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anism from

retroviruses

to

prime

the

reverse

transcription

reaction.

They are

derived

from

RNA

polymerase

II

tran-

scripts. A minority

of the

elements in

the

genome

are fully functional

and can

transpose autonomously;

others have

mutations,

and thus

can only transpose

as the result

of the action

of. a

trans-

acting autonomous

element.

.

Members

of the nonviral

superfamily

are identified

by external

and internal

features that

suggest that they originated

in RNA sequences.

In

these cases,

though.

we can only

speculate on how

a DNA copy was

generated.

We

assume

that they were

targets for

a transposi-

tion event by an enzyme

system coded

elsewhere, that is, they

are always

nonautonomous. They

originated in

cel-

lular transcripts.

They do not

code

for

proteins

that have transposition func-

tions.

The

most

prominent

component

of this family is

called short interspersed

repeated sequences

(SINES).

These com-

ponents

are

derived from RNA

poly-

merase III

transcripts.

i:i{,,rif.i.r

r.:.i..r

shows the

organization and

sequence relationships

of elements that code for

reverse

transcriptase. Like retroviruses,

the LIR-

containing retroposons

can be

classified

into

groups

according to the number

of independent

reading frames for

gag, pol,

and int, and the order

of

the

genes.

In

spite of these superficial

differ-

ences of organization, the common feature is

the

presence

of reverse

transcriptase and integrase

activities.

\pical

mammalian LINES

elements

have two reading frames;

one codes for a nucleic

acid-binding

protein

and the other codes for

reverse transcriptase and endonuclease

activity.

LTR-containing

elements can

vary

from

integrated retroviruses to retroposons

that

have

lost

the capacity to

generate

infectious

parti-

cles. Yeast and fly

genomes

have

the

Ty

and copia

elements that cannot

generate

infectious

par-

ticles. Mammalian

genomes

have endogenous

retroviruses that, when active, can

generate

infectious

particles.

The mouse

genome

has

sev-

eral active endogenous retroviruses, which are

able to

generate particles

that

propagate

hori-

zontal infections.

By

contrast, almost all endoge-

nous retroviruses lost their activity

some

50

million

years

ago

in

the human lineage, and

the

genome

now has

mostly inactive remnants

of the endogenous retroviruses.

LINES and SINES comprise a major

part

of

the animal

genome.

They were defined origi-

nally by the existence of

a large

number of rel-

atively

short sequences

that

are related

to one

another

(comprising

the moderately

repetitive

DNA

described

in Section

4.6,

Eukaryotic

Genomes Contain

Both Nonrepetitive

and

Repetitive DNA Sequences).

The

LINES com-

prise

long interspersed

sequences,

and the SINES

comprise short interspersed

sequences.

(They

are described as interspersed

sequences

or inter-

spersed repeats

because

of their common

occurrence

and widespread

distribution.)

Plants contain

another

type of small

mobile

element, called

MITE

(for

miniature inverted-

repeat transposable

element).

Such elements

terminate

in inverted

repeats,

have a 2 or 3 bp

target sequence, do

not have

coding sequences,

and are

200 to 500 bp

long. At

least nine such

families exist in

(for

example)

the rice

genome.

They

are often

found

in the

regions flanking

protein-coding genes. They have

no relation-

ship to SINES or

LINES.

LINES and SINES

comprise

a significant

part

of the repetitive

DNA

of animal

genomes. In

many higher eukaryotic

genomes,

they occupy

-50%

of the

total DNA.

i:iil"tfli:

;i:.,l'* summarizes

the distribution

of the

different

types of trans-

posons

that constitute

almost

half of

the human

genome.

Except for the

SINES,

which are

always

nonfunctional, the

other

types of

elements all

consist of both

functional

elements

and

ele-

ments that have suffered

deletions

that elimi-

nated

parts

of the

reading

frames

that code

for

the

protein(s)

needed

for transposition.

The rel-

ative

proportions

of these

types

of transposons

are

generally

similar

in the

mouse

genome.

A common

LINES

in mammalian

genomes

is called Ll.

The typical

member

is

-6500

bp

long and terminates

in an

A-rich tract.

The two

open

reading frames

of a

full-length

element

i:r::iigi: ;:;i. t

i'

Retroposons

that

are ctosely

related to

retrovjruses have a simjlar

organization,

but

LINES share

onty the

reverse transcriptase

activ'ity.

LTR

Homologywith:,i;:,,9a9

$SSPol

mtnt

22.9

Retroposons

Fa[[

into Three Classes

563

Element

Organization

Length

(Kb) Human

genome

LINES

(autonomous),

e.9., L1

AFIFI

.{po|,

.

..,.,

SINES

(nonautonomous),

e.9., Alu

DNAtransposon

)',.'Tr*nspoeaee'r.

d

Number Fraction

1-11 450,000

8%

6-8 850,000 17%

<0.3

1,500,000

15"/"

2-3

300,000 30/o

FIGURE22.1B

Fourtypesoftransposableetementsconstituteatmosthatfofthehumangenome.

are called

ORFI and ORF2. The number

of full-

length

elements is usually

small

(-50),

and the

remainder

of the

copies are truncated. TIan-

scripts

can be found.

As implied

by

its

presence

in

repetitive

DNA, the LINES family

shows

sequence

variation

among individual members.

The

members

of the family

within a species,

however,

are relatively homogeneous

compared

to the variation

shown

between species. LI is

the

only member

of the LINES family

that has

been active in

either the mouse

or human lin-

eages. It

seems

to

have

remained highly

active

in

the mouse,

but has

declined in the human

lineage.

Only

one SINES has

been active in

the

human

lineage:

the common Alu

element. The

mouse genome

has a counterpart

to this ele-

ment

(Bl),

and also

other SINES

(B2,ID,B4\

that have

been active. Human

Alu and mouse

Bl

SINES

are

probably

derived

from the 7SL

RNA

(see

Section

22.10, The

AIu Family Has

Many

Widely

Dispersed Members).

The

other

mouse

SINES appear

to have originated

from

reverse

transcripts

of tRNAs. The

transposition

of the

SINES

probably

results from

their recog-

nition

as substrates

by an active

Ll element.

individual members

of the

family

are dispersed

around

the

genome

instead of being

confined

to tandem clusters. Again, there is

significant

similarity between the members

within a species

compared

with variation between

species.

In the human

genome,

a

large

part

of the

moderately repetitive

DNA exists

as sequences

of

-300

bp that are interspersed

with nonrepet-

itive

DNA. At Ieast half of the renatured

duplex

material is

cleaved by the restriction

enzyme

AluI

at a single site located 170

bp along the

sequence. The

cleaved sequences

all are mem-

bers of a single family known

as the Alu fam-

ily, after the means

of

its

identification. There

are

-100,000

members in

the haploid

genome

(equivalent

to one member

per

6 kb of DNA).

The

individual Alu sequences

are

widely dis-

persed.

A related

sequence family is

present

in

the mouse

(where

the 50,000 members

are

called the Bl family), in

the Chinese

hamster

(where

it is called the Alu-equivalent

family),

and in other mammals.

The individual

members

of the Alu family

are related rather

than identical. The

human

family

seems to have

originated

by

means

of a

130

bp tandem

duplication, with

an unrelated

sequence of 3I

bp

inserted

in the right

half of

the dimer. The

two

repeats

are

sometimes

called

the

"left

half"

and the

"right

half"

of the Alu

sequence. The individual

members

of the Alu

family have

an average identity

with

the con-

sensus sequence

of.87'/". The mouse

Bl repeat-

ing

unit is 130

bp long and

corresponds

to a

monomer

of the human

unit. IthasT0o/o-80o/o

homology

with the human

sequence.

The Alu

sequence is related

to 7SL RNA,

a

component

of the signal recognition particle

(see

Section

I0.9, The

SRP Interacts

with the

SRP Receptor). The

7SL RNA

corresponds

ro

the left

half of

an

Alu

sequence

with an inser-

tion

in the middle.

Thus the ninety

5'terminal

bases

of 7SL RNA

are homologous

to

the left

end

of Alu, the

central 160

bases of 7SL

RNA

The

ALu Family

Has

Many

WideLy

Dispersed

Members

.

A major

part

of repetitive

DNA in mammatian

genomes

consists

of repeats

of a single famity

organized

[ike

transposons and

derived from RNA

potymerase

III transcri

pts.

Ihe most

prominent

SINES

comprises

mem-

bers

of a single family.

Its

short length

and high

liifi

:['lJ',"'::1fi

:B'iT,Tii:xT;rfi

CHAPTER 22

Retroviruses

and Retroposons

564

999

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ri,,,:r,.,'

Atransposonistranscribedintoan

RNAthat

is

transtated

into

proteins

that move independently

to the

nucleus, where

they act on any

pair

ofinverted repeats with

the same sequence as the originaI transposon.

insertion

of an active copy, because the

proteins

are acting on a transcript

of

the

original active

element.

By contrast, the

proteins produced

by the

DNA

transposons

must

be

imported

into the

nucleus after being synthesized in the cyto-

plasm,

but they have no means

of distinguish-

ing full-length transposons from inactive deleted

transposons.

r-r;,r:ril

,r

:t .r

i

shows

that

instead

of

distinguishing these two types of transposons,

the

proteins

will

indiscriminately

recognize any

element by virtue of the repeats that mark the

ends.

This

greatly

reduces

their chance of act-

ing on a full-length element as opposed to one

that

has

been deleted.

The

consequence

is

that

inactive elements accumulate, and eventually

the

family

dies

out

because a transposase

has

such a small chance of finding a target that is a

fully functional transposon.

Are

transposition events currently occur-

ring in these

genomes,

or are we seeing only

the

footprints of ancient

systems?

This

varies

with the species.

There are

only a

few

currently

active transposons

in

the human

genome,

but

by contrast

several active transposons are known

in the mouse

genome.

This

explains the fact

that spontaneous

mutations

caused by

LINES

insertions occur at a

rate

of

-3o/"

in mouse,

but

only 0.17o

in man. There

appear to be

-10

to

50 active LINES elements

in

the human

genome.

Some

human diseases can be

pinpointed

as the

result

of

transposition of LI into

genes,

and oth-

ers result

from unequal crossing-over events

involving

repeated copies

of

LI. A model sys-

tem in which

LINES transposition occurs in tis-

sue culture

cells suggests

that a transposition

event can introduce several

types

of collateral

damage as

well as inserting

into a

new site; the

damage

includes chromosomal

rearrangements

and deletions. Such

events

may be

viewed as

agents of

genetic

change.

Neither

DNA trans-

posons

nor

retroviral-like

retroposons

seem to

have been active

in the human

genome for 40

to 50 million

years,

but

several active

examples

of both are found

in the

mouse.

Note

that for transpositions

to survive,

they

must occur

in

the

germline. Presumably

simi-

Iar

events occur

in somatic

cells,

but do

not sur-

vive beyond one

generation.

Sum

mary

Reverse

transcription

is the unifying

mecha-

nism for reproduction

of

retroviruses

and

per-

petuation

of

retroposons.

The cycle

of each type

of element

is in

principle

similar,

although

retro-

viruses are usually

regarded

from the

perspec-

tive of the free

viral

(RNA)

form,

whereas

retroposons

are regarded

from

the stance

of the

genomic

(duplex

DNA)

form.

Retroviruses

have

genomes of single-

stranded

RNA that are

replicated

through

a

double-stranded

DNA

intermediate.

An

indi-

vidual

retrovirus contains

two copies

of

its

genome.

The

genome

contains

the

gag, pol,

and

env

ge\es

that are

translated

into

polyproteins,

each of which is cleaved

into smaller

functional

proteins.

The Gag and

Env components

are con-

cerned with

packing RNA and

generating the

virion;

the

Pol components

are concerned

with

nucleic acid synthesis.

Reverse transcriptase

is the major

compo-

nent of

Pol,

and

is

responsible

for synthesizing

a DNA

(minus

strand)

copy

of

the viral

(plus

strand)

RNA. The

DNA

product is longer than

the RNA template;

by

switching

template

strands,

reverse

transcriptase

copies

the

3'

sequence

of the

RNA to the

5'end

of the

DNA,

and copies

the 5'sequence

of

the

RNA to the

l'

end of the

DNA. This

generates the character-

istic LTRs

(long

terminal

repeats)

of the

DNA.

A similar switch

of templates

occurs

when the

plus

strand

of

DNA is synthesized

using

the

minus

strand

as a

template.

Linear

duplex

DNA

is inserted into a

host

genome

by

the

integrase

enzyme.

Transcription

of

the integrated

DNA

from a

promoter

in the

left LTR

generates

fur-

ther copies

of the

RNA sequence.

Switches

in template

during

nucleic

acid

synthesis allow

recombination

to

occur by

copy

22.13 Summary

567

choice. During

an infective

cycle, a

retrovirus

may exchange

part

of its

usual sequence for a

cellular

sequence; the resulting

virus is

usually

replication-defective,

but can

be

perpetuated

in

the course

of a

joint

infection

with a helper

virus.

Many

of the defective

viruses have

gained

an RNA

version

(v-onc)

of a cellular

gene (c-onc)

The

onc sequence

may be any

one of a number

of

genes

whose expression

inv-oncform

causes

the

cell to

be transformed into

a tumorisenic

phenotype.

The integration

event

generates

direct tar-

get

repeats

(like

transposons that mobilize via

DNA).

An inserted

provirus

therefore has direct

terminal

repeats

of the LTRs, flanked

by short

repeats

of target

DNA. Mammalian

and avian

genomes

have

endogenous

(inactive)

proviruses

with

such

structures.

Other elements

with

this

organization

have

been found in

a variety of

genomes,

most

notably in

S. cerevisiae

arrd

D. melanogaster.

p

elements

of

yeast

and copia ele-

ments

of flies

have coding

sequences with

homology

to reverse

transcriptase and mobi-

Iize via

an RNA form.

They may

generate par-

ticles

resembling

viruses,

but do not have

infectious

capability. The

LINES sequences

of

mammalian genomes

are further removed

from

the retroviruses,

but retain enough

similarities

to

suggest a

common origin.

They use a differ-

ent type

of

priming

event to initiate reverse

transcription,

in

which an endonuclease

activ-

ity

associated

with the reverse

transcriptase

makes

a nick that

provides

a 3'-OH

end for

priming

synthesis

on an RNA template.

The fre-

quency

of LINES

transposition is

increased

because

its

protein products

are cls-acting;

they

associate

with

the mRNA from

which

they were

translated

to form

a ribonucleoprotein

complex

that is

transported

into the

nucleus.

The

members

of another

class

of

retro-

posons

have

the hallmarks

of transposition

via

RNA,

but

have no

coding sequences

(or

at

least

none

resembling

retroviral

functions).

They

may have

originated

as

passengers

in a

retroviral-like

transposition

event, in which

an RNA

was a target

for a reverse

transcrip-

tase.

Processed pseudogenes

arise by such

events.

A

particularly

prominent

family

that

appears

to have

originated

from a

processing

event

is the

mammalian

SINES;

it includes

the

human

Alu

family.

Some

snRNAs, including

7SL

snRNA

(a

component

of the SRP),

are

family.

References

The

Retrovirus

Life

Cvcle Involves

Transposition-Like

Events

Review

Varmus,

H. E.

and

Brown,

P. O.

(1989).

Retro-

viruses. In Howe,

M. M. and Berg,

D. E., eds.,

Mobile DNA Washington,

DC: American

Soci-

ety for Microbiology,

pp.

53-108.

Resea rc h

Baltimore,

D.

(1970).

RNA-dependent

DNA

poly-

merase in

virions

of RNA

tumor

viruses.

Nature 226, 1209-l2ll.

Temin, H. M.

and

Mizutani,

S.

(1970).

RNA-

dependent DNA

polymerase

in

virions

of

Rous

sarcoma

virlus. Nature 226, l2ll-1213.

Virat DNA is

Generated bv Reverse

Transcription

Reviews

I(atz, R. A.

and Skalka, A. M.

(1994).

The retrovi-

ral

enzymes. Annu. Rev. Biochem.

63,

B3-17J.

Lai, M. M.

C.

(

1992). RNA recombination

in

ani-

mal and

plant

viruses.

Microbiol

Rev.

56, 6l-79.

Negroni, M. and Buc, H.

(2001).

Mechanisms

of

retroviral recombination.

Annu.

Rev.

G

enet.

3 5.

275-302.

Resea rc h

Hu,

W. S. and Temin, H. M.

(1990).

Retroviral

recombination

and

reverse

transcription.

Sci

ence 250, 1227-12)).

Negroni,

M.

and Buc, H.

(2000).

Copy-choice

recombination

by reverse

transcriptases:

reshuffling

of

genetic

markers

mediated

by

RNA

chaperones. Proc

Natl. Acad

Sci. USA 97

6385-6390.

Viral. DNA

Integrates into

the Chromosome

Review

Goff, S. P.

(1992).

Genetics of retroviral

integra-

Iion. Annu. Rev.

Genet.26, 527-544.

Resea rc h

Craigie, R., Fujiwara,

T., and Bushman,

F.

(1990).

The IN

protein

of Moloney murine

leukemia

virus

processes

the

viral DNA

ends and

accomplishes

their integration

in vitro

Cell 62,

829-837.

CHAPTER

22

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