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RATES OF POINT MUTATION
The rate of mutation = the number of new
sequence variants arising in a predefined
target region per unit time.
Target region = a specific sequence of
predefined length and location, a gene, a
gamete, a chromosome, or a genome.
Time units may be (1) taxon specific, such
as replication time or generation time, or (2)
absolute, such as chronological time (days,
years).
The chief difficulties in estimating the rate of
mutation is (1) the fact that mutations occur
at a very low rate and (2) that many
mutations are highly deleterious or lethal
and, therefore, unobservable.
There are essentially three main approaches to
estimating mutation rates.
First approach (Danforth 1923; Halda 1927, 1935).
Based on the assumption that deleterious alleles in a
population exist because of a balance between (1) the
process of mutation creating these alleles and (2)
purifying selection eliminating them.
For autosomal dominant mutations, the equilibrium allele
frequency, q, can be calculated as
q s
where μ is the mutation rate and |s| is the selection
coefficient associated with the deleterious mutant. The
mutation rate is, therefore
 qs
For X-linked recessive mutations, such as hemophilia,
the mutation rate is
 qs 3
(the denominator contains 3 since one-third of the X
chromosomes in the population are carried by males)
If most hemophiliacs do not reproduce (i.e., if s ≈ -1),
mutation rate is roughly one third the
then the
frequency of male carriers.
By using empirically determined values of s and q,
Haldane (1935) inferred that mutations causing
hemophilia arise at a mean rate of roughly 2  10–5 per
generation.
The second method of estimating mutation rate is based on the very
important theoretical result (Kimura 1968) that the neutral mutation
rate (μ) is equal to the rate of substitution for neutral alleles (K).
Thus, homologous stretches of nonfunctional DNA, on which
selection does not operate and which evolve by random genetic
drift, can be compared between two species to calculate the amount
of sequence divergence. If the generation time and the time since
the two species have diverged from each other are known, then the
mutation rate per generation can be easily estimated.
Example: This approach has been used for synonymous sites and for
pseudogenes in comparisons between human and chimpanzee, and
these studies suggested mutation rates of about 2 × 10–8 per
nucleotide site per generation.
Given that the total length of the human
diploid genome is approximately 7  109
base pairs, we can multiply the mutation
rate per site per generation (2 × 10–8) by
the genome size, and deduce that each
newborn in the human population carries
around 140 new point mutations not
found in their parents.
The third method of inferring mutation rate is the most direct. In
this method, large nonrecombining stretches of DNA, such as human
Y chromosomes, are sequenced in individuals related to one another
by descent. One the pedigree below, about 10 Mb of Y-chromosome
DNA was sequenced from two males (and their living relatives)
separated by 13 generations.
The common ancestor of the two individuals was born in 1805, i.e.,
about 200 years before the
analysis. Four mutations have
been discovered. Thus, the rate of
mutation in the human nuclear
genome was estimated to be
4/(107  200  2) = 1  10–9
mutations per site per year.
Do you know your great-great-greatgreat-great-father?
With the dramatic drop in the cost of sequencing from about 3
billion dollars per haploid human genome in the 1990s to about
50,000 dollars per diploid genome in 2010, it has become practical
to sequence whole genomes of parents and children and identifying
all mutations.
One such study (Roach et al. 2010) yielded an unbiased point
mutation rate estimate of 1.1  10–8 mutations per site per
generation, which translates into a mutation rate of about 0.4  10–9
mutations per site per year under the assumption that the current
generation time in humans is 30 years. Thus, every newborn carries
on average 70 new mutations in their diploid genome.
Other findings: The transition-to-transversion ratio was
approximately 2.3, and the rate of mutation in males was higher
than that in females.
Caveat: Mutations having large deleterious
effects on fitness cannot be observed.
In some experimental organisms, one can overcame the problem of
our inability to detect deleterious mutations, by using the fact a
mutation will behave as a neutral mutation as long as its selective
disadvantage, s, is smaller than 1/(2Ne), where Ne is the effective
population size.
By keeping Ne at the absolute minimum, one can ensure that all but
the most deleterious mutations will be observed. For instance, one
can use a population of the hermaphrodite nematode,
Caenorhabditis elegans, in which a single individual in each
generation is used to produce the succeeding generation. Such an
experiment can last hundreds of generations.
One such experiment yielded a mean estimate of about 10–6 point
mutations per site per year, i.e., the mean mutation rate in C.
elegans was inferred to about three orders of magnitude larger that
that in the nuclear genome of mammals.
The rate of mutation in mammalian mitochondrial
DNA has been estimated to be at least 10 times
higher than the average nuclear rate.
The mean rate of mutation in the mitochondrial
genome of Drosophila has been estimated to be
approximately 6 × 10−8 per site per generation,
which translates into a rate of about 10−6 per site
per year (Haag-Liautard et al. 2008).
Mutation rates in viruses span a range of approximately
six orders of magnitude, from the single-stranded RNA
swine vesicular stomatitis virus at about 10–3 mutations
per site per year, to the double-stranded DNA
herpesvirus at about 10–9 mutations per site per year.
swine vesicular stomatitis virus
herpesvirus