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Molecular Clock
M.Tevfik
Dorak, M.D., Ph.D.
The controversial
hypothesis of molecular clock (MC) is a consequence of the neutral theory of
evolution. It holds that in any given DNA sequence, mutations accumulate at an
approximately constant rate as long as the DNA sequence retains its original
functions. The difference between the sequences of a DNA segment (or protein)
in two species would then be proportional to the time since the species
diverged from a common ancestor (coalescence time). This time may be measured
in arbitrary units and then it can be calibrated in millions of years for any
given gene if the fossil record of that species happens to be rich. MCs do not
behave metronomically, i.e., neutral mutations do not
yield literally constant rates of molecular change but are expected to yield constant
average rates of change over a long period of time (known as
‘stochastically constant’ rates). The concept of MC fits well with
Kimura’s neutrality theory because the rate of neutral evolution in
genetic sequences is equal to the mutation rate of neutral alleles. Even where
selection operates, an averaging of selection coefficients over long periods
could also provide a MC for times of divergence. Undeniably, different DNA
sequences (or proteins) or even different parts of the same gene (or protein)
evolve at markedly different rates. Different functional constraints on
structure and varying intensities of selectional
forces as well as generation time (the rate of meiotic production of gametes)
are the major sources of variation in evolutionary rates. In general, rRNA evolves slowly and mtDNA rapidly. Among other
proteins, fibrinopeptide changes relatively rapidly
and is useful for studying closely related species but cytochrome c is useful
for studying the whole period of life on earth. Fast mutating sequences cannot
be used to go back in evolutionary time because the mutations effectively
randomize the sequences. It is also possible that reverse mutations will occur
and the comparisons will be very difficult. Introns
and pseudogenes evolve rapidly and nondegenerate
sites in protein coding sequences (exons) slowly.
Molecular differences between species are used to infer phylogenetic
relationships. Molecular evolution from living fossils provides an example that
constant rate of molecular evolution occurs
independent of morphological evolution.
A MC must be calibrated
first and this requires a reliable fossil record. Only after this calibration,
a MC can be used for phylogenetic inference. A conventional calibration for
evolutionary rate of animal mtDNA is about 2% sequence divergence per million
years between pairs of lineages separated for less than 10 million years (or
20x10-9 substitutions per site per year). Beyond
15-20 million years, mtDNA sequence divergence begins to plateau, presumably as
the genome becomes saturated with substitutions at variable sites. 16S rRNA gene, however, has an evolutionary rate of 1% sequence
divergence per 50 million years. Although mean evolutionary rates in the
nuclear genome may vary among taxa, they do so in a consistent
fashion. For example, molecular evolution appears slower in primates than in
rodents and especially slow in hominoids. Using the highly conserved protein
cytochrome c sequences, it has been found that the two most divergent species
by far are two species of ascomycetes (fungus) that
separated twice as long ago as the ancestors of mammals separated from the
ancestors of insects.
To test a MC, a relative
rate test that does not depend on absolute divergence times is used. Each test
requires at least two related species (A and B) and an outside reference
species (C) known to have branched off prior to the separation of A and B.
Theoretically, the distances (A to C) and (B to C) estimated by the MC should
be similar. If there is a statistically significant difference, then this
particular MC is unreliable for this taxa. Many relative rate tests have been conducted for
molecular data from different species. Uniform average rates of DNA clocks in
birds, rats, mice and hamsters have been established. The relative rate test
does show up some discrepancies in molecular rates in many cases. This is not
surprising as many allele frequencies are clearly modulated by natural
selection. The main advantage of today’s favorite phylogenetic analysis
method, cladistics, is that it does not rely on MCs.
Microsatellite loci have
properties that make them suitable for dating evolutionary events. The mutation
rate is so high (5.6 x 10-4 in dinucleotide
microsatellites) that a reasonable number of
mutational events can occur within the short time of modern human evolution.
For CA dinucleotide microsatellites,
the average estimate for mutation rate is about 1/5000 per generation. The
application of the microsatellite data to human population studies gave an
estimate of 156 (95 to 290) thousand years for separation of Africans and
non-Africans.
Since most molecular
systems evolve at heterogeneous rates across most taxa,
if precise clocks exist, they are local rather than universal. MCs keep far
from perfect time, but in certain cases (where they have been tested and
approved), they provide invaluable information in
phylogenetic studies.
M.Tevfik Dorak, MD, PhD
Last
updated 9 January 2007
Evolution Genetics Population
Genetics HLA MHC Inf & Imm Genetic
Epidemiology Epidemiology Glossary Homepage