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THE NEUTRAL THEORY OF MOLECULAR EVOLUTION Genetic drift causes more substitutions than does natural selection. Molecular evolution is a balance between drift and mutation. Motoo Kimura (1968)
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NEW TOPIC: MOLECULAR EVOLUTION THE NEUTRAL THEORY OF MOLECULAR
EVOLUTION
Genetic drift causes more substitutions than does natural
selection. Molecular evolution is a balance between drift and
mutation. Motoo Kimura (1968) OBSERVATIONS THAT PROMPTED THE
NEUTRAL THEORY
Observed rates of amino acid substitutions in proteins were
surprisingly high. The amount of heterozygosity in natural
populations seemed too high to be explained by selection. UNIFORM
RATE OF AMINO ACID SUBSTITUTION
Amino Acid Differences FUNCTIONALLY IMPORTANT PARTS OF THE AMINO
ACID SEQUENCE EVOLVE MORE SLOWLY THAN OTHER PARTS Variation in the
Rate of evolution in different types of DNA THE FIXATION OF NEUTRAL
MUTATIONS
For any locus, 2N mutations enter a population each generation.
Each new neutral mutation has a probability of being fixed equal to
its initial frequency, 1/(2N). The average number of substitutions
per locus per generation is equal to the product of these, 2N x
1/(2N) = = BASIC TENANT OF THE NEUTRAL THEORY:
The substitution rate = the mutation rate = EQUILIBRIUM
HETEROZYGOSITY
Basic Neutral Theory models consider only panmictic populations, so
migration and nonrandom mating are ignored. By eliminating
considerations of selection as an important force in molecular
evolution, neutral theory models a balance between drift and
mutation. As a result, at equilibrium, F = 1/(1 + 4N), and H =
4N/(1 + 4N) PREDICTION: Because the strength of random genetic
drift depends on Ne, neutral mutations should take longer to drift
to fixation in large populations (on average, 4Ne generations).
Therefore, large populations should contain many alleles at
intermediate frequency, whereas small populations should exhibit
little polymorphism. POSITIVE RELATIONSHIP BETWEEN HETEROZYGOSITY
AND POPULATION SIZE PREDICTION: Low High
GENES, OR GENE REGIONS, WITH A HIGHER SUBSTITUTION RATE SHOULD SHOW
INCREASED POLYMORPHISM. Low High REGIONS OF PROTEIN CODING GENES
WITH HIGH SUBSTITUTION RATES HAVE HIGH LEVELS OF POLYMORPHISM
FIXATION OF NEUTRAL VS. BENEFICIAL ALLELES
Drift Dominates if:Selection dominates if: 1/2N >> 2s /2N
95%) is noncoding. Most mutations in these regions are silent.
Approx. 24% of base substitutions in protein coding regions are
silent (synonymous). SYNONYMOUS VS. NONSYNONYMOUS SUBSTITUTIONS IN
THE - GLOBIN PROTEIN CODING REGION SYNONYMOUS VS. NONSYNONYMOUS
SUBSTITUTIONS SYNONYMOUS RATE NONSYNONYMOUS RATE Detecting
selection on DNA sequences
Synonymous substitutions: do not change protein Should evolve at a
neutral rate Estimated by ks (number of synonymous substitutions /
1 kb) Nonsynonymous substitutions: change protein Faster evolution
than synonymous sites indicates positive selection Slower evolution
than synonymous sites indicates purifying selection Estimated by ka
(number of nonsynonymous substitutions / 1 kb) The ratio ka/ks can
be used to infer the action of selection on protein coding genes.
Signature of positive selection Positive selection on FOXP2
ESTIMATION OF THE MUTATION RATE PER NUCLEOTIDE SITE
ANCESTRAL SPECIES SPECIES ASPECIES B t years = mutation rate per
nucleotide site per year Expected number of changes per site
between species A and B at synonymous (silent) sites = 2 t Observed
number of changes per site between species A and B = D Estimated
mutation rate = = D / (2 t) 1 sub./site/100 MY 1 sub./site/100 BY
ESTIMATED RATES OF MUTATION PER NUCLEOTIDE SITE
SYNONYMOUS SUBSTITUTION RATE (substitutions/site/billion years) n =
NUCLEAR GENOME m = MITOCHONDRIAL GENOME c= CHLOROPLAST GENOME FROM:
Lynch & Blanchard Genetica :29-39. THE MOLECULAR CLOCK Because
the substitution rate = , the rate of molecular evolution should be
a constant over time as long as the mutation rate does not change
over time. DATING THE TIME OF EVOLUTIONARY DIVERGENCE BETWEEN TWO
LINEAGES
ANCESTRAL SPECIES SPECIES 1SPECIES 2 AATGGTGGCT AATCCGGGCT t d =
estimated rate of nucleotide substitutions / site/ year (from a
calibrated molecular clock) D = observed fraction of nucleotide
sites differing between two species (0.3 in the example above) 2 x
t x d = expected fraction of nucleotide differences between species
Estimated time of divergence = t = D / (2d) The molecular clock can
be calibrated with dates from the fossil record
46 32 30 21 16 DATING THE TIME OF EVOLUTIONARY DIVERGENCE BETWEEN
TWO LINEAGES
EXAMPLE: The substitution rate per site is d = 10-8, and the
nucleotide sequences from two species differ at a fraction D = 0.2
of the nucleotide sites. We estimate the time since isolation
between the two lineages as: t = 0.2 / (2 x 10-8) = 107 years
Species A: T C G Species B: T A G CAVEATS TO THE MOLECULAR
CLOCK
Two sequences may have similar sequences BUT not because of common
descent. Species A:TCG Species B:TAG Convergence lineages may
diverge and then acquire the same base by further mutation.
MUTATIONAL SATURATION
Since nucleotides have only four possible states (A,G,T,C), DNA
sequences will not be expected to diverge 100% even after an
infinitely long period of time. Maximum Divergence: 75%
Mathematical models can be used to correct for the saturation
effect by making the relationship between divergence and time
linear. DIFFERENT GENES EVOLVE AT DIFFERENT RATES
Variation in the selective constraints on different genes leads to
differing rates of molecular evolution. Thus, a calibration of the
molecular clock must be done separately for each gene. NEUTRAL
THEORY: SUMMARY
The Neutral Theory provides an intentionally simplified model of
nature (drift/mutation balance), which makes quantitative and
testable predictions about the patterns of molecular evolution in
nature. The Neutral Theory provides a NULL MODEL for statistical
tests of selection at the molecular level. The predictions of the
Neutral Theory are generally supported by the empirical data.
NEUTRAL THEORY OF PHENOTYPIC EVOLUTION
For quantitative traits the rate of increase of between-population
variance = 2 x U x average squared mutation effect = 2Vmt The rate
of divergence of a neutral character is equal to twice the rate of
polygenic mutation. THE RATE OF DIVERGENCE OF SKELETAL MORPHOLOGY
IN MAMMALS TENDS TO BE WELL BELOW THE NEUTRAL EXPECTATION Upper and
lower bounds of the neutral rate (Vm / Ve) Rate of increase of
between-population variance (in units of within-population
variance) FROM: M. Lynch Am. Nat. 136:
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