kimura 1968 nature evolução molecular
TRANSCRIPT
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8/18/2019 Kimura 1968 Nature Evolução Molecular
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Evo l u t i on a ry Ra te
a t
t h e Mo l ecu l a r Level
b y
MO T 0 0
KIMURA
National Insti tute of
Genetics,
Japan
Calcu la t ing the ra te of e vo l u t i o n i n t e r m s of nucleot ide subst i tu t ions
seems t o g ive a va lue
so
h igh tha t many
of
the mu ta t ions nvo lved
mus t be neutral ones.
COMPARATIVE
tudies
of
haemoglobin molecules among
change in for
a
chain consisting
of
some amino
different groups
of
animals suggest that, during the acids.
For
example, by comparing the and chains
o
evolutionary history of mammals, amino-acid substitution manwith those of horse, pig, cattleand abbit, he
has taken place roughly at the rat e
of
one amino-acid
figure
of
one amino-acid change in
x
was obtained
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is roughly equivalent to the rate of one amino-acid
n for a chain consisting of
comparable value has been derived from the study
the haemoglobin
of
primate s. The rate of amino-acid
c (consisting of abou t 100 amino-acids)
48 x 106 yr
(ref.
3).
phosphate dehydrogenase with th at of ra bbit and
figure of a t least one amino-acid substitution
every X yr can be obtained for the chain con-
of abo ut amino-acids. This figure is roughly
ent to the ra te of one amino-acid substitutio n in
x
yr for a chain consisting
of
amino-acids.
c
phate’ dehydrogenase gives an evolutionary
28
x
108 yr for
100 amino-acids.
intend to show that this evolutionary rate, although
a
of cytochrome c, actually amounts to
a
very high
for the entire genome.
DNA
content in each nucleus is roughly the
as man,
rat see,for example, ref. 5 . Furthermore, we
e that the
G-C
content of
DNA
is fairly uniform among
40-44 per
These two facts suggest that nucleotide substitution
a principal part in mammalian evolution.
n th e following calculation, shall assume th at the
d chromosome complement comprises about 4 x
loo
is the number stimated by
rom the DNA content of human sperm. Each
is coded by a nucleotide triplet (codon), and
a polypeptide chain of
100
amino-acids corresponds to
nucleotide pairsn
a
genome. Also amino-acid
codon. Because roughly 20 per cent of nucleotide
mutation
is
estimated to be
is, it codes for the same amino-acid,
about
bme pair replacements in the genome. The average
bme
pair replacement within
a
genome
4 x
10
28
x
IO6yr
-2)
yr
t in t he evolutionary history of mammals,
ide subs titution has been
so
fast that, on average,
nucleotide pair has been su bstitu ted in the population
figure
s
in sharp contrast to Haldane’s well known
hat, in horotelic evolution (standardate
a,new allele may be substitu ted in a population
300 generations. He arrived at th is figure
assuming that thecost of natural selection per genera-
n (the substitutional load in my er mi no log y is
0.1,
while the total cost for one allelic subst itu-
is abou t 30. Actually, the calculation of the cost
R
at
the ra te of one substitution every
2
yr,
he substitutional oad becomes so large thatno
species could tolerate it.
have calculated can only be reconciled with the
mutations produced by nucleotide replacement are
atura l selection. t can be shown tha t
a population of effective size if the selective advan -
new allele over the pre exi stin g alleles is
, assuming no dominance, the tota l load for one gene
substitution is
S
where and p is the frequency of the new allele
at the st ar t. The derivation of the foregoing formula will
be published elsewhere. In he expression given here
is the probability
of
fixation given
1 e -
Now, in the special case of formulae
and 2) reduce to
Formula 1’)shows that for a nearly neutral mutation the
substitutional load can be very low and there will be no
limit to he ate of gene substitutionn evolution.
Furthermore, for such mu tan t gene, the probability of
fixation (that
is,
the probability by which
it
will be
established in he population) is roughly equal to ts
initial frequency as shown by equation
2’).
This means
that new alleles may
be
produced at the same rate per
individual as they are substituted in the population n
evolution.
This brings the athe r surprising conclusion tha t n
mammals neutral
(or
nearly neutral)mutations are
occurring
at
the ra te of roughly per yr per gamete.
Thus, if we tak e t he average length of one generation in
th e history of mammalian evolution the mutatio n
rate per generation for neutralmutations amounts to
roughly two per gamete and our per zygote
x
10-10 per
nucleotide site per generation).
Such a high rate of neutral mutations
is
perhaps not
surprising, for Mu k a i has demonstrated tha t in
Droso
phila the otal mutatio n rate for “viability polygenes”
which on the average depress the fitness by about
2
per
cent reaches
at
least some 35 per cent per gamete. This
is a much higher ra te han previously considered. The
fact that neutralr nearly neutral mutations re occurring
a t a ather high rate is compatible with the igh frequency
of heterozygous loci that has been observed recently by
studying protein polymorphism in human and Drosophila
populations18-16.
Lewontin and H u b b y estimated thatn atural
populations of Drosophila psseudoobscura an average of
about 12 per cent of loci in each individual is heterozygous.
The corresponding heterozygosity with respect to nucleo-
tide sequence should be much higher. The chemical
structure of enzymes used in this study does not seem to
be known
at
present, bu t in the ypical case of esterase-5
the molecular weight was estimated to be abo ut by
Narise and H u b b y . I n higher organisms, enzymes with
molecular weight of th is magnitude seem to be common
and usually they are “multimers”17. So, ifwe assume
that each of those enzymes comprises on the average
some 1,000 amino-acids (corresponding to molecular
weight of some 120,000), themutation ate for the
corresponding genetic site (consisting of a bou t 3,000
nucleotide pairs) is
U 3
X
103X
X 1.0-10 1.5 X 10 6
per generation. The entire genome could produce more
than a million of such enzymes.
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In applying this value of
zd
to
Drosophila
i t must bc
noted that hemutation ate
per
nucleotidepair pe:
generationcan differ inman and
Drosophila.
There i;
some evidence th at with respect to the definitely dele
terious effects of gene mutation, the rate of mutation pe.
nucleotide pair pergeneration s oughly ten times a;
high in
Drosophila
as in manl8.10, This means th at tha
corresponding mutation ate or Drosophila should bl
U 1.6
1O 6 rather han
zc
1-6x 10-6. Another con
sideration allows us to suppose tha t u 1.5
x
10-6 is prob
ably ppropriate for theneutralmutation ate
of
e
cistron n Drosophila. If we assume tha t th e frequency
of occurrence of neutralmuta tions is about one pel
genome per generation (tha t
is,
they are roughly two t c
three
times more frequent than hemutation ofhe
viability polygenes), themutation ate pernucleotide
pair per generation is
1/ 2x loa),
because the DNA con
tent
per
genome in
Drosophila
is about one-twentieth
o
that of manzo. For a cistron consistingof 3,000nucleotide
pairs, this amounts to u
1.5
x
10-5.
Kimura nd Cr ow have shown thatforneutra
mutations he probability thatan individual is homo.
zygous is 1/ 4Neu+ ) , where N e s the effective population
number, so tha t he probability that an individual
is
heterozygous is H e = 4Neu/ 4iVeu+). I n order to attain
at least
H e = 0.12,
it is necessary that
at
least N e = 2,300
For
a higher heterozygosity such as H 0.35, N e has
t c
be about 9,000. This might be a little too large for thc
effective numbern
Drosophila,
but withmigration
between subgroups, heterozygosityof 35 per cent may bc
attained even if N e is much smaller for each subgroup.
We return to he problem
of
totalmutation rate
From a consideration of th e average energy
of
hydrogen
bonds and also from the informationonmutation of
rIIA gene in phage T,, Watson22 obtained
IO- - lo-9
as
the average probability of
error
in the nsertion of a new
nucleotide during DNA replication. Because in man the
number of cell divisions along the germ line from the
fertilized egg t o
a
gamete is roughly80, the rate of muta-
tion resulting from base replacement according to these
figures may be
BO x 10 8
SO X
10-0
per nucleotide pair
per generation. Thus, with 4
x
IO9 nucleotide pairs, the
total number of mutations resulting from base replace-
ment may amount t o 200-
2,000.
This is
100-1,000
times
larger than the estimate of 2 per generation and suggests
that he mutationrate pernucleotidepair
is
reduced
during evolution by natura l selectionl8~19.
Finally, if my chief conclusion is correct, and if the
neutral or nearly neutral mutation is being produced in
each generation at
a
much higher rate than has been con-
sidered before, then
we
must recognize the great impor-
tance of randomgeneticdriftdue to finitepopulation
numberz3 n forming t he genetic structure of biological
populations. The significance of random genetic drift has
been
deprecatedduring thepast decade. This attitude
1as
been nfluenced by the opinion a t almost
no
muta-
ions are neutral, and also th at th number of individuals
forminga species is usually
so
Iarg
f
ha t random sampling
)f gametes should be negligdle in iletermining the course
)f evolution, except possibly through the “founder prin-
: i ~ l e ” ~ * .o emphasize the founderprinciple but deny
he importance of randomgeneticdriftdue to finite
population number is, in
my
opinion, rather similar
to
assuminga great flood to explain the formation of deep
valleys bu t rejecting a gradual bu t long lasting process of
erosion by water as insufficient to produce such a result.
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