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Molecular clock
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The molecular clock (based on the molecular clock hypothesis (MCH)) is a technique in molecular evolution to relate the time that two species diverged to the number of molecular differences measured between the species' DNA sequences or proteins. It is sometimes called a gene clock or evolutionary clock.
notion of the existence of a so-called "molecular clock" was first attributed to Emile Zuckerkandl and Linus Pauling who, in 1962, noticed that the number of amino acid differences in hemoglobin between different lineages roughly changes with time, as estimated also from fossil evidence.
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The molecular clock (based on the molecular clock hypothesis (MCH)) is a technique in molecular evolution to relate the time that two species diverged to the number of molecular differences measured between the species' DNA sequences or proteins. It is sometimes called a gene clock or evolutionary clock.
Early discovery and genetic equidistance
The notion of the existence of a so-called "molecular clock" was first attributed to Emile Zuckerkandl and Linus Pauling who, in 1962, noticed that the number of amino acid differences in hemoglobin between different lineages roughly changes with time, as estimated also from fossil evidence. They generalized this observation to assert that the rate of evolutionary change of any specified protein was approximately constant over time and over different lineages.
The Genetic equidistance phenomenon was first noted in 1963. The author wrote: "It appears that the number of residue differences between cytochrome C of any two species is mostly conditioned by the time elapsed since the lines of evolution leading to these two species originally diverged. If this is correct, the cytochromes c of all mammals should be equally different from the cytochromes c of all birds. Since fish diverges from the main stem of vertebrate evolution earlier than either birds or mammals, the cytochromes c of both mammals and birds should be equally different from the cytochromes c of fish. Similarly, all vertebrate cytochrome c should be equally different from the yeast protein." For example, the difference between the cytochrome C of a carp and a frog, turtle, chicken, rabbit, and horse is a very constant 13% to 14%. Similarly, the difference between the cytochrome C of a bacterium and yeast, wheat, moth, tuna, pigeon, and horse ranges from 64% to 69%. Together with the work of Emile Zuckerkandl and Linus Pauling, the genetic equidistance result directly led to the formal postulation of the molecular clock hypothesis in the early 1960s. Genetic equidistance has often been used to infer equal time of separation of different sister species from an outgroup.
Later Allan Wilson and Vincent Sarich built upon this work and the work of Motoo Kimura observed and formalized that rare spontaneous errors in DNA replication cause the mutations that drive molecular evolution, and that the accumulation of evolutionarily "neutral" differences between two sequences could be used to measure time, if the error rate of DNA replication could be calibrated. One method of calibrating the error rate was to use as references pairs of groups of living species whose date of speciation was already known from the fossil record.
Calibration
Originally, the possibility was explored that all of the variables influencing DNA replication error-rate might cancel somewhat and show some level of constancy when averaged over time, across species and over parts of the genome. Because the enzymes that replicate DNA only vary slightly between species, the assumption might have seemed reasonable a priori to Pauling or Zuckerkandl as in vitro biochemists. This pioneering effort to integrate the fields of evolutionary and molecular biology can be said to have set aside the variation in rate of DNA repair and natural selection in time, space, and across taxa until molecular evidence accumulated enough to make those variations suitable topics of study in their own light. While the MCH cannot be blindly assumed to be true, individual molecular clocks can be tested for accuracy and utilized in many cases. In general terms, they need to be calibrated against material evidence such as fossils before firm conclusions can be based on them (see also Lovette). Measures in regions of low selection (silent substitutions) showed rates of 0.7-0.8% per Myr in bacteria, mammals, invertebrates, and plants. In the same study, genomic regions of very high selection (encoding rRNA) were considerably slower (1% per 50 Myr).
In addition to such variation in rate with genomic position, since the early 1990s, variation among taxa has proven fertile ground for research too, even over comparatively short periods of evolutionary time (for example mockingbirds
). Tube-nosed seabirds have molecular clocks that on average run at half speed of many other birds, possibly due to long generation times, and many turtles have a molecular clock running at one-eighth the speed it does in small mammals or even slower. Effects of small population size are also likely to confound molecular clock analyses; cheetahs for example, having gone through at least 2 population bottlenecks, could not be adequately studied based on a molecular clock model alone. Researchers such as Ayala have more fundamentally challenged the molecular clock hypothesis. According to Ayala's 1999 study, 5 factors combine to limit applications molecular clock models:
- Changing generation times (A mutation generally becomes fixed only from one generation to another. The shorter this timespan is, the more mutations can become fixed)
- Population size (Apart from effects of small population size, genetic diversity will "bottom out" as populations become larger as the fitness advantage of any one mutation becomes smaller)
- Species-specific differences (due to differing metabolism, ecology, evolutionary history,...)
- Evolving functions of the encoded protein (can be ameliorated by utilizing non-coding DNA sequences or emphasizing silent mutations)
- Changes in the intensity of natural selection
Molecular clock users have developed workaround solutions using a number of statistical approaches including maximum likelihood techniques and later Bayesian modeling. In particular, models that take into account rate variation across lineages have been proposed in order to obtain better estimates of divergence times (and other parameters that may be estimated from substitution rates, such as effective population size.) These models are called relaxed molecular clocks because they represent an intermediate position between the 'strict' molecular clock hypothesis and Felsenstein's many-rates model and are made possible through MCMC techniques that explore a weighted range of tree topologies and simultaneously estimate parameters of the chosen substitution model. It must be remembered that these are still based on statistical inference and not on direct evidence and that therefore, strictly speaking even a relaxed molecular clock can only support but never prove a scientific hypothesis. This problem is approached by using the fossil record, which quite often is good and well-documented enough to provide hard evidence, to calibrate the molecular clock accordingly. Alternatively, for viral phylogenetics and ancient DNA studies, two areas of evolutionary biology where it is possible to sample sequences over an evolutionary timescale, the dates of the sequence themselves can be used to calibrate the molecular clock.
Uses
The molecular clock technique is an important tool in molecular systematics, the use of molecular genetics information to determine the correct scientific classification of organisms or to study variation in selective forces.
Knowledge of approximately-constant rate of molecular evolution in particular sets of lineages also facilitates establishing the dates of phylogenetic events, including those not documented by fossils, such as the divergence of living taxa and the formation of the phylogenetic tree. But in these cases - especially over long stretches of time - the limitations of MCH (above) must be considered ; such estimates may be off by 50% or more.
See also
Further reading
External links
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