Lewin Benjamin (ed.) Genes IX

19,

sauosorxolql

posdeu/is

uoaMlaq

srnllo uorlpurqulolau

snoboloruoH

z.6I

ur spuerls

aFurs

Jo

lueluenlo^ul

Jql JoJ

Iapou

IeJauJS

p

sMoqs

S'6I

JrnSrd

'spuens

JISurs

uaeMlaq,{.lrreluauraldtuol

:aruanbas yo

stseq

aql

uo JJr{loue

auo ezruSorJr

o} sprJe

JrelJnu

JOJ rusrueqf,Jru

Juo z(1uo

1o-

Mou>l JM

'rrPo

JSeq

Ienpr^rpul

erll

Jo Ia^el

eql

1e

uorsrlard

qlr.nr pa8ueqrxa

aq

01

IPrJJlerx

s^^ollP

leql

Jeuueu f,rJr)

-ads

z(p8q

e ur salnJJlorrr

o.trl eql ur sJJuJnbJs

SurpuodsarroJ

Jo

rred .r(ue

uJJMlaq

rnJ)o

ol uoIlJPeJ

srql JoJ

alqrssod Jq

lsnlu

1I

'Jruosolu

-orq)

Ieqlo eql uor]

pllPruoJqJ

Jetsrs P

Jo

vNQ

xaldnp

eql

qlrM

1)eJetur

ol

prtpruoJqJ

Jalsrs

'sypq

xaldnp rno1

eql

JO

OMl A^lo^ur

luana

rarro-6urssoll

lenpnrpur

/{ue

1o

suoqlelalur ielnlaloul aql

'pua

eql

1e

fluo

elqLsLn seuroloq

a1e1s

palerrldnp

eq1

q6noqlle'(sprleuorqr

telsLs) serqdar orvrl

Jo

slsrsuol

qlrqm

J0

qtpa

'seuosoutolql

aql

1o

arueteadde

aql

fiq peugap

ere aseqdord

1o

sa6e1s aql'aseqdotd

lrloreul

lslg

oql 6uunp srnoro

uorlpurquolou

?.i:

;.

:liJillt:*

ruo

Jo

y51q

xaldnp aqt s,lrolle

leql

ruslueq)eru

p

serrnber

uorlpurqruoJeg

'VN11

Jo

sJlnlelou

xaldnp JnoJ suretuoJ

tuJlelrq

qJpa

os

'xaldnp

ygq

a18urs e suretuoJ

plletuorqJ

Jalsrs

qJeA

zsluJ^e

JSJqI JoJ srseq rPlnralolu aql

$

leq

a

'luapr^a

aruo)Jq

spueuroJr{J JnoJ

IIe

pue

esuapuoJ

sJruosoruoJq) aql

uJqM alqISIA rnPruar

eleursprqf, aqJ

'(s'*E

Isfi*Is)

luJ^a

JaAo-3uI

-ssoD

aqt

sluasa.rdar Bruser-q)

p

reql

sploq ssLpue

Ipuonpe{L

'rJAo

Sursson

rpauaS;o seJnlpal aql

lalpred

eterusprqf,

Jo

uoltnqlrtslp

pue

JJqrunu

Jt{J'Blprusp1qJ

pJIle)

satls

JlJrJsrp

1e

raqlaSot

pleq

eq 01 uaas

eq ueJ ,{aql

'aleredas

ol

u6aq

srruosoruorqJ eql

uaq

a'rJqlo

qJee

qllM pe>luu

uaqt

pup

ua>lorq

ureq enpq

(y1qq

1o

xaldnp e 8ut

-uretuoJ

qrea)

sprleruoJqJ

relslsuou o,lrl

q)IqM

ur

/uolunar

pup

a8p>IEeJq

e se

paluasarder

^dlensn

'sged

;o

a8ueqrxa

prrs,{qd

e seAIoAuI

seruosoruorqJ

uaeMleq

uollPulquo)ed

'saDads

uJJllrleq slrelap aql

uI uoIlPIJeA

aprM sr araqr

q8noqlp

'sanads

qJeJ

uI aJnlJnJls

f,rlsrJelJeJpqf,

e seq

q)lqm

'xalduror

leur

-auoldBuIs

p

Jo

ruJoJ

Jqt ut

palplJosse

d11era

-lpl

eJe sauosoruoJqr

aqr

'paraldruof,

sI ssaro.rd

Jq1 uaq6'8u1rpd aurosotrroJqr

ro

qsdeu,{.s

paller

sr ssarord aq1

'3o1oruoq

sll

qtlM pasodde

sr JruosoruoJqJ

qJee yo

qr8ual

eJIluJ Jql

Illun

spualxa

Surrte4

'sluelp^Iq

Sutruroy

'suorSar

Jrour Jo euo

ur rred o1 urSaq

pue

rJr{loue

auo

qreorddp

saurosoruorqt

snoSolouoq

aqJ

'y1qq

xaldnp

p

suretuo)

q)lqM

Jo

qJpe

'splleru

-oJqJ

JJlsrs oMl

Jo

slsrsuoJ

pue.dlsnoulard

paler

-qdar

seq sauosouroJqJ

asJqt

Jo

qJpf

'alqlst,r

aruolJq

seuosoruoJqJ

IenpIAIpu

q)tq,r.

1e lutod

aqt

dq

pJ>lJpru

sI slsoleru

yo

Suruut3aq aq1

'VNo

Jo

saxaldnp

uJJMleq

leualeur

3ut

-Sueqrxa

ur

pellolur

eJe

leql

suollJpJelul

reln

-Jelou

Jql

qlrM

aseqdord

rrloleru

Jo

sa8els a.tq

aqr

q8norqr

saurosoruoJqr

;o

ssarSord alqrsrn

aql saredruoJ

t"*T sHili*x;i

'slsolaur

;o

aseqdord

paperlord

aqt

Suunp srnJ)o

uolteulqruoJeU

'uppruoJq)oJelaq

Jo

suor8ar ellpern

pue pJsuep

-uoJ

eql

;o

LlruDrrr aql

ur

passarddns

sI JeAo

-Sursson'aldruexa

JoJ

jeJnlJnJls

euosotuoJqJ

uodn spuadap

rbuanbar;

str

'aruouaS

eql ulqll6

'suerunq

Jlpru ur

se apruJ] ut

trltuanbarJ sp JJIM1

s.rnJJo

uolleurqruorar

lrurads uI

pue

salu(roo

ul

luJJJJJrp

aq

,(eru .{ruanbar;

IIeJe^o

JqJ

'spaJJe

le)ol

pup pqop qtoq z(q

paruangul

sI

tnq

'aruouaS

aql

tnoq8noJlp luelsuoJ

lou

sI uoueulq

-ruoJJJ;o

l:uanbary

aq1'(sraqro

JeAo

peJo^e;

eq z(eru saruanbas

;o

sad,{.1

aruos

q8noqtle)

sJteJlsqns se saluanbas

snoSoloruoq;o

rted

Lue

esn

ueJ alqrsuodsar

saui.zua eql

leql

sI JJnl

-pel

IeJrtrJJ

sll

'VN11

;o

saxaldnp

o,rtt uJaMlaq

uorlJeeJ e

sr uorlpulqruoJal

snoSolourog

uor]€ruul

SplleuojLlc lolslS o/vu

lo

slsrsuoc

puP

'polecrloor

seq

aurosou.roJqc L.lcPf

suor6er

ro uor0el

payu,rr;

ur 6uured

urbeq seurosouotq3

aue1o6{7

suorlceralur relncalon

srsorour

l.lono.r

Lll ssoroord

qree

uorJ

puprls

Juo

Jo

Surlsrsuol

uorSar e seq

xaldnp

qtpJ

'uorleurqruoJJJ

Jo

atrs eqt

tV

'1u1oI

lueulqruo)ar

Jqr

prllpJ

sr

rJqto

eqt 01 xaldnp Juo

ruorJ sJSSo-r)

VNC

Jo

pupJts

Ienpr^rpur

ue

q)rqnl.

lp lurod

JqJ

'alnJalotu

lurol

e

pJIIe)

sr saxaldnp

;o

led

pJtJJu

-uol

JqI'saxaldnp

VNC

o..lr1 eql ueeMtJq uorl

-)auuoJ

e saleaJJ a8ueqrxa

lerordoar

aq1

'xaldnp

Jeqto Jqt ur

tuJrueldruoJ

slr

qllM

Jred

01

rJAo

sassorJ

pue

rauued su sJlpel

pueJls q)eE

's>lJru

aqt ,{q

palEJrJ

spuJ JJJJ Jql

Jo

tuJruJloru

smollp

a8elearq aq1

'saxaldnp

ypq

parred

oMt

Jo

spueJts snoSoloruoq

aqt

;o

slurod

SurpuodsarroJ

Jql

te

a8elearq

qtru

suels

teqt

ssarord e

sJlpnsnllr

* +=i

igi:1:ij

'uoIleuIqruoJel

ur

pe^lolur

sassaro,rd

aql SurpuelsJJpun

ol

IpJluJJ

are deazr

srql ur

pJleeJ)

saln)Jloru aql

;o

sarlradord

aql asneraq

'(palerlrur

L11en1re

sr

tr

aroq dUressarau

lou

sr srqt

tpql

JJS

lleqs

a,vr

q8noqlp)

sa8ueqrxa puerts-alSurs

Io

stuJJl

ur uorllear

uorleurqruoJer

eql eur8erur

ot

1n;

-esn

sr

lI

'uorlpurquo)al

ur

spueJls a13urs Lrel

-uarualdruoJ

uaJMtJq

Surrred eseq

Io

Jsn Jql

Jo

MJrA:no

Surpuedxa

.dq sgels

JroJeJeql uoll

-eurqruoJJJ

;o

srs.dleue

Jpln)aloru

rn6'ssarord

uorteurquroteJ

ar{]

Jo

ueeq

Jql

]p

sl

vN(I

Jo

seln)Jloru xaldnp

o,trl SurtrauuoJ

Jo

lJp

JqJ

'uorlnlosar

6uunp

pellru

etp

spup.lls

Jo

tLed taqlo eq1 ro

abueqrxa

leurbuo

oLll ur

pello^ur

spuells eql leqlaLlM

uo spueoep

poul.loJ

a.re

sluPutquola.r leqleqfi

.

'spu

Pjls

burlrauuor eqlJo

oml 6uLlrru

fq salnralour xaldnp

elplpdas

o/v\l olur

pe^losal

sr elnleloul

luLol

eql

.

'alnlelou

lurof

e aletaue6

o1 firessarau

ere sa6ueqrxa

(lerotdtret)

orvrl

o

'luared

qree

uol1

puplls

auo

1o

buqsrsuoo

y116

xoldnpolalaq

Jo

qtlolls

e saleteuab

ebueqrxa aql

.

'arnllnrls

paqluPlq

e soleait

1r

'xaldnp

laqlo aql ur

ledtelunor

s1r sareldsrp xaldnp

auo

ulolJ

puells

e16urs

e uo{/!\

r

'spuPtls

a16uLs;o a6ueqrxe

sr selnlalout

y116

xaldnp

oMl

uoaMloq uoqpurqurolel

u!

lua^a

fie1

aq1

r

VNO

xaldnporalaH

sa^lo^uI

uoqeurquiolau l$Dads-a]l5

pue

snobolor.uoH

6I

ulldvHl

uee^l.leq uorlJPJJlur seAIoAur uorlJPeJ

l€rJel

-Jpq

aql

'seln)Jloru

xaldnp uJJ,tlrtJq a8ueqrxa

)IlEUE8 JSNE)

lPql

UMOU>I JJP SJIlIAIlf,E

IEIN

-Jelou

qJIqM

ur

'PrJJlJPq

ur alqelrenP sr ssarord

uorleurquoJJr aql

lnoqe

uorleruJoJur

pJIrPtJ(

'srsorJru

;o

sa8els

aterurxordde

qllM

sdals reln

-JJIoru

Jqt

Jo

euos elplJJJoJ ot alqrssod

tr

apeu

seq

lsea,{

ur sluelnru

Jo

uorlelosr eql JaAJMor{

Llluarau

'(panresqo

z{1aso1;

tsoru

uJJq seq srs

-oreru

qJrqM

ur) s11ar JltoIJe>lna

raq8rq ur uoll

-PurqruoJJJ

ur

pJAIoAur

slue^e JPlnrelolu Jql

lnoqe

uoIlPuJoJuI

pelelJp

ou sI aJaqJ

'sJluos

-oruoJqJ

Jql

Jo Ie^el

Jql

le

pJAJJsqo

3Je

leqt

sa8ueqr Jqt

qll,lt,{.1sno:o3rr

stuene

rpln)Jloru

eseql elelal arnlrunI srql

le 1ouuef,^e14

'uorunJr

pue

atsP>leJJq

e

Jo

spueuep Jqt ot spuodseJJoJ

leql

JJAossoJJ

p

Io

sueJu

[q

salnralou

xaldnp

letuared

Jqt

tJauuoJ

ot alqrssod sr

1r

'uJql

3u1unr

relpl

pue

spuerts

qtoq

Sur8upqrxa ,{g

'saxaldnp

Jql UJaMlJq

UOII)aUUOI

JAISUeJXJ eroru

Jq uer JJeql

'pJpuelxa

sr a8ueq)xe

pueJls

aqt

;1'saruanbas

Surpuodsauo)

te

pat)Juuor.dlerr

-;nads

Jq

IIIM

sJInJJIoru xaldnp o.trl eql

'xaldnp

JJqlo Jql

ur

puerls

SurpuodsarroJ

Jql sareld

-srp

puprls

auo

(tsea1

1e)

;1

'pasealeJ

Jq ueqt ueJ

xaldnp

teqt

Jo

spuprts rqt

Jo

qtoq

ro aug

'xaldnp

vNO

q)pJ

ur

>leeJq

e J>lpur o1 sr spuerls a13

-urs

Surprnord

ur dats

tsrrJ

JqJ

'uorteurqruoJJJ

'sy116

leluared

oMl eql

Jo

spup.lls Arelueuald

-ulor

uaamlaq 6uured sanlonur uorleurqurolau

11"*i

3*i"i*Ij

sluPurquloceu

I

alerpor.!Jelur uorleurqurocou

t

salnsalour

vNo leluaj€d

uorunau puP

e6e)Par8

@

'leAJI

Jeln)eloru

eq1

te

ureldxa

ol a8ets

tlnJrIJrp

lsoru

eql

surpureJ sJurosoruoJqr

rpofuelna;o srs

-deu,{s

aqJ

'seuouaS;o

Surrred arrluJ

ue ueql

JJqlpr

'q8noqr

'auroua8

aql

yo

suor8al

paDrJlsar

DNA

duplexes

parr

Homologous

strands

are nicked

Broken

strands

Crossover

point

moves oy

branch migration

Nicks are

sealed

I

exchange

between duplexes

11

Second nicks

/ \ Second nicks

made in same strand

made

in other strand

|JlTio"*

I

Genomes

are not

recombinant, but

coniain heteroduplex

regron

Reciprocal recombinant

genomes

are

generated

fl**R*

3ll.S Recombinatjon

between two

paired

duplex

DNAs

coutd

invotve

reciprocal

singte-strand exchange. branch

migration,

and

nicking.

of the

parental

DNA

molecules. This region is

called hybrid DNA

or

heteroduplex

DNA.

An important feature

of a recombinant

joint

is its ability

to move along the

duplex.

Such

mobility is

called branch migration.

Fi*13fi[

1*.;

illustrates the migration

of a single

strand in a duplex. The

branching

point

can

migrate in

either direction as

one strand is dis-

placed

by the other.

Branch migration is important

forboth the-

oretical and

practical

reasons. As

a

matter

of

principle,

it confers a dynamic

property

on

recombining structures.

As a

practical

feature,

flEGUft$.

t#.? Branch

migration can occur

in either direc-

tion when an unpaired sing[e

strand displaces

a

paired

strand.

its existence means that

the

point

of

branching

cannot be established

by examining

a

molecule

invitro

(because

the branch

may

have migrated

since the molecule

was isolated).

Branch migration

could

allow the

point

of

crossover in the recombination

intermediate to

move in either direction.

The rate of branch

migration is uncertain,

but as seen

in vitro

is

probably

inadequate

to support

the formation

of extensive regions

of heteroduplex

DNA

in

natural

conditions.

Any

extensive branch

migra-

Iion in vivo

must therefore

be catalyzed

by a

recombination enzyme.

The

joint

molecule

formed by

strand

exchange must be

resolved

into two separate

duplex

molecules. Resolution

requires a {ur-

ther

pair

of

nicks. We can

most easily

visualize

the

outcome

by viewing

the

joint

molecule

in

one

plane

as a

Holliday

junction.

This is illus-

trated

in

Fi*{Jltf

ii}.i}, which

represents

the struc-

ture of

Figure I9.6 with

one duplex

rotated

relative to the other.

The outcome

of the reac-

tion depends on

which

pair

of strands

is nicked.

If the nicks are

made

in the

pair

of

strands

that were

not originally

nicked

(the pair

rhat

did not initiate

the strand

exchange),

all four

of

the

original

strands

have

been nicked.

This

releases splice

recombinant

DNA

molecules.

The duplex of one

DNA

parent is covalently

linked to the duplex

of

the other

DNA

parent

via a

stretch

of heteroduplex

DNA.

There has

19.3 Breakage

and Reunion

Invotves Heteroduptex

DNA

Nicking controls

outcome

Nicks in

same

strands release

patch

recombinants

i:+ij*lF 1*.*

Resotution ofa Hotlidayjunction

can

gener-

ate

parentaI

or

recombinant

duplexes,

depending on which

strands

are nicked. Both

types of

product

have a region of

heteroduotex

DNA.

been a conventional recombination

event

between

markers located

on either side of the

heteroduplex

region.

If

the same two

strands involved in the

orig-

inal

nicking are nicked

again, the

other two

l'",:l*,;xniT,1il;lllff

[T?.;T,ff :,'l;

with the exception

that each has a residuum

of

the event in the form

of a length

of

heteroduplex

DNA.

These are

called

patch

recombinants.

These

alternative resolutions

of the

joint

molecule

establish the

principle

that a

strand

'

:'l

;,:!;

:; #;:: !:; l

:

: tr i' ;y #: :::;';:;'#l

';"7';':'::'accompaniedbvrecombinationofthe

What is the minimum

length

of the region

required

to

establish the connection

between

the recombining

duplexes? Experiments

in

which short

homologous

sequences carried

by

plasmids

or

phages

are introduced into

bacte-

ria suggest

that the rate

of

recombination

is

sub-

CHAPTER

19 Homologous

and Sjte-Specific

Recombination

stantially

reduced if

the

homologous

region is

<75bp.

This distance is appreciably longer than

the

-I0

bp required for association between

complementary

single-stranded regions,

which

suggests that recombination imposes demands

beyond annealing of complements

as such.

Double-Strand Breaks

Initiate Recombi nation

Recombination is

initiated

by making a

doubte-

strand break

in

one

(recipient)

DNA

duptex.

Exonuclease action

generates

3'-single-stranded

ends that invade the other

(donor)

dup[ex.

New DNA

synthesis

reptaces

the material

that

has

been degraded.

This

generates

a recombinantjoint motecute

in

which the two DNA duptexes are connected

by

heteroduolex

DNA.

The

general

model of Figure 19.4

shows that a

break

must

be made in one duplex in

order to

generate

a

point

from which

single strands can

unwind to

participate

in

genetic

exchange. Both

strands of a duplex must be broken to

accom-

plish

a

genetic

exchange.

Figure

I9.6 shows a

model

in which individual breaks

in single

strands occur successively.

Genetic exchange,

however, is

actually

initiated

by a

double-

strand break

(DSB).

The

model is illustrated

in il5$l.JR* t$.*.

Recombination is initiated

by an endonu-

clease that

cleaves one of the

partner

DNA

duplexes, the

"recipient."

The

cut is enlarged

to a

gap

by exonuclease action. The

exonucle-

ase(s) nibble

away one strand on

either side of

the break,

generating

3'single-stranded

ter-

mini. One of the free 3' ends

then invades

a

homologous

region in the

other

("donor")

duplex. This is called

single-strand invasion.

The formation of heteroduplex

DNA

generates

a D loop, in which

one strand of the

donor

duplex is displaced. The

D loop is

extended by

repair

DNA synthesis, using

the free J'end

as

a

primer

to

generate

double-stranded

DNA.

Eventually

the

D loop

becomes

large

enough to

correspond to the entire

length of

the

gap

on the recipient

chromatid. When

the

extruded single

strand reaches the far

side of

the

gap,

the complementary

single-stranded

sequences

anneal. Now there is

heteroduplex

DNA

on either side

of the

gap,

and the

gap

itself is represented

by the

single-stranded

D

loon.

The duplex integrity

of the

gapped

region

can

be

restored

by repair synthesis

using the 3'

end on the left side

of the

gap

as a

primer.

Over-

all, the

gap

has been repaired

by two individ-

ual rounds of single-strand

DNA synthesis.

Branch migration

converts

this structure

into

a molecule with two recombinant

joints.

The

joints

must

be

resolved

by cutting.

If both

joints

are resolved

in the same

way,

the original

noncrossover

molecules

will be

released, each with

a

region

of altered

genetic

information that is a footprint

of the exchange

event. If the two

joints

are resolved in opposite

ways, a

genetic

crossover is

produced.

The structure

of the two-jointed molecule

before it is

resolved

illustrates

a critical differ-

ence between the double-strand

break model

and models that invoke

only single-strand

exchanges.

.

Following the

double-strand break, het-

eroduplex DNA has been formed

at each

end of the region

involved in the

exchange. Between

the two heterodu-

plex

segments is the region

correspon-

ding to the

gap,

which now has the

sequence of the donor DNA in

both

mol-

ecules

(Figure

19.9).

Thus the arrange-

ment of heteroduplex

sequences

is

asymmetric, and

part

of one

molecule

has

been converted to the sequence of

the other

(which

is why

the

initiating

chromatid is

called the recipient).

.

Following reciprocal

single-strand ex-

change, each

DNA

duplex has heterodu-

plex

material

covering the region from

the initial site

of

exchange

to the

migrat-

ing

branch

(Figure

19.6). In variants of

the single-strand

exchange

model in

which some DNA is degraded and resyn-

thesized, the initiating

chromatid

is

the

donor of

genetic

information.

The double-strand

break model does

not

reduce the importance of the formation of het-

eroduplex

DNA,

which

remains

the only

plau-

sible

means by which two

duplex

molecules

can

interact. By

shifting the

responsibility for initi-

ating recombination from single-strand to dou-

ble-strand breaks, though, it influences our

perspective

about the ability

of the cell

to manip-

ulate DNA.

The involvement of double-strand breaks at

first

seems surprising. Once a break

has

been

made right across a DNA molecule, there is no

going

back. Compare the events of Figure

19.6

and Figure 19.9. At no

point

in the single-strand

exchange model

has

any information been

lost.

lilirliill.

.L',r,ii Recombination

is initiated by

a double-strand

break, fotlowed by

formation

of single-stranded

3' ends,

one

of

which m'igrates

to a homologous

duplex.

In the double-strand

break

model,

though,

the

initial

cleavage

is

immediately

followed

by

loss

of information.

Any error

in retrieving

the

infor-

mation

could

be

fatal. On

the other

hand, the

very ability to

retrieve

lost information

by

resyn-

thesizing

it from

another

duplex

provides

a

maior safetv

net for

the cell.

Recombining

Chromosomes

Are

Connected

by the

SynaptonemaI

Complex

.

During the early

part

of

meiosis.

homologous

chromosomes

are

paired

in the

synaptonemaI

comotex.

.

The mass of chromatin

of each

homotog

is

separated

from the other

by a

proteinaceous

co m

p

lex.

A basic

paradox

in

recombination

is that the

parental

chromosomes

never seem

to be

in close

enough

contact

for

recombination

of

DNA

to

19.5 Recombining

Chromosomes

Are Connected

by the SynaptonemaI

Complex

465

iia::-:rii

::-:. -::: The

synaptonemaL

complex brings

chromosomes into

juxtaposition.

Reproduced

from D. von

Wettstejn. 1.971.. Proc.

Natl.

Acad.

Sci.

USA. 68:851-855. Photo

courtesy

of D. von Wettstein,

Washington

State University.

ir

;:.ii:jiii

.i*-

j,;.i

Each

pair

of sister

chromatids has

an axis made of

cohesins.

Loops

of chromatin

project

from

the axis. The

synaptone-

mal

complex

is formed

by tinking

together

the axes via zip

proteins.

occur. The

chromosomes

enter meiosis

in the

form

of replicated

(sister

chromatid)

pairs,

which

are visible

as a mass

of chromatin.

They

pair

to

form

the

synaptonemal

complex,

and it has

been

assumed for

many

years

that this repre-

sents

some

stage involved

with recombination-

possibly

a necessary

preliminary

to exchange

of DNA.

A more recent view

is

that the

synap-

tonemal

complex is

a consequence

rather

than

a cause

of recombination,

but, we have

yet

to

define

how

the structure

of the

synaptonemal

complex

relates

to molecular

contacts

between

DNA

molecules.

Synapsis

begins

when

each chromosome

(sister

chromatid pair)

condenses

around a

struc-

ture

called

the axial element,

which is appar-

CHAPTER

19 Homotogous

and

Site-Specific

Recombination

ently

proteinaceous.

The

axial elements

of cor-

responding

chromosomes then become

aligned,

and the synaptonemal complex

forms as a tri-

partite

structure,

in

which the axial

elements,

now

called lateral elements,

are separated

from

each other by a central

element.

F:*iififl

:il"3i:

shows an example.

Each chromosome at this

stage appears

as

a mass

of chromatin bounded by

a

lateral

ele-

ment.

The two lateral elements

are separated

from each

other by a

fine,

but dense,

central

element. The triplet of

parallel

dense

strands

lies in a single

plane

that

curves and twists

along

its axis. The

distance between the homologous

chromosomes is considerable

in molecular

terms, at more

than

200

nm

(the

diameter of

DNA is 2

nm). Thus a major

problem

in under-

standing the role

of the complex is that,

although

it aligns homologous

chromosomes,

it is far from

bringing homologous DNA

molecules

into

contact.

The only visible link

between the

two sides

of the

synaptonemal complex

is

provided

by

spherical or cylindrical

structures observed

in

fungi

and insects. They lie

across the

complex

and are called nodes

or

recombination

nod-

ules; they

occur with the

same frequency

and

distribution as the

chiasmata. Their name

reflects

the

hope

that they may

prove

to be

the sites of

recombination.

From mutations

that affect

synaptonemal

complex formation,

we can relate

the

types of

proteins

that are involved

to its

structure.

IItuiJiqil

i.*"1: presents

a molecular

view

of the

synaptonemal

complex. Its

distinctive

struc-

tural features are

due to two

groups

of

proteins:

.

The

cohesins form a

single linear

axis

for each

pair

of sister chromatids

from

which loops of chromatin

extend.

This

is equivalent

to the lateral

element

of

Figure I9. 10.

(The

cohesins

belong

to a

general group

of

proteins

involved

in

connecting

sister chromatids

so

that they

segregate

properly

at mitosis

of

meiosis.)

.

The

lateral elements

are

connected

by

transverse

filaments

that are

equivalent

to the central

element

of Figure 19.10.

These are formed

from

Zip

proteins.

Mutations in

proteins

that

are needed

lor

lateral

elements

to form are found

in

the

genes

coding for

cohesins. The

cohesins

that are

used

in

meiosis include

Smc3p

(which

is

also used

in mitosis)

and Rec8p

(which

is

specific

to meio-

sis and is related

to the mitotic

cohesin

Scclp).

The

cohesins appear

to bind

to specific

sites

along

the chromosomes

in both

mitosis

and

466

L9'

s)earg

puprls-alqnoo

reue

surol xalduol

lpLuauoldpufs

eql

g'6I

ur

Suured JurosouroJqJ

r{srloqp

lpql

suoll

-Elnru

[e

leql

uMoqs seq >lJoM

tue]ar

pue

'paqs[

-qelsJ

IIJM

sr uorteuloJ xJlduo)

Ipuauoldpu^s

pue

uoleurquroJJJ

ueeMlJq uoueleJJoJ 3qI

vN(

xJldnp

snoSolouoq

Jpenur ol spuJ

pJpueJls-elSurs

aql selqpuJ

uaql

dnorS JJqlouV

'spuJ

pepue-rts-alSurs

Ho-,€

Surpnrto:d

olur s>lpJJq

pueJts-JIqnop

JI{t

ueluoJ

o1

parrnbar

sr suralord

yo

dnor8 aug

's>leeJq

pueJts-elqnop

aql ssarord ot

parrnbar

are

suralord

raqlo auru

tspJl tV

'uortrp

aseapnu

Lq

peMolloJ

urqt

sr

IIods

Jo Ielorua5

'xaldruor

I I

ods Jql salerJossrp

teqt

uralord rJqtoup

qlIM

uorlf,eJJlur ue dq

arnlrnJls

lueuelu:ad

e olur

peue^uoJ

sr

>leaJq

eqt

1VNC qtrm ,ilqrsranar

st)prelur

I I

ods

leql

stsaSSns

ij

i.'

i:r i

,it

ai1"ri

j

ul

uMoqs uorDeJJ

slql JoJ

Iepou

JqJ'$lPerq

puPns

-Jlqnop

eql setpJJuJB

lBql

au.,i.zuJ J>lrl-aspJeru

-osrodot

e aq ,{.eru

I Iods

teqt

slsaSSns sIqI

'seseJeruosrodor

I

ad,{r

;o

Llue;

e

Jo

strunqns

rr1L1e1er

Jqt ol snoSoloruoq sr

qlrqM

'I

Iods

utalord

aql o]

palJauuo)

JJe s>lparq

pueJls

-alqnop

rql

Jo

spue

,E

eql

'sluelnru

)spat

uI

'>leaJq

pueJls

-Jlqnop

eql

Jo

alrs

aql uoJJ saseeJrur

eJuelslp

se

paleraua8

aq

IIIM

uor8ar

papuens-a13urs

e

leqr,(rmqeqord

Suruqrap aqt Lq

prurruratJp sI

luarper8

eqJ

'uorleurqruoJeJ

ro;

Lressarau are

s>learq

pueJts-Jlqnop

leqt

stsaSSns srql

'uorl

-eurqruoJar

ur JArpelJp sr uorsnnord

pJpuerls

'slPa.rq

pu

erls-olqn0p

Jo

spua,9 aql ol

peuLo[A11ua1enor

sL

11od5

ri

i'i; i

;]i,:jit:ii;r

-a18urs

eql o1ut

pua qsnlJ

aql

Jo

uolsre^uo) eql

$lrolq

leql

(ospat)uouelnru

1sea.d

y

'6'61

arnSrg

Jo Irporu

eql

q

umoqs

sp

'spue

papuBrls-al3

-urs

,g

3uo1

otur sepls

qloq

uo

pJuanuo)

,{ptde:

Jre >leJrq

puPJls-elqnop

Jq]

zi.q

palea;r

spua

lunlq

JqI

'sruJel

JelnJelolu

uI s>lEeJq

pueJls

-Jlqnop

Jo

JIoJ aqt

tardlalut,uou

r{eu a14

'1I

tuoJJ

peards

11tLr

stuene uortpurqruoJeJ

eqt

leql

z(itlqeeord aql

spalJeJ

luarper8

eqt

pue

'pateppl

sI uoltpulq

-uro)Jr

qJIqM

le

etIS Jqt

sJIJItuepI

lodsloq

aq1

'1ods1oq

aql

Jo

sJpIS

qloq

Jo auo

uo

luatper8

e ut

seullJap uopeurqrxoJar

;o

trruanbJJ] JqI'uperu

-oJqJ

Jo

suor8ar

alqrsse)le arou

qll,lr

apI)uIoJ

o1

leraua8

ur

pue

suor8ar

raloruord

uI rnJ)o ol

pual .daq1

'rqoads

aruanbas

tou

eJp suolleJol

rraqJ

'uorleulqruo)JJ

ro; slodsloq

apr,tord

leqt

sJlrs

lP

Srsoraru

ur,{.Fea JnJf,o

oslP s>leeJq

puPJls

-elqnog

'(snto-IJVW

luatdttag

aqt

.dq

paterlrul

sI uorlrsodsue{

IeuoItJJrIpFn

'€Z'6I

uolttes

aas)

raqloue

.{q aruanbas euo

Jo

luaruareldar

Jqt sa^lo^u

r{JIqM

'adrb

Suueru

yo

a8ueqr

aqt ur

palerrldrur L1er1ru1 eJe,lr s>leJrq

pueJls-elqno(

'uorleurqurorar

rt;nads-elIS

pue

snoSolouoq

qloq

ur

uorleurqruo)er

elPIlIuI s>lealq

puerls

-Jlqnop

teqt lseau(

uI af,uJplna

poo3

sr eJeql

'uuo]

louuel

xalduror

leuauoldeufis

aql

'pelrolq

st uot]PutQtltolet

Jl

r

'sLuio;

xalduor

leueuoldeuAs

aql

aloJaq tnllo

uotlPUtqu0l0l

aleqtut

lPql

s)Pelq

puells-alQn0[

r

slParB

puPrls-alqnoo

JauP

sruJol

xalduol

rL rL

a .

lcPllE

I

osealcnu

Aq

pa/v\ollol

I

ttods lo le^ourag

r-..J

I

f

eoeneerc otqrsre^eu

lPruouoldeufi5

aq1

'srrcd

prleurorqr

JJlsrs

Jq1

Jo

sluJruele

IeJJlel

Jql

pJuuol

]eql

sluJru€lrJ

esrelsuer]

ruJoJ sule]oJd

dt7

1o

dnor8

aqJ'Idlz

qtlmpazllerol osp arc'2dr7pue

7dr7

'suralord

raqlo

o^4L

'sluJruelJ

IeJelel

aql

ut

pezl

-lPJol

sr

ureuop

IeuIruJJl-)

Jql

lnq'luJruJIJ

IeJt

-ueJ

eql uI

pJZIIeJol

sr

uralord

IdIZ

Jo

uleruop

IeurrurJl-N

aq1

'pasdeu.ds

Llasolt aruoJJq

tou

op,{aqr

rnq'pau8rle

aluof,aq

01

pue

uJoJ ol

stuJrlJlJ

IpJJtel

sMollp

uouelnu

1dg

a'q1

'slupurquoJal

Jo

uollpruJoJ

>llolq op

.daql

's>leJJq

puPrls-Jlqnop

Jo

uoIlPuJoJ

Jql

luJ^

-ard

lou

op suollplnru

asaqr

q8noqlle

esneJJq

'uorleurquroJJJ

Jo

sa3e1s

Jelel

aq1 ro; Lres

-sJ)au

aq.deru

slueruale

lpJelel

eql

Jo

uolletu

-roJ

aql

'srsorJru

lV'uorle8ar8es

Jruosourolql

uI

aloJ

IprntJnJls

e

Leld o1

.d1a41 are.daql'sISoIJru

sra^ossorr ot ro

(vNC

pllq^q

Jo

qJlrlls

IpnprsJr

e

qllM)

sDnpoJd JJ^ossorf,uou

laqlrJ

ol JsrJ seArB

eJnlf,nJls srql

Jo

uorlnloseJ

Jql

leql

pJunsse

uJJq

sPq

1l

'pesodord

se^^ JrnlJntls ^eprlloH

p

er^ uorleurquroJJJ

JoJ

Iapou

eql Jf,urs re^a

^

'srsotJur

Jo

sJSels

rJlel JoJ

perrnbJr

sr

pue

'SurrrBd

JuosotuoJqf,

8urnao11o;

'uorleurquof,ar

Jo

af,uenbasuor

B se

sruroy xalduor

leruauotdeuLs

aql

leqt

stsaSSns

srql

'xaldtuor

leruauoldeuLs

B

dolanap o1

pe;

osle

'rJAeMoq 'uorlPurquoJJJ

qsrloqe

lpql

suorl

-elnw'slueurquroJar

aleraua8

uer xaldurot

leru

-auoldBur(s

IpruJou

e >lJel

lpql

sluetnur auros

JSnPJJq

'r{tns

se uorlpurqurofJl

Jo} ,{ressalau

aq ot readde

tou

saop

tI'sJln)alou

tupurquro)Jr

Jo

uorlerurol

aql

Irlun

stsrsrad

tl

pup

'uorlpu

-rqurof,Jr

alPrlrur

]eql

s>lpJrq

puelts-Jlqnop

Jql

reue

suuoJ xaldruor

leruauoldeu.ds

aqt snql

'saxalduor

leruauoldeu.ds ;o

uorlPuroJ

3q1 JelJp

IUJAJ

uorlpurquoJal

Jql

;o

uorlaldruor aqt

sareld dlJealJ

srrlJ

'aua/.qred

Jo

pue

aql

le

readde

stueurqurolJJ

leqt

Moqs

o1 alqrssod

ueeq spq

1r

'q8noqt

'sJtrs

uortJutsaJ

ltsou8erp Sururetuo:

sJlnf,elou

VN11

Jo

uorl

-rnpord

Jqt

Jo

srurJt

ur Lllrarp

tseJ^

ur stueurq

-uroJJJ;o

aruereaddp

Jql Surssesse Lg

'srsoraru

;o

uorlalduoJ

eql JJUe

slupurquroJeJ

Jo

eJue

-;eadde

aql.dq

passasse

sr uorleurquroJeJ

esneJJq

'srsdeu.{.s

}o

a8Bts

eqt

lp

srnJ)o uorleurqruof,eJ

rJqlJqM auruJelJp

ot

tlnJrJJrp

uJeq seq

1I

'uorlPurquolar

Jo

sluJAJ

relnleloru aqt

aparard

ol Suurpd JrrrosoruoJqf,

roJ

pJJu

aql sluasardar

xaldruor

leurauotdeuLs

ar{l

leq]

srsoraur

Io

MJrA

IeuorlrpeJl

eql selnJer

uollpurquolau ll;nads-alrs

pue

snobolorxoH

6I

UlIdVHl

srql'saxalduoJ

IpruJuoldeu.ii.s

olur sluJruJla

IPrxP

lJa^uo)

louuP)

7uelrl.Lv)spar

eql

leql

uorl

-enJesqo

aqt.dq

pagoddns

sr

papr

srqJ

'uorteu

-rqruoJJJ

Jo

sJlelpJruJJlul

rJlel

olur uorsJa^uo)

rrJql

pue

sleerq

puens-alqnop

Jo

uorl)np

-orlur

Jql er^ uorleurqruoJJr

Jo

uorlerlrur Jql

ruoJJ

stlnsJJ

xaldruor

leuauoldeur(s

aqr;o uort

-euJoJ

ler{l

slsaSSns slue^J

1o

8urur1 J^rlelaJ

srql

'saxalduo)

Ieueuoldeuu(s

olur saurosour

-orqr

parred

Jql

Jo

uorsJJluol eql Suunp read

-desrp

,{aq1

'ruro;

sluJruale

Ietxe

ueqM

porrad

aqt Surrnp readdB

s>learq

puerts-JlqnoC

'elrs

IeuosouroJqJ

aues

Jql

le

uorssJJ)ns ur rnf,Jo saJnpnJls

lueu

-rqruof,JJ

Io

uorlpurroJ

pup

'suorDpJJ

Suured

Ienprlrpur's>leeJq

pueJls-alqnop

1eql

slsa33ns

stuJla;o

aruanbas aql

'readdesrp

DIeJJq

puprls

-Jlqnop

eqt JetJe uoos readde

'sJterpauJatur

uorleurqruorar

a,r.rlelnd JJp

q)rqm'selnJJloru

tutoI

lsrr;

aq1

'porrad

etnuru-09 e -ralo readde

-srp

uJqt

pue

readde

s>leerq

puprts-JIqnoC

':r

t"*i

"-:-*i}ltl.j

uI

PezIJeIu

-urns

sr sluenJ

;o

3unur1 JArlelJJ

etql'aatsnala)

satfwon4nas

ur srsoraur Surz[1eue ur ssarSord

uJJq spq araqt ^dltuarJJ

tnq

'uorleurquo)eJ

lp

stuJAJ

1el8o1oil.r

pue

JelnJJIou aredruor o1

a1q

-rssod

sr

U

qrrqM

ur srualsz(s loral

Jrp JJeqI

'uorleurquoJeJ

Jrlo

-rertr

IIe

s>polq aua? ap4doslte Jrtrl ur uorletnru

e

pue

'sa1o.dre1na

raq8rq

Iere^JS

ur

parJrluapr

uJJq elpq sSolouoq

11odg

'panrasuor.{lpraua8

SI UOIIEUIqIUOf,JJ

A]PIIIUI

lPql

S>IEJJq

PUEJ]S

-Jlqnop

Jqt SurlerJua8 ro; urals^ds

aqJ

'uorl

-eurqruof,JJ

luarrard

oslB

lsea,{

ur rc

alnldosotq

'aue1r\qred

Jo

pua

aq]

]P

paltalap

alp

sluPutquolai

VN0

l$un

lsLsred

pue

readde

salnrelou

lurol'saxelduor

leuauoldeufs 10

uorsuelxo

aq1 6uunp

readdesrp

pup

ulloJ sluauala

lprxp

ueqm teadde

sleerq

puells-elqno0

i

t

.*i

,:liil*1.:{

A

olercossrp

urol rurol

spue

I

sexelduoc

sexe;du.roc

sluor.rrola

uorlecrldet

I

--

I

leueuoldeuAg

leuleuoldeurg

lelxv

vruo

I

sluana

1ect6olop(3

I-

-

"o\i^odi

'ixii'

ostr

"btl--o;I

boi oe""'bg ov

oz

4""1"-fffifj

oueloldro

euey{qce6

auetob^Z eua1o1de1

-

-f

lstslod

Jeoooesto leeodv

sslncolou.llulof

slealqpueJls-alqnoc

ll

It

YY

sslncelouJ

slcnpotd

lueurquoceu

Ja ossoJcuoN

69'

]uepuadapul

arv uor.lprxroj

xelduol

leuauoldpufs

pue

buurpd

1'61

('parrnlo

seq uorleurquroJeJ

Irlun

sJruosorxoJqJ:raql

ale8ar8as ol

,ful

lou

op

sllJJ

leql

eJnsua o1

pren8ayes

e

saplLord

ruatsLs

srql

lpatalduror

d1n;ssarrns

uaeq seq uorteurq

-uoJer

ueqM

peurl

$ >polq

eql)

'pexnrro

tou

seq

uolleulqluo)el

JI

SISOIJIII >lJolq ol slstxa

ualsrls

,,lurod>1raqr ,,

e

pue

'srsorJru

q8norqt

ssarSord

roy Lressarau

sr uorlpurqruoJeJ

Jo

J)uJJJnJJo

eql

'eJoruJaqund 'sluelnu

urpuJJ ur

patdrustp

Lleraua8 sr

srJlossoJf,

Jo

sseuuopueruou

eql

Jsne)eq'IoJluoJ

JalossorJ

a18urs e

Jo

llnsJr

aqr

Llqeqord

st ssarord slqJ

'(

%

I'0>)

arol Lra.,l st

,rred Soloruoq

p

JoJ sJalossoJl

oraz

Jo.{1ilqeqord

aqt

tar(

'sJJAossoJ)

o^\l 01 auo.dluo sartnbre

s3o1

-ouroq;o

rrcd

qrea

'praua8

ur

'1eql

,{e.tr e

qJns

uI

palnqu$p

JJP eseql

tnq

'SJJAOSSOI)

se arnletu

,,i.[e

-nDe

suorlf,pralur;o Lluouru e L1u6

'loJluoJ

IerJ

-ua8

e o1

palqns

J]e

sluJle uollpurqruo)e5

'peqsrlqPlsJ

Jq 01 ureual uolleulq

-uroJJJ

ur suralord

JSJqI

Jo

selor

Dpxa

aq1

'(uta1

-ord

yrag

un'g

eW;o sSoloruoq are

qrrqaa)

IEpeU

pue

I)uO

pue (rredar

qJtpruslru uI

penlolur

suratord

lerJJppq

01

pJlelJJ

sr

qrq.Lr)

'HSW

epnlJur JseqJ'sa1rs elarJsrp 01

przrle)ol

eq

uP)

leq]

uorleurqruoJJJ

]sea.d

ur

pJAIOAUI

suralord

Jo

uortp)rJrtuJpr Jql u{q

paprno:d

ere

'JJAe1!l.oq

'sernlJnJls

snonurluoJsrp

Jo

uop

-eruroJ

Jqt

roJ

srseq JelnJJloru Jr.{}

otur stqStsul

'eleuserqJ

pue

sJlnpou uorlPurquroJJr

'sl

leql

'pa^rJsqo

ueeq a^Pq

leql

sarnlJnrls

alerf,

-slp

aql

qlrM

af,u3J.rnJ)o rrJr{] JlPIJJror

laz{

sp

lou

-ueJ

J,!t

lnq

'sJruosoruoJqr

)lloralu

uo slutod

alJJ)srp

le

rn)Jo slue^e uorlPulquof,au

'JlerpJruJJlur

lpntJe

aqt Surplto;d ueqt

JJqlpl

1UJAJ

UOrlPUrqrUO)aJ Jql

JO

lUeUIuJr

JUrOS

luesar

-dar,r{.aqr

reqt

slsa33ns,{.tr[qlxrlJ srr{J'seruosotu

-oJq)

aql

]o

spuJ eql

pJeMol

J^otu

Pleuselq)

eqt

'srsoreu

ur ralef

'pJ^losJJ

ueaq

ta.{ tou

seq

a8ueqrxa rpaua8 e JrJqM sJruosoruoJqr

snoSo

-louroq

uJJMlaq uorlJeuuoJ

p

sluas:;dar

lt reql

ro

'a8ueqrxa

palayduor

e

Jo

runnprsar

Jql stuJs

-ardar

tl tpqt

alqrssod sr

U

'u,uou>lun

sr erusplqJ

p

Jo

aJnleu JelnJalou eql

lnq

'a8ueqrxa

rrlaua8

e

Jo

eluJrJnJJo er{l

alpJrpur

o1

parunsard uaaq

seq srql'pJ])euuo) ere saurosouroJqJ

Jql I{lIq,&\

te

slurod se Jlqrsrn eruoJJq ueql etpurserqr

Jql

lxaldruor pruauotdeu.ds

aqt

paqs

seuosouorqJ

aqt

'(auaroldrp)

srsoraru;o a8ets

txau

rql

lV

'uollnlosJJ

pue'stsaqluzls

y1qq

'aBueqJXJ

pueJts

Jo

uorsualxe eql

J^lo^ul

qJrqm

'uorleurqruoJar

yo

sdals

luanbasqns

aqr

ziq

pardnno

sr

porrad

srql

teqt

aq

r(eru

tI'pelJJsqo

JJe slueurqruoJal

vNo

eJoJeq

'aua1z{qred

Surrnp suaddeq z(1ensn

ter{,lr

reelJ

tou

sl

1I

'y1qq

snoSolouoq

qtlM s>leerq

JSJqI

Jo

uollJpal JAISUJ]xJ

true alnbar

lou

saop

tI

's>leeJq

pueJls-elqnop

sarrnbar

xaldruor

pruauoldeuz(s aql;o uoueruJoJ

JI

'lBql

stsaSSns

srql'parredal

lou

aJe

daqr

rnq'sluplnlu

Tdoqp

saxaldruor

pruauoldeu,{s aqt uI saluosoluorqJ

parredsnu

aql ul

turoJ s>lpaJq

pueJls-elqno(

'burllPrJlur

uorJ

saruosouroJqr

snoSoloruoquou

luaaard

ol st

Tdog

yo

JIor

Ipnsn

aq1

'(satuanbas

y1qq

yo

uost

-redruor

alrsuJlxe

,{ue uo

pJseq

eq

louuef,

aJoJ

-JJJqt

pue)

LSoloruoq

Io

luepuedaput

st

qrns

se

saxaldruor

pruauoldeuLs

yo

uorleruJoJ aqt

teql

slsa33ns

srqJ'seruosoruoJqJ

snoSoloruoquou

ureluoJ

saxaldruor

IpnpIAIpuI

eql

lnq'stsoraru lB

ruroy

xalduror

leurauoldeuLs

;o

slunotu€

IeIu

-Jou

'stuelnu

7dor4

uI'aasnaln

'g

ut

7dot1

aua8

aqt [q

pallortuoJ

sI sauosoluoJql

snoSolouroq

ueamtaq

uollplf,ossp

;o

,hnrltrads_ aqJ

'uorlPruJoJ

xeloruo)

IPIu

-auotdeuz(s

Jo uorleulqluo)eJ

Jo

luapuadapur

sr

sSolouroq

uaJMlaq

uotltuSotar

snql

'saxald

-ruol

lpueuoldeuz(s

uroJ

lou

op

daqr

1nq

'rred

01 saurosouroJql

s^l.ollP uollPlnur

zdlz

JqI

'raqto

eql Surnage

lnoqllm

sassarord aq]

Jo

auo

s>lJolq

qrlqM

Jo

qleJ

'suollelnru

oA1.1

Jo

spJJJe

aqt.dq

uorleruroy

xaldruor

pruauoldeur{s

pue

Surrred;o sassarord

aql

qsln8upslp UPJ JM

'ssalo.td

raqlo

aql 6uLpa11e

lnoqlm

uotlpuroJ

xelduor

leLuauoldeur\s

to

6uuLpd auosotttorql

laqlte

u! lnllo

uel suo!]Plnfl

o

luepuadepul

arv

uo$eurol

xald

uol

lPuauoldeu^5

puP

6uutPd

.SIJAOSSOJJUOU

Jo

uorllnpord

aqr

JoJ alnor

Jaqlo auos

Jq

Leru

araql

lpql

lnq-selnJJlotu

luro[

1o

uol]nl

-osar

,{q-tq8noqr

dlsnonard

se

parnpord

are

srelossorJ

leqt

s1sa33ns

3unu1l

ut ,{.ruedanstp

eqJ

'erurl

arues

Jql

te

readde s1

ruJl{l

Dadxa

plnoM

a.tt.

lJle,lroq

'ssarord

uollnlosJJ

Jrues

aqt

,{q

parnpord

eJeM

lJnpord

1o

sad,(r

qloq

JI'(€I'6I

arn8rg

aas) salnraloru

turof

aql

qlllrt

.{.lsnoauellnurs

lsorule

readde

srelossoJf,uou

seJJaqM

'selnJeloru

luro[

;o

aruereadde

lsrr;

Jqt

JeUe

IIJM

lllun

readde

tou

op sJJAossoJ)

'anrl

Jq

1ou

,{eru slqr

leql

lsaSSns

'JJAaMoq

'seln)alolu

Ja^ossoJJ

pue

JJnossoJJuou

Jo

uop

-rnpord

Jo

serull

Jql

Jo

slueueJnseJru

lueleg

'(g'61

arn8r4

aas)

uollnlosJJ

uI

paAIoAuI

eJP

spueJts

rplq,lr

uo

Surpuadap

'(slueutqurola:)

'UOIIPUIqUOJJI

JO}

AIEJISqNS

E SI SIqJ

'AJUJNDAS

lLp

aql

lP

puJ

,€

P

qllM

vNo

pJpupJls-JlSurs

Jle

-Jaue8

01 sI uoll)pJelur

slql

Jo

llnsJJ

IIEJJ^O

JqJ

'peeds

snor^aJd

er{t

JIpq

lnoqp te-uorlp)olsueJl

J^rrp o1

lFnqns

g)eu

aql ^Iuo

Sursn Mou-ese)

-llJq

e sP uorpunJ

01 tJ^JMoq

'senurluoJ

tJ'^1r

-Arpe

aseJlJnu

slr sJsol

Ju^zuJ Jql

lurod

qlrqM

tP

'pJlP^Ipeur

Jruo)aq

ro

JlprJossrp ol

llunqns

(JaU

eqt sJSnpJ

et;S

lLp

aq1

Jo

uonru8onp'

u6t

1o

rq8rr

aql

01 saseq xrs

pue

rnoJ

uaeutJq

uoqrsod

e

]e

vN(

eql

Jo

puPrls

dot aql sr^eap

ueql

1I

'asned

ot arudzua

Jqt sasnef,

srqJ'uJoJ

papueJls

-a18urs

ur

el;rs tq) eql

Jo

pueJts

do1 aqr sazruSotar

u

'Jlrs

!ry

etqt saq)eJr

1l

ueqM

'puJ

,€

aql

qlIM

pueJls

a13urs

pasealal

aqt saper8ap

tr

'se)uelpe

61)g)a5

sy

'trunqns

OJJU

rql ,{q

uanrrp

z(leqrur

sr xrlaq

Jlqnop

aql Surpur^,vrun

pup

vNC

Suop uorlerolsue.{l',{1rre1od,S-,€

qlrm

suorpunJ

gJJU

pue

,{1rre1od

,€-,5

rtrfIM suortJunJ

OJaU

:serlrnrlJp

Jse)laq

JApq slrunqns

slr

Jo

o^41

'pua

prpue[s-elqnop

p

lE

vN(

01 spurq

cf,gJeu

'a]rs

t4)

e seq

leqr

VNCI

JlErlsqns

p

uo

peleurpJooJ

aJe suorl)pJJ

3saql ^loq

sMoqs

?I'6I

lU{l5H

'puJ

,€

JJIJ

p

qtrM

uor8ar

papue,rls-a13

-urs

e

aprnoJd ol

Jq Leur

uorleurqtuoJal

ur JIol

stl',{.lr,rrpe rspdJv

up

seq

tl

pue

'(gSS)

uratord

Surpurq

puerls-a13urs

e

yo

aruasard

er{l ur

vN(

xaldnp

purMun

ueJ

teql

sartrlrlJp

Jsetrleq

seq

u A

aseJlJnuoxa.r{.]r,rrlre

Jql

se

pJrJrluapr,{.11eu

-r8rro

se,lr

q)lrlm

'ypq

saper8Jp

tpql

asealf,nu

luJlod

P sI

1I'sJlllnrlJp

IpJJAes

sasrlraxa xald

-ruoJ

srqJ

'e)pal

saua8

aql z(q

papol

aru.dzua

ue

Jo

uorlJe Jql

JoJ sla8rel

Jrc

seTrs nl)

'uorlJJrrp

Juo ur

z(po xaldnp

aqt

3uo1e

enoru up)

ueqt

pue

,pua

uJ>loJq

e

le

VN(I

qll,lr

elerJosse

lsnru

snte:edde

uorleurquoJeJ

eql

leql nsaSSns

uorleluerJo

uo

aruapuadap

sq;'(anoqe

uMoqs

aruenbas aqr

;o

lq8rr

rqt

01) Jprs

teln)rued

auo

uo .dea,re

q1

Iprelrs

epeu >leJrq puerls-rlqnop

e ,{q

pare,r

-lne

eq

ueJ rtrs

u,p

v

'atrs

rqt urorJ qI

0I

ol dn

Jo

a)uelsrp

p

urqlrm

Les

z(lrurtt,l.

leraua8

slr ur

uortpurquoJJl

sJlplnrults

a:uanbas t4.r

y

.IIOIIPUIqIuOJEJ

JOJ

IPI]UESSE

lou

sr

ll leqt

sMoqs

'sluJruale

rrlaua8

raqlo

ruorJ osle

pue

'1trN11

epqruel

adLl-p1ru.

ruo,r1

aJuasqp

sll

'q{

0I

ol

E

.dra,ra

aluo

tnoqe

17Nq

tln'g

ur Llernleu

sJnJJo

a)uenbas

ltp

erl1-

,E

))Vf,)V9),€

,€

DDJ9CJf,',S

:dq

g

yo

aruanbas

1et

-rrlarurudsuou

luplsuoJ

e eJeqs

selrs asaqJ

'uoIleurqtuoJeJ

ur

pJAIoAUI

suralord

raqlo

Jo

JIoJ

eql ot sn

peel

sJlrs

eseqJ'uorleurqruoJeJ

alplnrulls

leql

saruanbas

uorleurquolaX r4oad5-e1Ls

pue

sn060louloH

6I

UlldVHl

ateerJ

leql

saSueqr rred-aseq

a18urs aterT'n1t

pJIIeJ

sluplnru

Io

ruroJ Jqt ur

ppquel

a8eqd ur

peJeloJsrp

aJaM rprr{,lr'slodsloq eseqJ'uouernq

-uroJar

alplnturls

teql

stodstoq urpuJl

Jo

eJuel

-sIXe

aq1

Jo

tlnseJ

P se

paJa^of,srp

uaaq sEq spue

elqplrns SurtBrauaS

roJ rusrueqJeru JUO

'paleraua8

aq

lsnu

spue

,€

pup

suot8ar

papuerrs-a13urs

,rana,lroq'(sa1o,{.re1na

ur srsoraur

1e

uorleurquoJJr ur

se) saln;a1oru

xaldnp

ora]

3ul^lo^ul saf,uelsurnJrlJ uI

'JIJTIJ

3ur11or e z(q

uorletrldar SuroS.rapun saruoua8

a8eqd,{q

pareraueS

aq,{eru slpt

papupJts-apurs

ro

la8eruep

uorlprppJJr

^dq

paleraua8

aq .{eru

sdeS

papuerls-a18urs

:(VNq papuerlg-a18urg

srelsup{l uorleSnfuo3

'0I'9I

uorlJas JJs :uorl

-e8nfuor

ur se) ruroy

papuerls-a18urs

ur

peprl

-ord

aq

z(eru

y1r1q

:spuJ

,€

papuerls-afurs

aJJJ

qllM

elqplre^e

aq

z(eru

VN(

'saseJ

aruos uI

'salo

-fue1ord

ur uoneurquroJJJ Jlerlrur

ol salnoJ snor

-:en

aq,{eur

aJeqt

tnq

'y1trq

xaldnp

Jo

stunourp

a8rel

a8ueqrxa Lllensn

tou

op

prJalJpg

'pelJ4uepr

uarq a^eq

oo1

,{1uau1

0l ual Jrxos

'uorleurquoJJJ

pezrleJa

-ua8

a>leuapun

o1 zfuqqeur Jqt sr

sluetnu--ral

]o

addtouaqd

aq1

'saua8

JrJql ur suorlplnru

-ral

Jo

eJueJJnJJo

eql ^q

perJrtuepr

uJaq

an€q uorl

-purqruoJal

ul

palpl[drur

saru,{.zua

IprJeDpg

'uorleurquoJar

JoJ

pa;rnbar

stuauoduroJ

aq1

Jo

aruos .d1uo

luasardar

,{.1q

-eqord

z(aqt

q8noqlle

'u,lrou>l

are a8els

qrea

ur

panlolur

saurz(zug

'saxaldnp

rauued

aql

sJAIoseJ

aspal)nuopue

up

pup

lpepuJlxJ

sr

Surrred;o uor8ar

aqt

txaldnp

rautred

e

qlrM

slJpJJtur elnJeloru

ua>loJq e ruorJ

puerls

a13

-uls

17

:q8noql

'relrurs

sr stuJAJ relnJeloru

Jo

rJpJo

IerJueS

aql

'saruosouroJqJ

pelur

ueql

raqleJ

selnJJloru

VNO

Jo

suor8ar

pJt)lJlsaJ

sa^lo^ur pup

rusrueqJsru uorleurqruoJaJ

aql

Jo larred

pue

lred

sr uorlJpJJ

uollluSoJaJ

Jql eJaH

'srualsds

IerJJpeq

ur

peqrJJSep

lsJrJ

seM sJlnJeloru

yNO

uJJMlaq

saruanbas

yo

a8ueqrxa

ur

pa^lo^ur

stuela

eql

Jo

eJnteu

aqJ

'Alnqre

aseallnu

pue

lrunqns

6rau

eql

Jo

ssol sra66u1 elrs t{, eq1

.

.olls

lq,

aql 01 se^our

1!

sP

,g_,€

urol]

puplls

auo saperbap

pue

'xeldnp

aql spulmun

'eluanbas

ry)

e

to

upallsuMop

VNo

ol spulq

lI

.

'sarlt^rllP

asPlnaq

puP

asPallnu seq xalduol

Ol8reu

eql

.

saruanbas

lrp

frq

patPlnu[s

{

uals^s

OL'

ol8lau

lPuatlPB

aql

Lewin Benjamin (ed.) Genes IX

Подождите немного. Документ загружается.