Are imprinting and inbreeding two related phenomena?

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Are imprinting and inbreeding two related phenomena?

C Biémont

To cite this version:

Forum

Are

_imprinting

and

_inbreeding

two

related

_phenomena?

C Biémont

Université

_Lyon

1

Biométrie-Génétique

et

_Biologie

des

_Populations,

URA 243

69622 Villeurbanne

Cedex,

France

(Received

20 June

1990; accepted

7 November

₁₉₉₀₎

Summary - This article presents a molecular

theory

of

inbreeding

mechanisms

involving

interactions between

_regions

of the male and female

_{genomic complement.}

This

theory

is based on the recent

developments

in

_imprinting

effects on male and female gametes,

which are now

_explained

in terms of

_protein-DNA

interactions which are manifested in some

_organisms

in the form of

cytosine methylation.

Such interactions are illustrated in

examples

from

_transposable

elements, which also

_{play a key}

role in

_genetic

load. This

theory

accounts for the effects observed in

_{particular mating}

systems of

_inbreeding

and

may be of interest for heterosis as well.

inbreeding

/

imprinting

/

protein-DNA interaction

_/

transposable element

Résumé - L’inbreeding et _{l’imprinting} ont-ils des mécanismes communs ? Cet article

présente

une théorie moléculaire des mécanismes de la

consanguinité

basée sur l’existence d’interactions entre des zones

_{complémentaires}

des

génomes

mâle et

femelle

du _zygote

et de

l’embryon.

Cette théorie

s’appuie

sur les récentes

_explications

des mécanismes de

l’empreinte génétique

des

_gamètes

mâle et

_{femelle qui impliquent}

des interactions

ADN-protéines

dont l’une des

_{manifestations}

serait la

méthylation

des

_cytosines;

ces interactions

joueraient

un rôle

fondamental

au cours du

_{développement}

des

_{organismes. L’importance}

de telles interactions est illustrée par des

exemples pris

chez les éléments

transposables

dont le rôle comme _agents mutateurs est actuellement indiscutable. Notre modèle rend

compte des

_{effets particuliers}

des

_systèmes

de croisements entre

_{parents-enfants}

et

frères-sceurs; il

est aussi

_{généralisable}

aux

effets

et mécanismes de l’hétérosis. Ce modèle doit être considéré comme une tentative d’introduire en

_génétique

des

populations

nos connaissances actuelles sur la structure du

_génome

et sa

_fluidité

_{ainsi que} sur les _processus moléculaires intervenant au cours du

_{développement}

des

_organismes.

consanguinité

/

empreinte génétique

/

interactions ADN-protéines

/

éléments transposables

INTRODUCTION

The classical theories of

_inbreeding

effects are based on an increase in the

degree

of

_homozygosity

of the inbred individuals

_(Wright,

1921, 1922a,b; Mal6cot,

1948).

Inbreeding

depression

is thus the result of

_segregation

at overdominant loci or of the

expression

of recessive deleterious or lethal alleles

usually

concealed in the genome

number of

_{enzymatic paths}

that control metabolism

_{(Haldane, 1954),}

and to

_perturb

the

_system

of homeostatic

_regulations

of individuals

_{(developmental homeostasis)}

as well as of

populations

(genetic homeostasis)

which then become

incapable

of

adapting

to modifications in the environment

_{(Lerner, 1954).}

Experiments

carried

out on the fruit

_{fly Drosophila}

and the Bruchidae

Acan-thoscelides

_obtectus,

in the first

_generation

of various inbred

_mating

systems,

have shown however that

_depending

on the

_mating

_system

used,

fitness

_components

such

as _egg

hatchability,

larvo-pupal

viability,

fecundity

(egg

production),

and some

other traits measured in adult

flies,

are not altered in the same _way

_(Bi6mont,

1972a,b, 1974a, 1976;

Bi6mont and

Bi6mont,

1973).

It was

found,

for

example,

that

_{father-daughter}

matings

lead to decreased larval and

_{pupal viability}

and

fe-cundity

of

F

1

females,

whereas mother-son

matings

decreased

_embryonic

_mortality.

Such results are not

_explainable

_{globally by}

classical

_genetic

_theory

based on

sim-ple

increased

_homozygosity

of deleterious recessive _genes, even with the addition

of

_{complex cytoplasmic}

controls or maternal effects. The

present

paper is thus an

attempt

to

_present

evidence

_regarding

recent discoveries on

_imprinting

effects and

mechanisms to

_explain

how maternal and

_paternal

chromosome sets

_might

be dif-ferentiated and

_might

lead to the above

_inbreeding

effects.

THE FACTS

It has been

theoretically

demonstrated that crosses between brothers and

_sisters,

fa-thers and

_daughters,

and mothers and sons, lead to the same value of the

inbreeding

coefficient for autosomal loci

_{(of 1/4).}

An

_inbreeding

_depression

of identical extent

should then result in the inbred

offspring

of these crosses,

although

as

_{postulated by}

Franklin

_(1977),

the

_parent-child

crosses should lead to less

_inbreeding

_depression

than brother-sister crosses.

_{By working}

on

_early

and late

_development

in

Drosophila

melanogaster,

we have shown that the above 3 kinds of crosses

_actually

_give

different

patterns

of

_{inbreeding depression}

for characteristics such as _egg

_hatchability

(No

of

hatched

_eggs/No

of fertilized

_eggs),

larval and

pupal viability

(No

of

F

2

adults/No

of hatched

_eggs),

and adult egg

production

(total

egg

production

during

the lifetime of the

_F

₂

adult

_flies,

_{maximum egg}

production,

longevity

of the inbred

_adult).

Tables

I and II summarize the effects of the 3

_mating

systems

on these traits. Note that

total

_viability,

which is what is

_usually

_measured,

is the

_product

_{of the egg}

hatch-ability

by

the

_{larvo-pupal viability}

values. Tables I and II

_clearly

show that

father-daughter

crosses do not decrease _egg

_hatchability

_(and

thus lead to a normal

embry-onic

_{development),}

but

_greatly

increase

_{mortality during}

larval and

_pupal

stages

(table I)

and decrease _egg

_production

characteristics of the adult inbred females

(2

way

analysis

of variance: F =

_4.5,

P _< 0.05 for total egg

production;

F =

8.4,

P = 0.008 for maximum

daily

egg

production).

Mother-son crosses in-crease the

embryonic mortality

but have

only

a

_slight

effect on

_larvo-pupal

devel-opment

(table I)

and _egg

_production

measurements

_(F

=

5.3,

P _< 0.05 for total

egg

production

while there was no

statistically significant

difference for maximum

daily

egg

production,

F <

_1).

Sib crosses

_provoke

a

_{general negative}

effect on all

An

_interesting

result that is worth

_pointing

out is the observation that total

viability

is reduced in the same _way in the 3 crosses, thus

leading

to the

_apparently

similar

_inbreeding

depression

in the 3

_mating

_systems.

Because

_only

total

_viability

is

usually

determined in

_experiments

on

_inbreeding,

we have no other data on

viability

components,

even in birds where

_parent-child

crosses were

_{experimentally analysed}

(Bulmer, 1973),

and in which 2

_{developmental}

_stages

sensitive to

_inbreeding

were

reported

(Lucotte,

1975).

New

_experiments

on

_inbreeding

could then be

_performed

in sea

_urchins,

for

_example,

in which

_embryonic

_development

_processes are now well

known,

and in vertebrates where many

components

of

_viability

can be

_analysed

and

in which

_development

cannot succeed

_{satisfactorily}

without the

_paternal

_genome.

THE INBREEDING MODEL

The above differential effects of

_parent-child

crosses led us to

_distinguish

2

_phases

in the _way

_inbreeding

_depression

takes

place;

a

_phase

in which the first

stages

of

_embryonic

_development

are

_perturbed

and which

_depends

on _{presence of} a

F

l

spermatozoon;

and a second

_phase

in which

_{larvo-pupal viability}

and some

characteristics of the

F

2

offspring

are

_perturbed,

and which

_depends

on _presence of

an

F

1

ovum.

To

_explain

the above results of

_inbreeding,

we

_postulated

that these 2

_phases

imply

the existence of interactions between the male and female chromosomal

complements

in the

_zygote

and

_embryo

_(Bi6mont

et

al, 1974; Bi6mont,

1974b).

We then formulated the

_hypothesis

that there exist on the male and female

sites in an active or inactive

_state;

the inactive state needs information from the active state to become activated. What is

important

in this

_hypothesis

is not

only

the number of active and inactive

_sites,

but the number of

interactions, ie,

the number of

_couples

of active-inactive

_homologous

sites. These interactions are

postulated

to be necessary for

complete

embryonic development.

Moreover,

the

model

_implies

that the maternal and

paternal complements

are

_{asynchronously}

activated so as to

_explain

the

_divergence

in

_inbreeding

_depression

_following

father-daughter

and mother-son crosses. Paternal factors are thus

_postulated

to act

first to activate the maternal

_complement;

such interactions control

_embryonic

development.

The maternal

_complement

acts second to activate the

_homologous

zones on the

_paternal

_complement,

and these interactions are _necessary for later

stages

of

_{development. Any perturbations}

on either the first or the second

phase

lead to deleterious effects on either

_{embryonic development}

or late

_development

and some adult characteristics

(Bi6mont

and

Boul6treau-Merle, 1978;

Bi6mont and

Lemaitre,

1978).

It is

_important

to note that normal

development

involves the confrontation of 2

_gametic

zones with

_patterns

of

activated/inactivated

sites

sufficiently

different so as to have _many interactions between the 2

_gametic

zones. The result of these

gametes.

We can thus understand how inbred

_matings

can lead to deleterious effects

throughout development

as a result of

_gamete

incompatibility.

The

similarity

of the

homologous

complements

between brothers and sisters makes many interactions

impossible

(see

the

_fig

_1);

deleterious effects for both

_early

and late

development

result. In the

_{father-daughter}

_mating

_system,

the

_pattern

of

_{active/inactive}

sites of the father is common to that of his

_daughter;

_{nevertheless,}

the

_daughter

_complement

contains some

_specific

active sites not seen in her

_father;

the

_{interactions,}

thus

possible,

account for the normal egg

hatchability

observed in such a

_mating

_system,

yet

provoke

a

_perturbation

in late

_development.

In the mother-son _crosses, the

interactions involved are

_opposite

to that of the

_{father-daughter}

crosses;

hence,

the

_opposite

effects are observed in this mother-son

_mating

_system:

embryonic

development

is

_perturbed

while the later

_{developmental}

_stages

are almost normal.

As a result of the site

interactions,

the 2

_{genomic complements}

have similar

patterns

of

_{activated/inactivated}

sites

_along

the

chromosome;

spontaneous

changes

thus a

_complete

_blocking

of

_development.

Variation in

_intensity

of such a _process

accounts for the differential responses to

_inbreeding

of

_organisms.

Note that in the years 1973-1974 no molecular

_knowledge

was available to render

the above

hypotheses

testable and

acceptable by

the scientific

_{community. Indeed,}

little was known on how the _genes were activated and

_{regulated throughout}

develop-ment,

and

_repression

of _gene

_expression

_by

non-histone chromosomal

_proteins

was

only

mentioned

_(Spiegel

et

al, 1970;

Asao,

1972;

Kostraba and

_Wang,

1973;

Stein

et

_al,

_1974).

The

_recognition

of the existence of a

_phenomenon

termed

&dquo;imprint-ing&dquo; by

Crouse

₍₁₉₆₀₎

was

_required

in order to

_distinguish

between maternal and

paternal

chromosome

_complements

in _{many processes} such as

_specific

chromosomal

elimination and inactivation

_by

heterochromatization in various

_organisms.

In

_1975,

Holliday

and

_Pugh

₍₁₉₇₅₎

_presented

their

_theory

of

_imprinting

based on

protein-DNA interaction and

_cytosine

_methylation.

In the

_following

_sections,

I summarize

our current

_knowledge

on this _very

_{exciting phenomenon}

of

_imprinting

and discuss

its

_importance

and

_pertinence

for the above model of

_inbreeding

mechanisms.

IMPRINTING

Heterochromatization and chromosome elimination in _many

_organisms

have in com-mon the selective

_silencing

_by

inactivation or elimination of

_specific

chromosomes or

_parts

of chromosomes in the _presence of unaffected

homologs.

The sex chromosomes of

_paternal

_origin

are eliminated in ratlike

_bandicoots,

inactivated in

_kangaroos

while random inactivation occurs in

placental

mammals

(Lyon,

1961; Sharman,

1971).

In the

_{coccids, Hemiptera,}

the chromosomes of

pa-ternal

_origin

are inactivated or eliminated. For

_example,

in lecanoids the

pater-nally

derived chromosomal set becomes heterochromatic and

functionally

inactive and remains so in most tissues

_throughout

_development

_(Brown

and

Nelson-Rees,

1961;

Brown and

_{Nur, 1964; Nur, 1967;}

Brown and

_Wiegmann,

_{1969; Kitchin, 1970;}

Sabour,

1972; Berlowitz,

1974);

in

_diaspidids

the effective

_{haploidization}

of the male

is

_{accomplished by}

elimination of the

_paternal

chromosomal set. In the olive scale

insect Parlatoria olea

_(Kitchin,

₁₉₇₀₎

the heterochromatic chromosomes

_disappear

by

intranuclear destruction in the

_primary

_spermatocyte

_shortly

before meiosis.

Oogenesis

is normal in ,Sciara _{where the egg receives} a

_haploid

set of autosomes

and one X chromosome

_(Crouse

et

_al,

_1971),

but in

_{spermatogenesis}

the

paternally

derived X chromosome and autosomes are discarded

(Crouse

et

_{al, 1971;}

_Sager

and

Lane,

1972);

the male transmits

_through

the _sperm

_only

the chromosomes that he received from his mother. In

_{Chlamydomonas,}

the

_chloroplast

genome from the male parent is not transmitted because it

_disappears

soon after

_zygote

formation

(Sager,

1972;

Sager

and

_Ramanis,

_1974).

Hence,

a

_phenomenon

is

_required

to

_distinguish

between the maternal and

paternal

chromosome

_complements.

Crouse

₍₁₉₆₀₎

has used the term

_imprinting

to describe the alteration which allows a

_given

chromosome to be

_{distinguished}

from its

_homolog.

Preferential

_expression

of maternal or

_paternal

_genes

_throughout

development

in some

_species

_(Courtright,

_{1967; Dickinson, 1968;}

_Wright

et

_{al, 1972;}

According

to Surani and Barton

₍₁₉₈₄₎

and Surani et al

_(1984),

_genomic

imprinting

could confer on some elements of the genome of

_reproductive

cells a

memory of their

parental origin,

so that the chromosomes or certain _genes are

marked

_by

their

_{path through}

the father and the mother. The maternal and

_paternal

genornes may &dquo;remember&dquo; this

parental origin

throughout

the

development

and life

of the individuals. The simultaneous presence of the 2 chromosomal

complements

marked

_by

the father and the mother are _necessary for the

_{embryonic development}

to be

_complete

_(Surani

and

_{Barton, 1984;}

Surani et

_{al, 1984;}

_Modlinski,

_1980).

From all these studies it _appears that the

_paternal

_genome is more

_important

for

development

of

_{extra-embryonic}

tissues while the maternal

_complement

is _necessary for

_embryonic

_development.

Brown and Chandra

₍₁₉₇₃₎

proposed

for mammals the

existence of sensitive sites

_subject

to

_imprinting,

which activate

_receptor

_sites,

which

in turn,

regulate

heterochromatization of the X chromosome.

It has been shown in animals that for

_particular

chromosomal

_regions

with maternal

_{duplication/paternal}

_deficiency

and its

_reciprocal,

anomalous

_phenotypes

depart

from normal in

_opposite

directions

_(Cattanach

and

_Kirck,

_1985).

Such

departure

suggests

a differential

_functioning

of some _{gene loci within this}

_region

and

also

_suggests

the existence of a form of chromosome

imprinting

that affects gene

activity.

According

to these

authors,

the male chromosomal

_region

may thus have

a

single

or earlier

_activity

while

_inactivity

or later

_activity

_may be a characteristic

of the

_{corresponding}

female

_region.

PROTEIN-DNA INTERACTIONS AND DNA METHYLATION

The mode of action of _genes

_during

_development

of the

_organism

from the _egg

to adult is _very

_poorly

_understood,

and the

_changes

_{in gene}

_activity

_throughout

development

are

_generally

referred to as

_epigenetic

(Waddington, 1965).

It is

usually

believed that

specific protein-DNA

interactions are

responsible

for such

_epigenetic

changes

in _gene

_activity.

It has been shown that such

_imprinting

is associated with DNA

_methylation,

which is a

key

element in the control mechanisms that govern gene function and

differentiation

_(Razin

and

_Riggs,

_1980;

_{Kolata, 1985;}

Reik et

_{al, 1987;}

_Sapienza

et

_al,

_1987).

In

_{eukaryotic methylation,}

certain

_cytosines

are converted to

5-methylcytosine

which acts

_just

like a new DNA base.

_Holliday

and

_Pugh

_(1975),

Riggs

(1975)

and

_Holliday

₍₁₉₈₇₎

have

_proposed

that

_methylation

is

_heritable,

passed

on from

_generation

to

_generation

as cells divide

(Kolata,

_1985;

Reik et

_al,

1987; Sapienza

et

_al,

_1987);

their

_proposition

was further verified and

_suggests

the

existence of

_specific

factors

_{(maintenance methylase) (Harrison}

and

_Karrer,

₁₉₈₉₎

capable

of

_recognizing

the

_{hemimethylated}

DNA formed after

replication

and that

can

methylate

the nascent DNA strands

_(Holliday

and

_Pugh,

_1975;

_Riggs,

_1975).

Holliday

(1987)

then

_postulated

that loss of

_methylation,

which can result from

DNA

_damage,

leads to heritable abnormalities in gene

expression.

Such

_epigenetic

defects in

_germline

cells as a result of this loss of

_methylation

can be

_{repaired by}

recombination at

_meiosis,

but some are transmitted to

_offspring.

Defects that are

not

_repaired

at meiosis will have

_properties

_{formally equivalent}

to

_mutations,

since

they

are heritable and can have

_{specific phenotypic}

effects. When

_{heterozygous,}

an

(Holliday,

1987);

the defects are thus &dquo;eliminated&dquo;

by

meiosis. With

inbreeding,

however,

some

_epigenetic

defects will become

homozygous

and will

stay

in this

state

_{throughout generations, depending}

on their

_probability

of

_being

removed as

heterozygotes

at meiosis.

_Holliday

thus

_proposed

that such _processes could

_explain

inbreeding

effects.

According

to

_Sager

and Kitchin

₍₁₉₇₅₎

differential heterochromatization and chromosome elimination are

_regulated

_by

modification of DNA

by

_enzymes, as

is the case in bacterial

_systems

(Luria

and

Human,

1952),

with

specificity

for

particular

recognition

sites. It is

_postulated

that the modification enzymes

protect

the

_recognition

sites

_by

DNA

_methylation

from attack

_by

the endonucleases.

Razin and

_Riggs

₍₁₉₈₀₎

_proposed

that

_methylation

could also lock nucleosomes

into

_position

on the

_DNA,

the control

_regions

of active genes not wound _{up in}

these nucleosomes

_being

fixed

_by

this

_methylation

process until a new state of

differentiation is _{established. This agrees with} the observation that nucleosome

positions

on the DNA _vary

according

to the state of differentiation of the cell. In such a

model, methylation

is

only

a

_secondary

controller of _gene

_expression,

the

primary

stage

being

assumed

_by

some kind of &dquo;determinator&dquo;

proteins

(Razin

and

Riggs,

1980).

It is

_striking

that researchers have not

_yet

found the enzymes that

originally

add

_methyl

_groups to DNA in genes which are then

_permanently

turned off

_during

development; only

&dquo;maintenance&dquo; enzymes

(Harrison

and

Karrer,

1989)

keeping

methyl

groups on

during

cell division are known. Note that the functional differences

between maternal and

_paternal

nuclei were found to be retained after the activation

of the

_embryonic

_genome at the 2-cell

_stage

_(Surani

et

al,

1986),

although

the somatic

_methylation

_pattern

has been found in 3-d

_embryos

of

_chickens,

in clusters of

_repeated

DNA sequences

(Sobieski

and

Eden,

1981).

Although

it now _appears that DNA

_{methylation plays}

an

_important

role in

gene

expression

during

development,

some

_organisms

_manage

_quite

well without

any extensive

methylation.

The mechanisms for

marking expressed

genes in such

organisms

are still unknown. Lower vertebrates in

general

have far less

methylation

than mammals.

_Twenty

_percent

of the lower vertebrate DNA is

_methylated

as

compared

to

80%

in mammalian

DNA,

and the DNA of the fruit

_fly

does not

seem to be

_methylated

at all

_(Bird,

_1980,

_1984).

It is

_possible

that some

_specific

protein-DNA

interactions,

which are associated in

higher organisms

with the

methylation

pattern,

survive to transmit the _memory, and that these interactions alone are sufficient to account for

imprinting

in

_Drosophila

_(Razin

and

_Riggs,

_1980).

Such

_DNA-protein

interactions have been

_suggested

to be themselves heritable

(Weintraub, 1985).

The lack of

_methylation

in

_Drosophila

_may at first

_sight

eliminate this

_species

as a candidate for

imprinting,

but remember that

preferential

expression

of some

_paternal

and maternal _genes occurs

during

development

in

Drosophila

melanogaster

(Courtright,

1967; Dickinson, 1968;

Wright

et

al, 1972;

Sayles

et

_al,

_1973;

Shannon,

1973).

Moreover,

as noted

above,

the genome

imprinting

process was first discovered in various

invertebrates,

but the

methylation

of

cytosine

THE TRANSPOSONS

Transposable

elements have

_recently

been shown to be submitted to a

regulation

system

involving methylation.

Because of their effects on _genes and their

ability

to induce chromosomal

rearrangements,

these elements are an

_important

source of

genetic

variability

(Syvanen, 1974)

and thus

_participate

in the

_genetic

load

_(Mukai

and

_Yukuhiro,

_1983;

Bi6mont et

al, 1985;

Yukuhiro et

_{al, 1985;}

_Fitzpatrick

and

Sved, 1986; Mackay,

1986).

Transposition

rates are

usually

found to be ,--

10-

3

per

generation

(Pierce

and

Lucchesi,

1981;

Young

and

Schwartz,

1981)

but

higher

rates of

_{transposition}

can be obtained either in crosses between certain strains

of

Drosophila melanogaster

(Br6gliano

and

Kidwell,

1983)

or under

_particular

conditions

_(Gerasimova

et

_{al, 1983;}

Junakovic et

al,

1986).

Although

in the

_long

run an elevated mutation rate could be

_advantageous

for

_population

adaptation

(Bi6mont

et

al, 1984;

Georgiev,

1984),

the

_potentially

harmful effects of

_high

rates of

transposition

may lead to selection for some mechanisms that

regulate

the

activity

of the

_transposable

elements.

The

_controlling

element Ac

_(activator)

in Zea _mags is

_capable

of

transposition,

and a derivative that has lost

_transposase

activity

has been shown to have

methylated cytosine

that is inherited

_through

sexual crosses; this inactive element

can revert to active Ac

_by

loss of

_methylation

_(Kunze

et

al,

1988).

The activities of this maize

transposable

element

_Ac,

as well as

,Spm

(En),

are thus correlated with

hypomethylation

(Burr

and

Burr,

1981;

Dellaporta

and

_Chomet,

_1985;

Chomet et

al, 1987;

Fedoroff et

_{al, 1988; Raboy}

et

al,

1988).

DNA

_methylation

of the maize

transposable

element Ac interferes with its

_{transcription.}

In the inactive

_phase,

the Ac DNA is

_{highly methylated}

and no Ac

transcript

is detectable

_(Kunze

et

al,

1988).

In the same _way, the

majority

of Mu _{elements in the maize genome} are

unmethy-lated in active stocks and

_methylated

in inactive stocks

_(Schwartz

and

_{Dennis, 1986;}

Bennetzen,

1987;

Bennetzen et

_al,

_1988).

An

_interesting

observation is that

inter-crossing

diverse mutator lines of maize leads to a discrete

hypermodification

of the

Mu elements with a loss of

_mutagenic

and

transpositional potential

(Bennetzen

et

al,

1987).

Modification of Mu elements may block their

ability

to interact with a

putative

transposase

as is the case with the IS 10 element in

prokaryotes

which is

regulated

by

adenosine

_methylation

_(Roberts

et

_al,

_1985).

In

_{mice, methylation}

concerns some but not all

copies

of the IAP

_repetitive

sequences

(Nlays-Hoopes

et

al,

1983).

In

the L1 element

family,

concerted

hy-pomethylation

of sequences has been observed in mouse

_{extraembryonic}

cells and

in transformed cell lines

_(Tolberg

et

_al,

_1987).

It is thus

_speculated

that in

L1,

methylation

may modulate

transcription

of some selected sites.

Thus DNA

_methylation

may be a mechanism for

heritably controlling genetic

element

_{transposition.}

Such modification may be one mechanism

regulating

the

possible

deleterious

_activity

in the cell

_(Chandler

and

_Walbot,

_1986).

Transposition

rate _may also be under

_genetic

control as in the switch in

mating

_type

of

_yeasts,

which is

_normally

confined to the mother cell

_lineage

_(Hicks

et

_al,

_1977).

Whether mobile elements are

really

involved in an

imprinting phenomenon

is not

_yet

clear,

during

development,

and such elements have a differential

probability

of

being

inactivated _{upon transmission}

_through

male or female

_gametes

(Fedoroff, 1989).

A UNIFIED THEORY

It is still a matter of

_speculation

as to whether the effects of

_inbreeding

are due

mainly

to loss of homeostatic

capacity

of the more

_homozygous

individuals or to

the effects of recessive deleterious factors

_present

in all wild chromosomes and

exposed by

the

_{increasing homozygosity}

of the genome. The

inbreeding

depression

thus results in a low

_viability

due to numerous causes of

_mortality

_throughout

the

development

of the

_organism

_{(Lewontin, 1974);}

_viability

has thus been

_postulated

to be controlled

_by

_polygenes

with an

_extremely

_high

_spontaneous

mutation rate

(Simmons

and

_Crow,

_1977).

From the above

_{considerations,}

we now _propose that

inbreeding

interferes

_with,

or is

_strongly

connected with mechanisms

_controlling

embryonic

development.

Such an

_inbreeding

model does not of course eliminate the

classical

hypotheses

(Wright,

1921,

1922a,b; Mal6cot, 1948; Haldane, 1954; Lerner,

1954;

Dobzhansky

et

_al,

_1963);

the

_inbreeding

_{depression reported}

_throughout

development

in many

organisms surely

involves more than 1 mechanism.

Inbreeding

and

_imprinting

have common bases:

- the molecular

memory of

parental origins

of the maternal and

paternal genomic

complements,

- the

necessity

of the simultaneous _presence of the chromosomal

_complements

marked

_by

the father and the mother for the

_{embryonic development}

to be

_complete;

hence the existence of interactions between the 2 chromosomal _sets,

- the _occurrence of sensitive sites which activate

receptor

sites in

_imprinting,

or

of interactions between activated and inactivated sites in

_inbreeding,

-

a differential

_activity

_{during development}

of the male and female

_complements,

- the

existence of some

_spontanous

site

_{deactivation,}

or errors in the activation process,

which

avoid a

complete blocking

of

development

from the first

_generation

of

_inbreeding

on. Note that this latter consideration _agrees well with the ideas that

changes

in

_protein/DNA

interaction

_pattern

can lead to heritable abnormalities in gene

expression

(Holliday, 1987),

and that some

specific

interactions which survive

to transmit the _memory can themselves be heritable

(Weintraub, 1985);

it is also

supported by

the recent observation of the failure of the

_germline

in mice to

erase the

_epigenetic

modifications at the TKZ751

_locus,

thus

_leading

to cumulative modifications of this locus

_through

successive

_generations

_(Allen

et

_al,

_1990).

Hence,

inbreeding

depression

viewed in terms of interactions between the 2

parental

chromosomal sets as occurs in

_imprinting

is more a

_quantitative

than

a

_qualitative

modification of a _process

_{existing normally}

in non-inbred

indi-viduals. The number of interactions

involved

in

_development

is

_merely

lowered

_by

inbreeding,

thus

_resulting

in a

_higher

_probability

for abnormal

_development.

Such

a

_quantitative

effect _agrees with the observation of an increased amount of histone

proteins

in inbred lines of _rye

_(Kirk

and

_Jones,

₁₉₇₄₎

and a

_{disappearance}

of some

biochemical

components

in

_Drosophila

_(Hoenigsberg

and

_Castiglioni,

1958;

King,

1969),

as could result if

_inbreeding

is associated with an increased

_repression

of

According

to our

model,

the absence of interaction between 2 related

gametic

chromosomal

_complements

blocks the first

_stages

of

_{embryonic development.}

But

a

_population

submitted to

_strong

_inbreeding

such as brother-sister

_matings

does

not

_disappear

in the first

_generations

as could result due to null fitness. Even in

the

_species

most sensitive to

_inbreeding

such as

Gallinacea,

3 inbred

_generations

are _necessary for the

_population

to

_collapse

_(Cole

and

_Halpin,

_{1916; Dunn,}

_1928).

Thus some

_spontaneous

changes

in the

_pattern

of

activated/inactivated

sites

along

the chromosomal sets are needed to

_permit

some interactions without

blocking

development entirely.

Such

_changes

in pattern could

_happen

as a result of error

in either the

_methylation

process or the

protein-DNA

interactions involved in the

imprinting

mechanism. These

_spontaneous

modifications and also the variation in the number of sites

_interacting

could be

_responsible

for the

_divergence

_existing

between inbred individuals and among sublines.

Indeed,

a

problem

in mouse

genetics

is the

unexpected

variation in

homozygous

inbred animals. For

_example,

the

frequency

of variation of some skeletal structures

is far

_higher

than

_expected

from classical mutation rates. Subline differentiation is

a

_continuing

_process, the

frequency

of

changes

_per variant

being

as

_high

as 0.01 _per

generation

(Hoi-Sen,

1972),

1000 times as common as _{the average} mutation rate

for a number of genes in the mouse

(Schlager

and

Dickic,

1967).

Murphy

(1966),

moreover, described a

_high

_frequency

of tumors in 16

_major

inbred mouse

stocks,

as if

_inbreeding

caused an increased rate of

_{tumorigenesis.}

Fitch and

_Atchley

₍₁₉₈₅₎

_supposed

that if a mutation _process, such as conversion or

switching,

were to occur to

_explain

subline

_divergence

in

_mice,

it would be as

high

as

10-

3

,

a rate similar to that observed in

_switching

on and off loci

_responsible

for

phase

variation in Salmonella. Such a rate of

10-

3

is

_exactly

_{the average value} of

_{transposition}

rate found in

_Drosophila

for

transposable

elements

_(Pierce

and

Lucchesi,

1981;

Young

and

Schwartz,

1981),

even in

_highly

inbred lines maintained

by systematic

brother-sister

_mating

_{during *}

108

generations

(data

on

_mdg-1

and

P

_{elements; unpublished}

_results).

_Holliday

₍₁₉₈₇₎

has thus

_postulated

that such

morphological

variation is due to heritable modification of

_germline

DNA. There

_is,

however,

no evidence of a

high

visible mutation rate in mouse inbred lines

_(Johnson

et

_al,

_1981).

It _may thus be that the factors

_promoting

line

_divergence

do not

_always

lead to _emergence of visible and detectable

_mutations,

as if

_only

some

_particular

regions

of the chromosomes were concerned.

Our

_inbreeding

model fits the data on heterosis as

_well,

with fitness values

_being

correlated with the number of

_interacting

sites

_(Bi6mont,

_1974b,

_1980;

Biémont

et

_al,

_1974).

The more the lines

diverge

the

higher

the number of interactions

resulting

from their

_crossing:

a

high

value of fitness of the

hybrid

should result.

Because _many

_interacting

sites are

concerned, crossing

sibs of such

hybrids

should

lead to a

_strong

_{inbreeding depression,}

as

_{experimentally}

observed

(Falconer, 1981).

Such _processes recall a heterosis model of

_{self-incompatibility}

based on

_prezygotic

expression

of

_genetic

load mediated

_through

_pollen-style

interactions determined

by

the

_genotype

of the 2

_parents

_(Mulcahy

and

_Mulcahy,

_1983).

A mathematical

_analysis

of the interaction

_system

has been

developed

with sib

matings

(Bi6mont,

1974b, 1980;

Bi6mont et

_al,

_1974).

This

_{probabilistic approach}

observations: a deleterious effect of

inbreeding

is

usually

observed which can even

lead to line

_extinction,

_depending

on the values of the model

_parameters.

It has

been observed that

inbreeding depression

generally

decreases with

_generations

and leads to stable lines

_(King,

_1918;

_Wright,

1922a,b;

Wright

and

Heaton,

1922;

Hyde,

1924; Petit, 1963; Ootmersen, 1970;

Legay,

1971; Kosuda,

1972).

This

_asymptotic

value could

_correspond

to the &dquo;inbred minimum&dquo;

_reported

by

King

(1918)

in certain

species

of rodents. Beneficial or neutral effects can also be obtained with the

model,

as sometimes

experimentally

reported

(Castle

and

Carpentier, 1906;

Rasmusson,

1951;

Lints,

1961).

One

_problem

with our model is that it

requires

_spontaneous

changes

in state

_{(active/inactive)}

with a

higher

rate than that usual for mutations. This

_problem

now seems to be overcome since processes such as

_{transposition}

of

mobile elements have a rate in the order of

10-

3

or even _more, and it appears

quite

reasonable that

_change

in

_methylation

_pattern

_may be modified with an elevated

rate,

at least under some conditions. For

example,

Mu elements in maize may

become modified after

self-pollination

(Chandler

and

Walbot,

1986)

or

_inbreeding

of mutator stocks

_(stocks

with

_high

rate of mutations and presence of active Mu

transposons) (Bennetzen,

1987;

Bennetzen et

_al,

_1988),

and such modifications are

correlated with lack of

_activity

_(Chandler

et

_al,

_1988).

CONCLUSION

It is clear that the kind of interactions between the 2 chromosomal

complements

is

one of the numerous facts in genome

_structuring

and

functioning

that

population

genetics

should take into account in the near future. Even _so, as stated

by

Lewontin

_(1985),

the existence of such

_phenomena

does not in itself

_guarantee

their

importance

to

_population

_{genetic considerations,}

_although

a recent mathematical

approach

tends to demonstrate the

_{potential population}

genetic

consequences of

molecular

_imprinting:

_apparent

_{heterozygote deficiency}

and a concurrent

_hybrid

vigor

(Chakraborty, 1989).

The

_knowledge

of the fine structure of these

_phenomena

may lead to the wish

that, by

changing

the environmental and

_{physiological}

conditions, they

could be acted upon and their effects modified in some _way;

they

would then become of considerable

importance

for

_population

_genetics,

_applied

quantitative genetics

and

_{evolutionary biology.}

ACKNOWLEDGMENTS

We thank C

Arnault,

P

_Caruso,

JR

_David,

C

_Gauthier,

R

_Grantham,

A Heizmann, JM

Legay

and D Pontier for their useful comments. This work was

_{supported by}

the Centre

National de la Recherche

Scientifique

(URA 243),

the Association pour la Recherche sur

le

_Cancer,

and the Hasselblad Foundation.

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