Lewin Benjamin (ed.) Genes IX

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Silencing

of one copy takes

-4

million

years

Active Silent

Duplication occurs at

1%/gene/million

years

Divergence accumulates at 0 1"/o/million

years

II*i-3RE {i"4 After a

gene

has been dupticated, differences

may accumulate between the copies.

The

genes

may acquire

different

functions or one of the copies

may become

i nactive.

develop

between the duplicated

genes,

one

of

two types

of event is likely to occur:

.

Both of

the

genes

become necessary.

This can

happen

either because

the dif

-

ferences

between them

generate pro-

teins with different

functions,

or

because

they are expressed specifically

in differ-

ent times

or

places.

.

If this does

not Jrappen,

one of

the

genes

is likely to be eliminated because

it will

by chance

gain

a deleterious

mutation,

and

there will be no adverse selection to

eliminate this copy.

\pically

this takes

-

4 million

years.

In

such a situation,

it

is

purely

a matter of chance in terms of

which of the two copies becomes

inac-

tive.

(This

can contribute to incompat-

ibility between different

individuals, and

ultimately

to

speciation,

if different

copies become

inactive in different

populations.)

Analysis of the

human

genome

sequence

shows IhaI

-5"/o

comprises duplications of

iden-

tifiable

segments

ranging in length from l0 to

100

kb. These duplications

have arisen rela-

tively

recently, that is, there

has not

been

suf-

ficient time

for divergence between them

to

eliminate

their

relationship. They include a

pro-

portional

share

(-6%)

of the expressed exons,

which shows

that the duplications are

occur-

ring more or

less irrespective of

genetic

con-

tent.

The

genes in these duplications

may

be

especially

interesting

because

of

the

implica-

tion that they

have evolved

recently

and there-

fore could be

important

for recent

evolutionary

developments

(such

as the

separation

of

man

from monkev).

GLobin

Clusters

Are

Formed

by

Duplication

and

Divergence

.

Att

gtobin

genes

are

descended

by duptication

and

mutation

from an ancestral

gene

that

had three

exons.

r

The ancestral

gene

gave

rise

to myoglobin,

leghemogtobin,

and cr

and

B

gtobins.

o

The

q,-

and

p-gtobin

genes

separated

in the

period

of earty

vertebrate

evotution,

after

which

dupl.ications

generated

the

individual

clusters

of

separate o-

and

B-[ike

genes.

.

0nce

a

gene

has

been

inactivated

by

mutation,

it

may

accumutate

further

mutations

and become

a

pseudogene,

which'is

homotogous

to the

active

gene(s)

but

has

no functional

rote.

The most common

tlpe

of

duplication

generates

a second

copy of

the

gene

close

to the

first

copy'

In some cases,

the

copies

remain

associated

and

further duplication

may

generate a cluster

of

The

best

characterized

example

of a

gene

cluster

is

presented by

the

globin

genes,

which

constitute

an

ancient

gene

family

con-

cerned with

a

function

that

is central

to the

ani-

mal kingdom:

the

transport

of

oxygen

through

the bloodstream.

RoshanKetab

O2L-66950639

The major

constituent

of the

red

blood

cell

is

the

globin

tetramer,

which

is associated

with

its heme

(iron-binding)

group in the

form of

hemoglobin.

Functional

globin

genes in all

species

have the same

general structure:

they

are

divided

into three

exons,

as shown

previously

in Figure 3.7

.We conclude

that

all

globin

genes

are derived

from a

single

ancestral

gene, and

by tracing

the development

of

individual

globin

genes

within and

between

species

we

may learn

about the

mechanisms

involved

in the evolu-

tion of

gene families.

In adult

cells,

the

globin tetramer

consists

of

two identical

cr

chains

and

two

identical

p

chains.

Embryonic

blood

cells

contain

hemo-

globin

tetramers

that

are different

from

the adult

form.

Each tetramer

contains

two

identical

cr-

like chains

and

two

identical

p-like

chains,

each

of which

is related

to

the

adult

polypeptide and

is

later replaced

by

it.

This

is an example

of

6.3

Gtobin

Ctusters

Are

Formed

by

Duplication

and

Divergence

101

b

(1

rfct$tr ct2 o1

0

+

1i,,,.+++

trcluster

e GrA't_F

6

B

+ ++

I

++

Bcluster

10

20

30 40

50 kb

+Functional gene

;

Pseudogene

;::':.,:

,

Each

of the

s-tike and

B-tike

gtobin gene

families

is organized

into

a singte cluster

that

includes

func-

tionaI

genes

and

pseudogenes

(y).

irr.r:.:::

i:,;.

Different

hemoglobin genes

are expressed

during

embryonic, feta[,

and

adutt

periods

of human

devetop-

ment.

developmental

control, in

which

different

genes

are

successively

switched

on and

off to

provide

alternative products

that fulfill

the

same func-

tion

at different

times.

The

division

of

globin

chains

into

a-like and

p-like

reflects

the organization

of the

genes.

Each

type

of

globin

is

coded

by

genes

organized

into

a single

cluster.

The structures

of the

two

clusters

in the

higher

primate

genome

are illus-

trated

in

i:ii;:-:r'i.i

ii,:1.

Stretching

over 50

kb,

the

B

cluster con-

tains five

functional genes

(e,

two

y,

5,

and

p)

and

one nonfunctional

gene (yp).

The

two

y

3:::

i i :['#

J,^,";:

: i':,1

#;

:

ffi ,'l

J""

11

position

I16,

whereas

the

A variant

has

alanine.

The

more

compact

cr cluster

extends

over

28

kb

and includes

one active

(

gene,

one non-

CHAPTER

6 Ctusters

and Repeats

functional ( gene,

two d

genes,

two

cr, nonfunc-

tional

genes,

and the 0

gene

of

unknown func-

tion. The two

clt,

genes

code for

the same

protein.

TWo

(or

more) identical genes present

on

the

same chromosome

are described

as nonallelic

copres.

The details

of the relationship

between

embryonic

and adult

hemoglobins

vary

with

the organism.

The human

pathway

has

three

stages:

embryonic, fetal,

and adult.

The

distinc-

tion

between

embryonic and

adult is

common

to mammals,

but the number

of

pre-adult

stages

varies. In

man, zeta

and alpha are

the

two s-like

chains. Epsilon,

gamma,

delta, and

beta are

the

B-like

chains.

l'g{iLiFii:

il:.i,

shows how

the

chains

are

expressed at

different stages

of development.

In

the human

pathway, (

is the first

o-like

chain to be

expressed,

but it is soon

replaced

by

cr. In

the

B-pathway,

e and

y

are

expressed

first.

with 6 and

B

replacing

them

larer.

In adults,

the

cr2p2 form

provides

97'h

of the hemoglobin,

a262

provide

s

-2o/"

,

and

-1"/o

is

provided

by

per-

sistence

of the fetal lorm

a2y2.

What is the

significance

of the

differences

between

embryonic

and adult

globins?

The

embryonic

and fetal forms

have

a higher

affin-

ity

for oxygen.

This is

necessary

in

order to

obtain oxygen

from

the mother's

blood.

This

explains

why there is no

equivalent

in

(for

example)

chicken, for

which

the

embryonic

stages occur

outside the

body

(that

is,

within

the egg).

Functional

genes

are defined

by

their

expression

in RNA

and ultimately

by the

pro-

teins for

which they

code.

Nonfunctional genes

are

defined as

such by their inability

ro

code for

proteins;

the reasons

for their

inactivity

vary,

and

the deficiencies

may

be in transcription

or

translation (or

both). They

are

called

pseudo-

genes

and

are indicated

by the

symbol

y.

A

similar

general

organization

is found

in

other

vertebrate

globin

gene

clusters,

but

details

of

the

types, numbers,

and

order

of

genes

all vary,

as illustrated

in

il.{i,:*l{i

ii..t.

Each

cluster

contains

both

embryonic

and adult genes.

The

total

lengths

of

the clusters

vary widely.

The

longest

is found

in

the

goat,

where

a basic

cluster

of

four

genes

has

been

duplicated

twice.

The

dis-

tribution

of

active

genes

and

pseudogenes

dif-

fers

in

each case, illustrating

the random

nature

of the

conversion

of one

copy

of a duplicated

gene

into

the inactive

state.

The

characterization

of these

gene

clusters

makes

an important general

point.

There

may

be

more members

of

a

gene

family,

both

functional

and

nonfunctional,

thqn

we would

suspect

on the

basis

Embryonic

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weeks):

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00E-

.

At

silent sites, mutation

only substitutes

one synonym

codon for

another, so

there

is no

change in

the

protein.

Usu-

ally

the

replacement

sites

account for

75'/. oIa coding sequence

and the silent

sites

provide

257o.

In addition to the

cr:ding sequence,

a

gene

contains nontranslated regions.

Here again.

mutations

are

potentially

neutral,

apart from

their effects on either secondary

structure

or

(usually

rather

short) regulatory

signals.

Although silent mutations

are neutral with

regard to the

protein,

they could

affect

gene

expression via the sequence

change in RNA.

For example, a change in

secondary structure

might influence transcription,

processing,

or

translation.

Another

possibility

is that a change

in

synonym codons calls for a different

IRNA

to respond,

influencing

the

efficiency of

translation.

The mutations in

replacement

sites should

correspond with the

amino acid divergence

(determined

by the

percent

of

changes

in

the

protein

sequence). A nucleic

acid divergence of

O.45oh at replacement

sites corresponds to an

amino acid divergence of I

%

(assuming

that

the average

number

oli

replacement

sites

per

codon is 2.25). Actually, the measured

diver-

gence

underestimates the differences that have

occurred

during evolution,

because of the occur-

rence

of

multiple

events at one codon. Usually

a correction is made for: this.

To

take the example of the human

p-

and

6-globin chains, there are l0

differences

in

146

residues, a divergence of 6.9oh. The DNA

sequence

has 3l changes in44l residues.

How-

ever, these

changes

are distributed very differ-

ently in the

replacement

and silent sites. There

are

I I changes in the 330 replacement

sites,

but 20 changes

in

only I I

I

silent sites. This

gives

(corrected)

rates of divergence

of 3.7'/.

in

the

replacement sites and )2o/o in the

silent sites.

almost an order of

magnitude in

difference.

The striking differe:nce in the divergence of

replacement and silent sites demonstrates the

existence of much

greater

constraints on

nucleotide

positions

that influence

protein

con-

stitution

relative to

those

that

do

not.

So

prob-

ably very

few

of the amino acid changes are

neutral.

Suppose we take the

rate

of mutation at

silent

sites to indicate the underlying rate of

mutational

fixation

(this

assumes that there

is

no selection

at all at the silent sites). Then over

the

period

since the

p

and 6

genes

diverged,

there

should have been chanses at 32o/o of the

330 replacement sites,

for a total

of 105.

All but

l l

of

them have been eliminated,

which

means

IhaI"

-90o/o

of the

mutations

did not survive.

The

divergence

between

any

pair

of

globin

sequences

is

(more

or

less)

proportional to the

time since they separated.

This

provides

an

evo-

lutionary clock that

measures

the accumula-

tion of

mutations at an

apparently

even rate

during the evolution

of a

given

protein.

The rate

of

divergence

can be

measured

as

the

percent

difference

per

million

years,

or as

its reciprocal, the unit

evolutionary

period

(UEP),

the time

in millions

of

years

that it takes

for lo/o

divergence

to

develop.

Once the

clock

has

been established

by

pairwise comparisons

between species

(remembering the

practical

dif-

ficulties in

establishing

the actual

time of spe-

ciation), it can be

applied

to related

geneswithin

a species. From their

divergence,

we

can calcu-

late how much time

has

passed

since

the dupli-

cation that

generated them.

By comparing

the sequences

of

homolo-

gous genes

in different species,

the

rate of

diver-

gence

at both

replacement

and silent

sites can

be determined,

as

plotted in

i'riir,iiiir

i:"1.

In

pairwise

comparisons,

there is an

aver-

age divergence of

I 0

%

in the replacement

sites

of either the

a- or

B-globin

genes

of

mammals

that have been separated

since the

mammalian

radiation occurred

-85

million

years

ago.

This

corresponds to a

replacement

divergence

rate of

0.12%

per

million

years.

The rate

is

steady

when

the

comparison

is

extended to

genes that diverged

in the more

i;lif;Lri'r:

l- r; Divergence

of

DNA sequences

depends

on

evolutionary

separation.

Each

point

on the

graph

repre-

sents

a

pairwise

comparison.

100

6)

6ao

o

:60

o

440

c)

o

920

o

6.4 Sequence

Divergence

Is the

Basis

for the

Evolutionary

Ctock

105

.

::

:

.,

Replacement

site divergences between

pairs

of

B-gtobin

genes

attow the history

of the human

cluster

to be reconstructed.

This

tree accounts for

the separation

of

ctasses of

globin genes.

distant

past.

For

example,

the average replace-

ment divergence

between

corresponding mam-

malian

and

chicken

globin genes

is 237o.

Relative

to

a separation-270

million

years

ago,

this

gives

a

rate

of 0.O9o/o

per

million

years.

Going

further

back, we can

compare the o,-

with

the

B-globin

genes

within

a species. They

have

been diverging

since the individual

gene

types

separated 500

million

years

ago

(see

Fig-

ure 6.8). They

have an

average replacement

divergence

of

-50"/o,which

gives

a rate

of 0. I

%

per

million

years.

The

summary

of these data in

Figure 6.9

shows

that replacement

divergence in

the

glo-

bin

genes

has

an average

rate

of

-0.096oh

per

million

years

(or

a UEP

of

10.4).

Considering

the uncertainties

in

estimating

the times

at

which

the species

diverged,

the results lend

good

support

to the idea

that there is

a

linear

clock.

The

data

on silent site

divergence

are much

less

clear. In

every case, it

is evident

that the

silent site

divergence is

much

greater

than

the

replacement

site divergence,

by a factor that

varies

from

2 to 10. The

spread

of silent

site

divergences

in

pairwise

comparisons,

though,

is

too

great

to show

whether

a clock is

applica-

ble

(so

we must

base temporal

comparisons

on

the replacement

sires).

From Figure

6.9, it

is clear

that

the

rate

at

silent

sites is not linear

with

regard

to time.

f

we assume

that

there must

be

zerl

diverqence

at

zerl

years

of separation, we see

that the rate of

silent site divergence is much

greater

for the

first

-100

million

years

of separation.

One

interpretation is

that a fraction of roughly

half

of the silent sites is rapidly

(within

I00 mil-

lion

years)

saturated by mutations;

this frac-

tion behaves as neutral

sites.

The

other fraction

accumulates mutations

more slowly,

at a rate

approximately the same as that

of the replace-

ment sites; this fraction identifies

sites

that are

silent with regard to the

protein,

but that come

under selective

pressure

for

some

other rea-

son.

Now we can reverse the

calculation

of

divergence rates to estimate

the times

since

genes

within

a species have been

apart. The

difference between the human

B

and

6

genes

is 3.7

o/"

for replacement

sites. At

a UEP of I0.4,

these

genes

must have

diverged I0.4

x

3.7

=

40 million

years

ago-about the

time of the

separation of the lines leading

to New World

monkeys, Old World monkeys,

great

apes, and

man. All

of these

higher

primates

have both

B

and 6

genes,

which suggests

that

the

gene

divergence commenced

just

before

this

point

in evolution.

Proceeding

further back,

the divergence

between the replacement

sites of

y

and e

genes

is l0%,

which corresponds

to a time

of separa-

tion

-100

million

years

ago. The

separation

between

embryonic and fetal

globin genes

there-

fore may have

just

preceded

or accompanied

the mammalian

radiation.

An evolutionary

tree

for

the human globin

genes

is

constructed in

,:;;i,:ii.i:

;a.':i.t.

Features

that

evolved before the mammalian

radiation-such

as the

separation of

B/6

from

y-should

be found

in

all mammals. Features

that

evolved

after-

ward-such

as the separation

of

B-

and

6-9lo-

bin

genes-should

be found

in individual

lines

of mammals.

In

each species,

there have

been compara-

tively recent

changes in the

structures

of the

clusters.

We

know

this because

we

see differ-

ences in

gene

number

(one

adult

B-globin

gene

in man,

two in mouse)

or in type

(most

often

concerning

whether there

are separate

embry-

onic

and fetal

genes).

When sufficient

data have

been

collected

on the sequences

of a

particular

gene,

the argu-

ments

can be reversed,

and comparisons

between

genes

in different

species

can

be used

to

assess taxonomic

relationshios.

106

CHAPTER

6 Clusters

and

Repeats

The

Rate

of

Neutral

Substitution

Can

Be Measured

from

Divergence

of Repeated

Sequences

.

The rate

of substitution

per

year

at

neutral

sites is

greater

in the mouse than in

the

human

genome.

We can make the best estimate

of the rate of

substitution

at neutral

sites by examining

sequences that do not code for

protein. (We

use

the term

neutral here rather

than

silent, because

there is no coding

potr:ntial).

An informative

comparison can be made by comparing

the

members of a common repetitive family in

the

human

and

mouse

genomes.

The

principle

of the analysis

is summarized

in

'iir--i::ii:

ir

,

:.

\A'/s

Start with a family of related

sequences that

have

evolved by duplication

and

substitution

from

an original family member.

We assume that the cornmon

ancestral sequence

can be deduced by taking

the base that is most

common at each

position.

Then

we can calcu-

late the divergence

of each individual family

member

as the

proportion

of bases

that differ

from the deduced ancestral

sequence. In this

example,

individual members

vary from 0.13

to 0.18 divergence and the average is 0.16.

One family used for

this analysis

in

the

human and mouse

genomes

derives from a

sequence that is thought to have

ceased to be

active at

about

the time of the divergence

between man and rodents

(the

LINES family;

see Section

22.9, Retroposons

Fall into Three

Classes). This

means

thLat it has

been diverging

without any selective

pressure

for

the same

length

of time

in

both species. Its average diver-

gence

in man is

-0.17

substitutions

per

site, cor-

responding

to a

rate

oI

2.2

x

I0-e substitutions

per

base

per year

over tl:re 75 million

years

since

the separation. In the rrrouse

genome,

however,

neutral substitutions have occurred

at twice this

rate,

corresponding to, 0.34 substitutions

per

site in the family, or a rate of 4.5

x

l0-e.

Note,

however, that if we calculated

the rate

per gen-

eration

instead

of

per

1,ear,

it would be

greater

in man than in mouse

(-2.2

x

l0-8

as opposed

to

-10

e).

cCCAGCGTAGCTTICATTACCCGTACGTTCATATTCGG

7138=0.18

cCTGGCGTAGC.TACGTTAGCGGTACGTGCATATTGGG

6/38=0.16

GGTAGCCTAaCTTAaGaTACCGGT!CGTGCTTGTTCGG

6/38=0.16

GGTAGCCTAGCTTAGGTTATTGGTAGGTGCATGTCCGG 6/38=0.16

cCTACCCTAGGTTACGTTATCGGTACGTGTCCGTTCGG

6/38=0.16

GCCACCC'AGCTCACGTTACCGGCACGTGCATGATCGC

7/38=0.18

CCTAGCCTCGCTTTCGTTAGCGGTACCTGCATCTTCCG

7/38=0,18

GCTTGCCTAGTTTACGTTACTGGTACGCGCATGTTGGG

5i38=0,13

GCCAGGCTAGCTTACGCCACCGGTACGTGGATGTCCGG

6/38--0.16

A

T

Calculate

Calculate consensus

sequence

divergence

I

trot

I

V

consensus

GCTAGCCTAGCTTACGTTACcGGTACGTGCATGTTCGG

SEqUENCE

i

I

r,ilrr'ir

r'r

.i

r

An

ancestraI

consensus

sequence

fora

familyis cat-

cutated by taking the

most common

base

at each

position.

The

divergence of each existing

current

member

of the fami[y

is ca[-

cutated as the

proportion

of

bases at

which it differs

from the

ancestraI sequence.

These figures

probably underestimate

the

rate of substitution

in the

mouse; at

the time of

divergence

the rates

in both species

would

have

been the same,

and the

difference

must

have

evolved

since then.

The current

rate of

neutral

substitution

per year in the

mouse is

probably

2-)x

grearer

than

the

historical average.

These

rates reflect the balance

between

the occurrence

of mutations

and the ability

of

the

genetic

sys-

tem of the organism

to

correct them.

The

dif-

ference between the

species

demonstrates

that

each species

has systems

that

operate

with a

characteristic ef

f iciency.

Comparing

the

mouse

and

human

genomes

allclws

us to assess

whether

syntenic

(corresponding)

sequences

show signs

of con-

servation or

have differed

at

the rate

expected

from accumulation

of

neutral

substitutions.

The

proportion

of

sites that

show

signs of

selection is

-5o/".

This

is much

higher

than

the

proportion

that

codes

for

protein

or

RNA

(-l'/.).It

implies that

the

genome includes

many

more stretches

whose

sequence

is

important

for noncoding

functions

than for

coding functions.

I(nown

regulatory

elements

are

likely to comprise

only

a small

part

of this

proportion. This number

also

suggests

that

most

(i.e.,

the

rest) of

the

genome

sequences

do not

have any function

that depends

on

the

exact seouence.

6.5

The Rate of Neutral Substitution

Can

Be

Measured

from

Divergence of

Repeated

Sequences

707

@

Pseudogenes Are

Dead

Ends

of EvoLution

o

Pseudogenes have no

coding function,

but they

can be recognized

by sequence similarities with

ex'isting functional

genes.

They

arise

by the

accumutation

of

mutations in

(formerty)

functional

genes.

Pseudogenes (Y)

are defined by

their

posses-

sion

of sequences that are related

to those of

the functional genes.

but that cannot

be trans-

lated

into a functional

protein.

Some

pseudogenes

have

the same

general

structure

as functional

genes,

with

sequences

corresponding

to

exons and introns in

the usual

locations.

They

may have

been

rendered

inac-

tive by mutations

that

prevent

any or all of the

stages of

gene

expression. The changes

can take

the form

of abolishing the

signals for initiating

transcription. preventing

splicing

at the

exon-intron

junctions,

or

prematurely

termi-

nating

translation.

Usually a

pseudogene

has several

deleteri-

ous mutations.

Presumably

once it ceased to be

active,

there was no impediment

to the accu-

mulation

of further

mutations. Pseudogenes

that represent

inactive versions

of currently

active

genes

have

been found in

many systems,

including globin,

immunoglobulins,

and histo-

compatibility

antigens,

where they

are

located

in

the

vicinity

of the

gene

cluster, often inter-

spersed

with the active

genes.

i

ii;tr i:r

,ir,

i"i.r Many

changes

have

occurred in a

B

gtobin gene

since

it

became

a

pseudogene.

CHAPTER

6 Ctusters

and Repeats

A typical example is the rabbit

pseudogene,

YB2,

which

has

the usual organization

of exons

and introns and is related most

closely to the

functional

globin gene

Bl.

The

rabbit

pseudo-

gene

is not functional,

though.

ljl*i.iiil: ri,i:i

sum-

marizes the many

changes that have

occurred

in the

pseudogene.

The deletion

of a base

pair

at codon 20 of Yp2 has

caused a frameshift

that

would

lead

to termination shortly

after. Sev-

eral

point

mutations have

changed later

codons

representing

amino acids that are highly

con-

served in the

p

globins.

Neither of the

two

introns

any

longer

possesses

recognizable

boundaries with the exons,

so

probably

the

introns could not

be spliced out even if

the

gene

were transcribed. However, there

are no tran-

scripts corresponding to the

gene,

possibly

because there have been changes

in the 5'flank-

rng reglon.

This list of defects includes

mutations

poten-

tially

preventing

each stage of

gene

expression,

thus we have no means

of telling which

event

originally inactivated

this

gene.

If

we measure

the divergence between the

pseudogene

and

the functional

gene,

though,

we

can

estimate

when

the

pseudogene

originated

and when its

mutations stafied to accumulate.

If the

pseudogene

had become

inactive as

soon as

it

was

generated

by

duplication from

pI,

we should expect both replacement

site

and

silent site divergence rates

to be the same.

(They

will be different

only

if

the

gene

is

translated to

create selective

pressure

on the replacement

sites.) In fact, there

are

fewer

replacement

site

substitutions

than silent site substitutions.

This

suggests that at first

(while

the

gene

was

expressed) there

was selection against

replace-

ment

site substitution. From

the relative

extents

of substitution in the

two types of

site, we can

calculate that Yp2

diverged from

Fl

-55

million

years

ago, remained

a functional

gene

for 22

million

years,

but

has

been a

pseudogene

for

the last 33

million

years.

Similar

calculations can be

made for

other

pseudogenes.

Some appear

to have

been active

for

some time

before becoming

pseudogenes;

others appear

to have been inactive

from

the

very

time

of their original

generation.

The

gen-

eral

point

made

by the

structures

of these

pseudogenes

is

that each has

evolved indepen-

dently

during the development

of the

globin

gene

cluster in each

species. This reinforces

the

conclusion

that the creation

of new

genes-

followed

by their acceptance

as functional

dupli-

cates, variation

to become new

functional genes,

or inactivation

as

pseudogenes-is

a continuing

108

60I

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Seq aruosoruoJq)

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(lueurquorar)

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taqlo aql

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Z

aua6

qlLm

srted eLuosouorqr

auololauab11

'reno-6urssolrlenbeun[qpabueqraque]laqunuauag

i:i'l:i

jelil:.r:'ri

Lewin Benjamin (ed.) Genes IX

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