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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