxa or species to the appearance of a viral epidemic. But this tool is made possible by an incredibly simple observation: the range of difference of DNA between species is essentially a function of the time ever since their divergence. Though the practical applications may seem subtle, molecular clocks put the final nail in the coffin of claims that HIV was first propagated by tainted polio vaccines in the 1950's, made using SIV (simian immunodeficiency virus) by dating the strain back to the 1930's. Essentially, the modern molecular clock has shown that a given protein has a characteristic rate of molecular evolution while genes are different in their characteristic rates . And that molecular evolution per se better fits into a neutralist rather than selectionist view. Linus Pauling reported a range of constant rates of evolution for different proteins (histones are characteristically slow, cytochrome c is slightly quicker (yet slower than haemoglobin) and fibrinopetides are quicker overall). Motoo Kimura and Tomoko Ohta explained away this fairly constant characteristic rate for each protein by positing that most amino acids changes were effectively neutral, so the change has no influence on the overall fitness and as a result the rate of change was no under the effects of natural selection. So on average, beneficial mutations were predicted to be rare, deleterious ones would be quickly wiped out by natural selection and a large fraction of the amino acids changes are effectively neutral. The actual mutation rate of the neutral mutations would only shaped by the mutation rate (and would be fairly constant, taken that the base mutation rate remained unchanged). Such predicts that in a species, the long-term rate of neutral molecular evolution is equivalent to the neutral mutation rate in the individuals. But why do different proteins have different characteristic rates of evolutionary change? We may explain these variations in terms of the assumption that proteins differed in the proportion of amino acid positions that were neutral (so that altering an amino acid has zero selective effect) or constrained (so any mutation was probably deleterious).

Summing up, the greater proportion of neutral sites, the more rapid the rate of molecular evolution. So in accordance with the neutral theory, the rate of which genes evolve is determined by the overall rate of mutation and proportion of neutral sites. Darwin actually predicted two phenomena (rate of fixation of mutations and high level of polymorphisms), which may be accounted by the neutral theory. And the amount of divergence between genes tends to increase (with time) since their evolutionary separation. But molecular clocks themselves may vary either as a result of 'sloppiness' of the tick-rate or variation in the mutation rate; since the clock is probabilistic (ticks are irregular intervals which can be described by a Poisson distribution), but where did this variation stem from? An important source of variation comes from the influence of population size on the rate of fixation of mutation. Ohta expanded the neutral theory (with the nearly-neutral theory) by acknowledging the important role of effective population size; smaller populations are more severely influenced by fluctuations in allelic frequency, so genetic drift can vanquish selection for alleles with small selection coefficients. So in effect, the fixation of of nearly-neutral alleles of small selection effect is predicted to be the greatest in the smallest populations, if a population undergoes a decrease in population, this might coincide with an influx of fixation of nearly-neutral alleles, so population flux can increase the sloppiness of molecular clocks. Another application of molecular clocks can be made to the Hawaiian Islands, where the phylogeny of endemic birds and fruit flies is confirmed by molecular dates that follow a linear correlation between divergence and time in which DNA distance is compared against Island age. Since viruses leave behind no fossil record, we can also reassemble the history of viral outbreaks using viral lineages (viral molecular clock). In the case of endogenous retroviruses (ERVs), dates of origin can be fine tuned by comparing the pair of long terminal repeats (LTRs) that surround the genome. 

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