Lewin Benjamin (ed.) Genes IX

10

20

30

40

50

60 70

^

80 90 100

.t1o

GGACCTGGAATATGGCGAGAAAACTGAAAATCACC'GAAAATGAGAAATACACACTTT

AGGACGTGAAATATGGCGAGIAAACTGAAAAAGGTGGAAAATTTGAAATGTccAcTGTA.

GGACGTGGAATATGGCAAGAAAAOTGAAAATCATGGAAAATGAGAAACATCCACTTG

ACGACTTGAAAAATGACGAAATCACTAAAAAA@TGAAAAATGAGAAATGCACACTGAA

200 210 220 230

lI+:.j$il

ti":?+

The repeating

unit

of mouse

satellite DNA

contains

two half-repeats,

which are atigned to show the

jdentities

(in

btue).

l:{-irin*i:

ii.;::..

The

atignment

of

quarter-repeats

identifies

homologies

between the

first

and

second half

of each half-repeat.

Positions

that are

the same in

atl

four

quarter-repeats

are shown

in

gray;

identities

that

extend

onty through

three

quarter-repeats

are

indicated

by

btack tet-

ters in

the

green

area.

quarter-repeats

are aligrred

in

$i.*#*l

ri=itl,. The

upper

two lines represent

the first

half-repeat

of Figure

6.24; the lower

two

lines

represent

the

second half-repeat.

We see

that the

diver-

gence

between

the four

quarter-repeats

has

increased

to 23 out

of 58

positions,

or 407o.

The

first three

quarter-repeats

are

somewhat

better related,

and

a large

proportion

of the

divergence

is

due to

changes in

the fourth

quarter-repeat.

Looking

within

the

quarter-repeats,

we find

that

each consists

of two related

subunits

(one-

eighth-repeats),

shown

as the

cr and

B

sequences

in

Fli-=ijli:

{r.;-:r-:. The

O( sequences

all

have an inser-

tion of a

C, and the

p

sequences

all have

an

insertion

of a trinucleotide,

relative

to a com-

mon

consensus

sequenc(:.

This

suggests that

the

quarter-repeat

originated

by the

duplication

of

a sequence

like the

consensus

sequence,

after

which

changes

occurred

to

generate

the com-

ponents

we now

see as

cx, and

B.

Further

changes

then took

place

between

tandemly

repeated

ap

sequences

to

generate

t.he individual quarter-

and

half-repeats

that exist

today.

Among the

one-eighth-repeats,

the

present

divergence

is

19 l3I

=

610/o.

The

consensus sequence

is

analyzed directly

in l3:ii.rtiii *-"1,i,

which denlonstrates

that the

cur-

rent

satellite sequence

can be

treated as

deriv-

atives

of a 9 bp

sequence.

We can recognize

three

variants of this sequence

in

the satellite,

as

indicated

at the bottom of the figure. If in

one of the repeats

we take

the next most fre-

quent

base at two

positions

instead

of the

most

frequent,

we obtain three

well-related 9

bp

sequences:

GAAAAAC GT

GAAAAAT

GA

GAAAAAAC T

The origin of the satellite could

well lie in

an amplification

of one of

these three nonamers.

The

overall consensus sequence of the

present

satellite is

GAAAAAf."t,

*hi.h is effectively an

amalgam

of the three

9

bp

repeats.

The average

sequence

of the

monomeric

fragment

of the

mouse satellite DNA explains

its

properties.

The longest repeating unit of

234bp is

identified by the

restriction cleavage.

The

unit of reassociation between single strands

of denatured satellite DNA is

probably

the I I 7

bp

half-repeat,

because

tl:'e 234 bp

fragments

can

anneal

both

in register

and

in half-register

(in

the latter case, the first half-repeat of

one strand

renatures with

the second

half-repeat of the

other).

So

far,

we have treated

the

present

satel-

lite

as though it consisted of

identical copies of

6.13

Mammatian Satettites Consist of

Hierarchical Repeats t2t

g1

GGACCTGGAATATGGCGAGAA

AACTGAA

pl

AATCACGGAAAATGA

GAAATACACACTTTA

CI2

GGACGTGAAATATGGCGAGAGA

AACTGAA

92

AAAGGTGGAAAATTTA

GAAATGTCCACTGTA

O3 GGACGTGGAATATGGCAAGAA

AACTGAA

O3

AATCATGGAAAATGA

GAAACATCCACTTGA

A4 CGACTTGAAAAATGACGAAAT

CACTAAA

F4

AAACGTGAAAAATGA

GAAATGCACACTGAA

cont"n.ty.tt,#ffi$ffiffi

ffiw.'..

:

ta.

. . . .

Ancestral?

AAACcTGAAAAATGA GAAATGCACACTGAA

a:i:iiii+

ii.iil The atignment of eighth-repeats

shows

that each

quarter-repeat

consists of an

s

ha[f and a

B

hatf. The consensus

sequence

gives

the

most common

base at each

position.

The

"ancestra["

sequence shows a

sequence

very closety

retated

to

the consensus sequence,

which coutd

have

been the

predecessor

to the cx

and

B

units.

(The

satettite sequence

is con-

tinuous, so that

for

the

purposes

of deducing

the consensus

sequence

we

can treat

it as a cjr-

cutar

permutation,

as

indicated by

joining

the

last GAA triptet

to the

first

6 bp.)

the 234 bp

repeating unit. Although this unit

accounts for the majority of the

satellite, vari-

ants of it also are

present.

Some of

them are

scattered at

random throughout the satellite;

others are clustered.

The existence of variants

is implied by our

description of the starting material

for the

sequence analysis as the

"monomeric"

frag-

ment. When the satellite is digested by

an

enzyme that

has

one

cleavage site in the

234

bp sequence, it also

generates

dimers,

trimers,

and

tetramers relative to the 2)4bp length.

fhey arise when a repeating unit

has lost the

enzyme cleavage site as the result of

mutation.

The monomeric

234

bp unit

is

generated

when two adjacent repeats each

have

the

recog-

nition

site.

A

dimer occurs

when one unit has

Iost the site, a trimer is

generated

when

two

adiacent units have lost the site, and so on.

With

some restriction enzymes, most of the satellite

is cleaved into a member of this repeating series,

as

shown

in the example

of

*ii,t::+*,

*.::ij;.

The

declining number of dimers, trimers, and so

forth shows that there is a random distribution

of

the repeats in which

the enzyme's

recogni-

tion

site

has

been eliminated by

mutation.

Other

restriction

enzymes show a different

type of behavior with the satellite DNA.

They

continue

to

generate

the

same series of bands.

Ihey

cleave,

however,

only a small

proportion

of the DNA, say 5oh-looh. This implies that a

certain reqion of the satellite contains a con-

CHAPTER

6

Ctusters and Repeats

centration

of the

repeating units with this

par-

ticular

restriction site. Presumably the

series of

repeats in this domain

all are derived

from an

ancestral

variant that

possessed

this recogni-

tion site

(although

in the usual way, some

mem-

bers since have

lost it by mutation).

A satellite DNA

suffers unequal recombi-

nation. This has additional

consequences when

there

is internal repetition

in

the

repeating unit.

Let us

return to our cluster consisting of

"ab"

repeats. Suppose that

the

"a"

and

"b"

compo-

nents of the

repeating unit are themselves suf-

ficiently well related to

pair.

Then

the

two

clusters can

align in half-register, with the

"

a"

sequence

of one aligned with

the

"b"

sequence

of the other.

How frequently this occurs will

depend

on the closeness of

the relationship

between the two

halves of the repeating unit.

In mouse satellite

DNA, reassociation between

the denatured satellite

DNA strands invitro com-

monly occurs

in

the

half-register.

When a recombination event occurs out of

register, it changes the

length

of the

repeating

units

that are involved in the reaction:

ffisl*.ffiffi,$i*ffiffii*hg.i$aba

ba babababababy

'{'

xa ba ba ba ba bababiili*,F.i{,Hffitrtftii$iilHi*tifi$i#iii

J

xababababababababaababababababababv

t'

xababababa ba ba ba bbabababababababv

722

GGACCT

GGAATATGGC

GAGAAAACT

GAAAATCAC

GGAAAATGA

GAAATCACT

TTAGGACGT

GAAATATGGC

G

A G AGA

A A

C T

GAAAAAGGT

G G

A A

TTT

A

G

A A

A T-C

A C T

GTAGGACGT

GGAATATGGC

AAGAAAACT

GAAAATCAT

GGAAAATGA

G A A

A C-C

A

C T

TGACGACTT

GAAAAATGAC

GAAATCACT

AAAAAACGT

GAAAAATGA

G A

A A T-C

A C T

GAA

GzoAro&r A2oA12A17T8

G11 As

Tz%&QTrs

c?

.

indicates

inserted

triplet in

B

sequence

C

in

position

10

is extra

base in

cr sequence

li...iiSi:: r:.":.:,

The

existence

of an

overatI consensus

sequence is

shown

by

writing

the sateltite

sequence in

terms

of a 9

bp

repeat.

In

the upper

recombinant

cluster,

an

"

ab"

unit has been

replaced

try an

"aab"

unit. In the

lower

cluster,

lhe

"ab"

unit has

been replaced

by a

"b"

unit.

This

type

of event

explains

a feature

of the

restriction

digest

of rnouse

satellite

DNA.

Figure

6.28

shows

a fainter

series

of bands at

lengths

of Y', l'/r, 2Yr,

an<I 3/z repeating

units, in

addition

to

the stronger

integral

length repeats.

Suppose that

in the

preceding

example,

"ab"

represents

the 234

bp repeat

of

mouse satellite

DNA,

generated

by cleavage

at a site in

the

"b"

segment. The

"a"

and

"b"

segments

correspond

to the I I7

bp half

-repeats.

Then,

in the

upper recombinant

cluster, the

"aab"

unit

generates

a

fragment

of I

% times the

usual

repeating length.

In

the lower

recombi-

iriirr.iii;l

ir,,1

:l

Djgestion of mouse satetlite DNA

with

the restriction enzyme EcoRII identifies a

series of repeating units

(1,

2, 3) that are mutti-

mers

of 234 bp and atso a minor series

('/,,

1'/,,

2%)

that

inctudes

half-repeats

(see

text this

page).

The

band at the far left is a fraction resistant to

digestion.

nant cluster,

the

"b"

unit

generates

a

fragment

of

half

of the usual length.

(The

multiple frag-

ments in

the half-repeat series are

generated

in

the

same way as longer fragments in the inte-

gral

series,

when some

repeating units have lost

the restriction

site by

mutation.)

Turning

the argument the other way

around, the identification of the half-repeat

series

on the

gel

shows that the

234bp repeat-

ing

unit consists

of

two half-repeats well enough

pair

sometimes

for recombination.

Also

visible in Figure 6.28 are some rather faint

bands corresponding to',4- and

Z-spacings.

These

will

be

generated

in

the same way

as

the z-

spacings,

when recombination occurs between

clusters aligned in a

quarter-register.

The

decreased relationship

between

quarter-repeats

compared

with half-repeats explains

the reduc-

tion in frequency of r}":'e

/^-

and %-bands com-

pared

with the

Z-bands.

Minisatellites

Are

UsefuL

for

Genetic

Mapping

.

The

variation between

microsate[tites

or

minisatellites

in individuaI

genomes

can be used

to

identifo

heredity unequivocalty

by showing that

50%

of the bands

in

an

individuaI are derived

from

a

particu[ar parent.

Sequences that resemble satellites

in consisting

of

tandem

repeats

of

a short unit, but that

6.14

Minisatettites

Are

Useful

for Genetic Mapping 723

ii.i--l,riii:::.,;.:r Attetesmaydifferinthenumberofrepeatsataminisatellitetocus,sothat

cteavage on either side

generates

restriction fragments that differ

in

length.

By using a

minisatettite with altetes

that differ between

parents,

the

pattern

of

inheritance

can

be

fottowed.

overall are much shorter-consisting

of

(for

example) 5 to 50 repeats-are common

in mam-

malian

genomes. They

were discovered

by

chance as fragments whose size is extremely

variable in

genomic

libraries

of

human DNA.

The variability is seen when a

population

con-

tains fragments

of

many different sizes that

rep-

resent

the same

genomic

region;

when

individuals

are examined,

it turns out that there

is

extensive

polymorphism,

and

that many dif-

ferent alleles

can

be found.

The

name microsatellite

is

usually used

when the length of the

repeating

unit

is

<10

bp,

and the name

minisatellite is

used when

the

Iength

of the repeating unit is

-10

to

100

bp.

The terminology is not, however,

precisely

defined. These tlpes of sequences are also called

variable number tandem repeat

(VNTR)

reglons.

The cause of the

variation

between indi-

vidual

genomes

at microsatellites or

minisatel-

124

CHAPTER 6 Ctusters and Repeats

lites

is

that

individual

alleles

have

different

num-

bers of the

repeating

unit. For example,

one

minisatellite

has a repeat

length of 64 bp and

is

found

in the

population

with

the following

distribution:

7% 18 repeats

II%

16 repeats

43%

14 repeats

360/o

13 repeats

4% I0

repeats

The

rate of

genetic

exchange at

minisatel-

lite sequences

is high,

-I0aperkb

of

DNA.

(The

frequency of

exchanges

per

actual

locus is

assumed

to be

proportional

to the

length of the

minisatellite.)

This rate

is

-l0x

greater

than the

rate of

homologous

recombination at

meiosis,

that

is, in any

random DNA sequence.

The high

variability of minisatellites

makes

them especially

useful

for

genomic

mapping,

because

there

is a high

probability

that individ-

uals will

vary in their

alleles at such a

locus. An

example of

mapping by

minisatellites is

illus-

trated in

FISUR{ $"t9. This shows

an extreme

case

in

which

two

individuals both are

heterozy-

gous

at a

minisatellite

locus, and in fact all

four

alleles

are different.

AII

progeny gain

one

allele

from each

parent

in the usual way,

and it is

pos-

sible unambiguously

to determine the source

of every

allele in the

progeny.

In the terminol-

ogy of

human

genetics,

the meioses described

in this

figure are highly

informative because of

the variation between

alleles.

One

family of minisatellites

in the human

genome

share a common

"core"

sequence.

The

core

is a G-C-rich sequence

of l0 to l5 bp, show-

ing an asymmetry of

purine/pyrimidine

distri-

bution on

the two strands.

Each individual

minisatellite

has a

variant

of the core sequence,

but

-1000

minisatellites can be

detected on

Southern blot by a

probe

consisting of the core

sequence.

Consider

the situation shoq'n

in Figure 6.29,

but

multiplied many times by

the existence of

many such sequences.

The effect of the varia-

tion at

individual loci

is

to create a unique

pat-

tern for every

individual. This makes it

possible

to assign heredity unambiguously

between

par-

ents and

progeny

by showing

that 50% of the

bands in any individual are derived

from a

par-

ticular

parent.

This is the basis of the technique

known as DNA fingerprinting.

Both

microsatellites and minisatellites are

unstable, although

for different reasons.

Microsatellites undergo intrastrand

mispairing,

when

slippage

during replication

leads to expan-

sion

of the repeat,

as

shown in i:jr,rljFri:

ri .ii,r.

Sys-

tems

that repair

dameLge

to DNA-in particu-

lar

those

that recognize

mismatched

base

pairs-are

important

in reversing

such

changes,

as shown

by a large increase

in

frequency

when

repair genes

are inactivated.

Mutations

in repair

systems

are an important

contributory

factor

in

the development

of cancer,

thus

tumor cells

often display variations

in

microsatellite

sequences.

Minisatellites

undergo

the

same

sort of unequal

crossing-over

between repeats

that we have

discusse

d for

satellites

(see

Fig-

ure

6. 3

)

. One telling

carse

is that increased

vari-

ation is associated

wit.h

a meiotic

hotspot.

The

recombination

event is not

usually

associated

with recombination

b,etween

flanking

mark-

ers,

but has a

complex form

in

which the new

mutant

allele

gains

inlormation

from

both the

sister

chromatid

and the

other

(homologous)

chromosome.

It is

not clear

at w.hat repeating

length

the

cause

of the variationL

shifts from

replication

slippage to recombinartion.

@

Summary

Almost

all

genes

belorrg to

families,

which are

defined

by the

possession

of related

sequences

in

the exons

of indivirlual

members.

Families

evolve

by the duplicat.ion

of a

gene (or genes),

followed

by divergence

between

the

copies.

Some

copies suffer

inactivating

mutations

and

become

pseudogenes

that

no longer

have any

function.

Pseudogenes

also may

be

generated

as DNA

copies

of the mRNA

sequences.

An evolving

set

of

genes

may remain

together

in a cluster

or may

be dispersed

to new

locations

by chromosomal

rearrangement.

The

organization

of existing

clusters

can

sometimes

be used to infer

the series

of events

that has

occurred.

These events

act

with regard

to

sequence rather

than function,

and

therefore

include

pseudogenes

as well as

active

genes.

Mutations accumu.late

more

rapidly in

silent

sites than in replacement

sites

(which

affect the

amino acid

sequence). The

rate of

divergence at

replacement

sites

carL be used

to establish

a

clock, which can

be calibrated

in

percent

diver-

gence

per

million

years.

The clock

can then

be

used to calculate the

time of

divergence between

any two members

of t)re family.

A tandem

cluster consists

of many

copies

of a repeating

unit that includes

the transcribed

sequence(s)

and a nontranscribed

spacer(s).

rRNA

gene

clusters

cocle only

for a single rRNA

irri.il+lr:

L;

.

.,

Rep[ication stippage

occurs when the daughter strand stips back

one repeating

unit

in

pairing

wjth the template strand. Each slippage event adds

one repeating

unit to the

daughter strand. The extra

repeats

are extruded as a

singte-strand

[oop.

Reptication of thjs daughter strand

in

the

gener-

ates a

duplex

DNA

with an

increased number of repeats.

precursor.

Maintenance of

active

genes

in clus-

ters depends

on

mechanisms such as

gene

con-

version

or unequal crossing-over,

which cause

mutations to

spread

through the cluster so

that

they

become exposed

to evolutionary

pressure.

Satellite DNA consists

of

very

short

sequences repeated many times

in

tandem.

Its

distinct centrifugation

properties

reflect its biased

base composition. Satellite

DNA is concentrated

in centromeric heterochromatin, but

its func-

tion

(if

any) is unknown.

The individual repeat-

ing

units of arthropod satellites

are identical.

Those of mammalian satellites

are related and

can

be organized

into a hierarchy

reflecting the

evolution of the satellite

by the amplification

and divergence of randomly

chosen sequences.

Unequal crossing-over

appears to

have been

a major

determinant of

satellite DNA organiza-

tion. Crossover fixation explains

the ability of

variants to spread through

a cluster.

Minisatellites and microsatellites

consist of

even shorter repeating sequences

than satellites:

6.15 Summary

725

<10

bp for microsatellites and

I0

to

50 bp for

minisatellites. The number of repeating units

is

usually 5 to 50.

There is high variation in the

repeat number between individual

genomes.

A

microsatellite

repeat number

varies

as the result

of slippage during

replication; the frequency

is

affected by systems that

recognize and repair

damage

in DNA. Minisatellite repeat

number

varies

as the result of

recombination-like events.

Variations in repeat number can be used

to

determine hereditary

relationships

by

the tech-

nique known as DNA fingerprinting.

References

Gene

Duptication Is a Major Force

in Evolution

Resea rch

Bailey, J. A., Gu,

2.,

Clark,

R. A., Reinert, I(.,

Samonte, R. V., Schwartz, S.,

Adams, M. D.,

Myers, E. W., Li, P. W, and Eichler, E. E.

(20021.

Recent segmental duplications

in

the

human

genome.

Science 297, 1003-1007.

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Gtobjn Ctusters

Are Formed

by

Dup[ication and Divergence

Review

Hardison, R.

(1998)

Hemoglobins from

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@

The Rate of Neutral Substitution Can

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Resea rc h

Waterston, R. H.

et al.

(2002\.Initial

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420,

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rch

Hirotsune, S., Yoshida, N., Chen,

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Wynshaw-Boris,

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Yoshiki, A.

(2003).

An

expressed

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stability of

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Nature

42), 9 l-96.

Crossover

Fixation Coutd

Maintain

IdenticaI Repeats

Review

Charlesworth,

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Sniegowski,

P., and Stephan, W.

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tive

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Are Usefu[ for Genetic

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Research

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A. J.,

Murray,

J.,

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Neumann,

R.

(

1998). High-resolution

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crossovers

in human sperm defines a

minisatellite-associated

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ton, D. G., Neil, D.

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(L994).

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Jeffreys,

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and Thein, S. L.

(1985).

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Strand, M., Prolla,

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6.

726

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