Download Mutation Rates

TASSI DI MUTAZIONE
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Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
L'origine della variabilità genetica
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Ultimately, the source of genetic variation observed among individuals in
populations is gene mutation. Mutation generates new alleles, and these are the
substance of all evolutionary change.
The mutation rate is defined as the probability that a copy of an allele changes to
some other allelic form in one generation.
Mutation rates at the gene level depends on mutation rates at other levels:
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Mutation rates for different kinds of mutations can be expressed as mutations per
locus, per gene, per nucleotide, and per gamete. All of these indicate a specific type
of mutation occurring per generation (higher eucaryotes) or per DNA replication
(microorganisms), reflecting mutations arising anew in the unit time.
In addition, mutations rates may be expressed is relation to visible phenotypes or
in relation to of DNA sequence changes
Therefore, it is useful distinguishing between mutation rates:
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per base pair per generation (or replication)
per gene per generation (or replication)
per genome or gamete per generation (or replication)
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Frequenza delle mutazioni e tassi di mutazione
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To estimate the mutation rate, we need to estimate how many cell duplications
occurred to produce the extant population in each culture, and to estimate how many
times a mutation toward resistance occurred among all these cell duplications
Difference between mutation frequency and mutation rate.
• The number of mutant cells in the final population ( M) of this example is 10, and the
total number of cells (N) is 16 x 4 = 64 (mutation frequency = M/N =1.6 x 10-1).
• The mutation rate µ is the number of mutation events (ν = 2) among the total
number of cell duplications D (= 15 x 4 = 60); thus µ = ν/D = 3.3 x 10-2.
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Mutazioni “in avanti”
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Mutation rates
estimated by counting
mutant individuals
based on a Mendelian
phenotype include all
mutations that cause
the appearance of that
phenotype
In practice, this
approach estimate the
forward mutation rate,
or any DNA change
that abolishes or
severely impede the
production of a
functional product at a
locus.
Forward mutations are
changes away from the
wild-type allele
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Mutazioni “in avanti” e “di ritorno”
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In a locus with two possible
alleles (A and a) we can
consider both the forward
(µ) and the backward
mutation (ν) rate.
Forward mutation is the
mutation from wildtype
allele to the detrimental
allele. Backward mutations
undo the forward mutation.
Because there are many
ways to destroy the function
but fewer ways to undo that
harm, backward mutations
are normally more rare
than forward mutations.
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Stima dei tassi di mutazione
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Bacteria, Archae, and Eukaryotic microbes produce about one mutation per 300
chromosome replications. For E. coli this works out to be between 10 -6 and 10-7
mutations per gene per generation, however it is important to note that there are
certain "hot spots" or "cold spots" for spontaneous mutations.
Higher eukaryotes have the same rate of spontaneous mutation, so that rates per
sexual generation are about one mutation per gamete (close to the maximum
compatible with life). RNA viruses have much higher mutation rates - about one
mutation per genome per chromosome replication - and even small increases in their
mutation rates are lethal.
Because a complex individual has a trillion or so nucleotides, each individual is
likely to sustain one or more mutations.
Rates of expressed gene mutations average about 1 per 100,000 to 1 per million:
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rates of expression of phenotypic effects are often higher because they are controlled by
many genes
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Tassi di mutazione per sito nucleotidico
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Rates of spontaneous mutation seem to be determined by evolutionary balances
between the deleterious consequences of too many mutations and the additional
energy and time required to further reduce mutation rates.
In microorganisms, the rate of mutation for any nucleotide (point mutations) is
generally included between 10-9 and 10-10 per DNA replication.
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Although this rate of mutation may seem exceedingly small, the total amount of new
genetic variation introduced by spontaneous mutation at each DNA replication is
significant. Consider the genome of E. coli, of the size of about 5 x 106 bp. With a
mutation rate intermediate between those listed above (say 5 x 10 -10), 25 x 10-4, or one
every 400 cells carries a new point mutation.
This means that in a single large bacterial culture (1 litre), in which concentrations of 2 x
109 cells/ml are easily obtained (=2 x 1012 total cells), some 5 x 109 new mutations are
present, corresponding to 1,000 mutations for each base pair.
In practice, all possible nucleotide substitutions and all possible single
insertion/deletions, as well as many large rearrangements are represented in a moderately
large bacterial population
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Tassi di mutazione per malattie genetiche nell'uomo
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The mutation rate is a measure of the frequency of a given mutation
per generation (or per gamete, which is equivalent). Ordinarily, rates
are given for specific loci. Thus the mutation rate for achondroplasia
is 6-13 mutants per million gametes. This means that each gamete has
about 1 chance in 100,000 of carrying a new mutation for
achondroplasia.
Mutation rates are based almost exclusively on rare autosomal
dominant or X-linked recessive traits. It is virtually impossible to
measure autosomal recessive traits accurately. The range of known
mutation rates varies from 1 in 10,000 for Duchenne muscular
dystrophy and neurofibromatosis type-1 (the largest genes known) to
several genes in the range of 1 in 10,000,000.
Mutation rate studies never measure all the possible mutations at a
locus. Many of the mutations cause no obvious phenotypic effect and
could only be recognized by direct analysis of DNA sequences.
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Stima evoluzionistica dei tassi di mutazione
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The approach by Nachman and Crowell to measuring the human mutation
rate takes advantage of the well-known result that for neutral mutations, the
mutation rate is equal to the rate of mutation substitution
Knowing divergence time and generation length of two species allowed
them to estimate of the rate and pattern of mutation in stretches of DNA
without function
They sequenced 18 pseudogenes in humans and chimpanzees, including 12
on autosomes and 6 on the X chromosome. In this way, they
1. estimated the average mutation rate per nucleotide site
2. compared mutation rates for different sites and for different classes of mutation
to evaluate heterogeneity of mutation rate
3. compared rates of divergence on the X chromosome and on autosomes to
evaluate the hypothesis that the X chromosome has a lower mutation rate than
the autosomes
4. provided an approximation of the genomic deleterious mutation rate by
considering the total mutation rate and the fraction of the genome that is subject
to constraint
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Nachman e Crowell: differenze fra uomo e scimpanzè
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Nachman and Crowell: tassi di mutazione
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Nachman and Crowell: mutazioni dannose
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini
Tassi di mutazione nell'uomo
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Mutation rates per generation
• Per base pair ~10-8
• Per gene ~10-6 - 10-5
• Per genome
All point mutations: ~100 per gamete
 Deleterious mutations: 1 ~ 2 per gamete
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The rate of nucleotide substitutions is on the order of 1 per
100,000,000 nucleotides. Since there are 3 billion nucleotides per
genome, that means that every gamete has about 30 new mutations
involving nucleotide substitutions.
Genetica delle popolazioni
a.a. 10-11 prof S. Presciuttini