The Inheritance of Acquired Epigenetic Variations

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  • 7/29/2019 The Inheritance of Acquired Epigenetic Variations

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    J. theor. Biol. ( 1 9 8 9 ) 1 3 9 , 6 9 - 8 3

    The Inheritance of Acquired Epigenetic VariationsEVA JABLONKAt AND M ARION J . LAM B:~

    t Edelstein Center fo r the History an d Philosophy of Science, Technologyand Medicine, Hebrew Universi ty, Givat-Ram, Jerusalem 9 1 9 0 4 , Israel and~. Biology Department, Birkbeck College, Un iversity of London, M alet Street,L on do n W C 1 E 7 H X , U .K .(Received and accepted 2 2 February 1 9 8 9 )

    There i s ev idence t ha t t he func t i ona l h i s to ry o f a gene i n one genera t i on can i n fluencei t s express ion in the next . In somat ic ce l l s , changes in gene act ivi ty are f requent lyassoc i a t ed wi th changes i n t he pa t t e rn o f m e thy l a t i on o f the cy tos ines in D NA ;these m e thy l a t i on pa t t e rns a r e s t ab ly inhe r i ted . Recen t work sugges ts t ha t i n forma-t ion a bou t pa t t e rns o f me thy l a t i on and o the r ep igene t i c s ta t e s can a l so be tr ansm i t t edf rom paren t s t o o f f spr ing . Th i s ev iden ce i s t he bas i s o f a mode l fo r t he i nhe r i t anceof acqu i r ed ep igen e t i c va r i a t ions . Acco rd ing to t he mod e l , an en v i ronm enta l s timuluscan i ndu ce h e r i t ab l e chrom at in m odi f i ca t ions which a r e ve ry spec if i c and p red i c t ab l e ,and migh t r e su l t i n an adap t ive r e sponse t o t he s t imulus . Th i s t ype o f r e sponseprobab ly has mos t s i gn i f i cance fo r adap t ive evo lu t i on i n o rgan i sms such as fung iand p l an t s , which l ack d i s ti nc t s egrega t ion o f t he som a and ge rm l i ne . Howe ver , ina ll o rgan i sm s , the accu mu la t i on o f spec i fi c and r and om chrom at in m odi f i ca t ions inthe ge rm l i ne may be impor t an t i n spec i a t i on , because t hese modi f i ca t i ons cou ldl ead t o r eproduc t ive i so l a t i on be tween popula t i ons . Her i t ab l e chromat in va r i a t i onsm ay a l so a l te r the f r equ ency an d d i s t r i bu t i on o f c l a s si ca l mu ta t i ons and meio t i cr ecom bina t i on . The re fore , i nhe r it ed ep igene t i c changes i n t he s t ruc tu re o f chrom at inc a n i n f l u e n c e n e o - D a r w i n i a n e v o l u t i o n a s w e l l a s c a u s e a t y p e o f " L a m a r c k i a n "inher i t ance .

    I n t r o d u c t i o nG e n e t i c i n f o r m a t i o n r e s i de s in th e s e q u e n c e o f D N A b a s es , b u t m o r e t h a n D N As e q u e n c e i n f o r m a t i o n is t r a n s m i t t e d f r o m o n e c e l l g e n e r a t i o n t o th e n e x t . W h a t i st r a n s m i t t e d i s c h r o m a t i n , a t h r e e - d im e n s i o n a l c o m p l e x o f D N A a n d p r o te i n s. T h e r e -f o r e, in a d d i t i o n t o t h e i n s tr u c t io n s c o d e d i n th e b a s e s e q u e n c e o f D N A , g e n e s c a nc a r ry a n d t r a n s m i t in f o r m a t i o n e m b e d d e d in t h e st ru c tu r e a n d c o n f o r m a t i o n o fc h r o m a t i n . S u c h i n f o r m a t i o n i s e p i g e n e t i c i n f o r m a t i o n ( W a d d i n g t o n , 1 95 3, 1 96 8) ;i t w i ll re f le c t t h e d e v e l o p m e n t a l a n d f u n c t i o n a l h i s t o r y o f t h e g e n e s , a n d it w i ll b ei n v o l v e d i n t h e i r p r e s e n t a n d f u t u r e a c t i v i t y .

    T h e m o l e c u l a r m e c h a n i s m s u n d e r l y i n g h e r i t a b l e c h a n g e s i n c h r o m a t i n s t r u c t u r ea n d g e n e f u n c t i o n a r e n o t f ul ly u n d e r s t o o d . O n e f a c t o r w h i c h i s t h o u g h t t o b ei m p o r t a n t i s m o d i f i c a t i o n o f D N A b a s e s , p a r t i c u l a r l y m e t h y l a t i o n o f c y t o s i n e (H o l l i -d a y & P u g h , 1 9 75 ; R i g g s , 1 9 75 ). I t h a s b e e n s h o w n t h a t p a t t e r n s o f c y t o s i n em e t h y l a t i o n a r e s t a b ly i n h e r i te d in s o m a t i c c el l l in e a g e s , a n d t h a t s o m e c h a n g e s i ng e n e a c t i v i t y a r e c o r r e l a t e d w i t h c h a n g e s i n m e t h y l a t i o n p a t t e r n s ( R a z i n & R i g g s ,1 9 80 ; D o e r f l e r , 1 9 83 ). T h e i d e n t i f i c a ti o n o f a l te r e d p a t t e r n s o f c y t o s i n e m e t h y l a t i o n

    6 9

    0022-5193/89/130069+ 15 $03.00/0 1989 Academ ic Press Limited

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    70 E. JABLONKA AND M. J . LAMBas a possible molecular basis for epigenetic changes in somatic cell lines has led tothe suggestion that similar DNA modifications might also occur in the germ line,and thus influence gene expression in the next generation. Holliday (1987) hasdiscussed this possibility and explored the origin and consequences of defects inmethylation in both somatic and germ line cells. It is clear that epigenetic defectsresulting from methylation errors in somatic cells may be impor tant in cell transfor-mation and in ageing. Also, according to Holliday, epigenetic defects in germ linecells could be the reason for the morphological variation found within inbred strainsof mice, and for the high incidence of tumours in the offspring of mutagen-treatedparents.

    The clearest evidence that epigenetic characters can be transmitted through thegerm line comes from studies of genomic imprinting. It has been known for a longtime that the expression and transmission of a gene, a whole chromosome, or awhole set of chromosomes sometimes depends on the sex of the parent from whichit was inheri ted (reviewed in Monk, 1987; Marx, 1988). The genetic material inheritedfrom the male parent must differ in some way from that inherited from the femaleparent, i.e. the maternal and/or paternal chromatin must be "imprinted" (Crouse,1960) or modified in a way which reflects the sex of the parent and which resultsin differential expression of the two parental genomes in the offspring.

    In the following discussion we shall argue that genomic imprinting is a specialcase of inherited epigenetic variation. Using a model based on imprinting-likephenomena, we shall explore the evolutionary implications of the evidence thatepigenetic variations can be inherited. First, we shall show that it is possible tosuggest a plausible model of "Lamarckian" inheritance based on the inheritance ofepigenetic variations. According to this model, the relationship between an environ-mental stimulus and the heritable modification of a gene could be very specific andpredictable, and result in an adaptive response to the stimulus. However, we willshow that, although this type of Lamarckian inheritance may be quite widespreadin plants and in fungi, in the animal kingdom the opportunities for it to lead toadaptive changes are severely limited. Second, we shall show that the accumulationof inherited epigenetic variations may be important in speciation, since it could beinvolved in establishing reproductive isolation between populations. Finally, wesuggest that heritable epigenetic variations may alter the frequency of classicalmutations and meiotic recombination, and hence will affect the rate and directionof evolutionary change in another, indirect, way.

    The Inheri tance of Functional States in Cel l LineagesDuring embryogenesis, cells undergo a hierarchical series of changes which make

    them progressively more specialized until they reach a determined state which isusually very stable. Little is known about the developmental cues which providethe positional and temporal information necessary to initiate the events leading todetermined and differentiated states. It is clear, however, that the transmission ofthese states in cell lineages is frequently independent of the stimulus initiallyresponsible for inducing them. For example, many years ago Hadorn (1978) showed

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    INHERITANCE OF ACQUIRED VARIATIONS 71that imaginal disc cells from third instar larvae of D r o s o p h i l a could be cultured inthe abdomen of adult females for over a thousand cell generations, and still retaintheir original determined state.

    Although the details of the molecular events underlying heritable changes in thecapacity of genes to be transcribed are not known, usually base sequence changesare not involved. Rather, what seems to change is chromatin structure and conforma-tion; it is t h e g e n e ' s p h e n o t y p e which determines its functional state. The structureof actively transcribed genes can differ from that of non-transcribed regions ofchromat in in several ways. The features associated with active, or potentially active,genes include increased general sensitivity to DNase-I and other endonucleases,the presence of HMG (high-mobility group) and other non-histone proteins,modification of histones by ubiquitination, ace tylation or phosphorylation , replace-ment of one histone variant by another, undermethylation of cytosines, and thepresence of sites which are hypersensitive to DNase-I (reviewed in Reeves, 1984;Eissenberg et al . , 1985; Gross & Garrard, 1988). Exactly how these features arerelated to gene expression and to each other is not fully understood. At least someof them are stably transmitted through many rounds of cell division. In the case ofcytosine methylation, the way in which the pattern of methylation can be passedon to daughter cells is fairly clear. In many eukaryotes, the cytosines which aremethylated are found in CpG doublets or CpNpG triplets. Following replicationof methylated sites, a methyl transferase recognises the hemimethylated sites andmethylates the cytosine of the new strand of the DNA duplex. Since the enzymecatalyses methylation preferential ly at sites at which one strand is already methylated,it ensures the heritability of DNA methylation patterns (Holliday, 1987).

    Methylation patterns are not the only aspect of the gene's phenotype which canbe transmitted to daughter cells. Patterns of DNase-I hypersensitive sites are alsoclonally inherited, and plausible models for the way in which these sites and otherchromatin modifications can be propagated have been proposed (Groudine &Weintraub, 1982; Alberts et al . , 1977; Brown, 1984).

    E n v i r o n m e n t a l S t i m u l i a n d t h e G e n e ' s P h e n o t y p eIn recent years, it has been shown that genes whose functional activities change

    during development undergo progressive changes. The passage from an inactive toan active state seems to be a multistage process, rather than a simple switch. Becauseof this, terms like "inactive" or "active" genes are no longer satisfactory. "Inactivegene" is not an adequate description because it does not specify how many of thenecessary conditions for becoming transcriptionally active have yet to be satisfied.Similarly, the term "active gene" does not unequivocally describe the state of geneactivity, because a gene can be either stably or transiently active. Biologists nowtend to talk about "determined", "potentially expressible", "inducible", "express-ing", "non-expr essing", "repr essed" , "der epre ssed ", etc., states of genes (Weintraub,1985).In general, it is possible to distinguish two types of changes in response to astimulus. One is a v i s i b l e response which occurs when an already competent

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    72 E . J A B L O N K A A N D M . J . L A M Bc h r o m a t i n r e g i o n s w i t c h e s f r o m a s ta t e o f t r a n s c r i p t i o n a l i n a c t iv i t y t o a c t i v e t r a n s c r i p -t i o n , o r v i c e v e r s a . F o r e x a m p l e , s u c h a n " o f f - o n " re s p o n s e is s e e n in th e h e a t s h o c kg e n e s w h i c h v e r y r a p i d l y b e c o m e t r a n s c r i p t i o n a l l y a c t i v e f o l l o w i n g e x p o s u r e t os tr e ss c o n d i t i o n s ( C r a ig , 1 9 85 ). T h e s e c o n d t y p e o f r e s p o n s e i s c r y p t i c : t h e c o m -p e t e n c e a n d s t a b il it y o f t h e g e n e a r e c h a n g e d , b u t t h e r e i s n o c h a n g e i n i ts o v e r tf u n c t i o n a l s ta te . F o r e x a m p l e , i f t h e g e n e w a s s t a b l y i n a c ti v e , t h e s t i m u l u s d o e s n o ta c t i v a t e t h e g e n e , b u t m a k e s i t " e l i g i b l e " f o r a c t i v a t i o n b y t h e s a m e o r a n o t h e rs t i m u l u s a t a l a t e r s t a g e . A l t e r n a t i v e l y , t h e s t i m u l u s m a y c a u s e a n a l r e a d y i n a c t i v eg e n e t o b e c o m e m o r e s t a b l y i n a c t iv e , i.e . l es s p r o n e t o a c t iv a t i o n . A n e x a m p l e o f ac r y p t i c r e s p o n s e i s s e e n i n t h e a d u l t g l o b i n g e n e s d u r i n g d e v e l o p m e n t . A t a n e a rl yd e v e l o p m e n t a l s t a g e th e g e n e s a re i n a c t iv e a n d i n s e n s it i v e t o D N a s e - I ; t h e y t h e nb e c o m e D N a s e - I s e n s i t i v e ( s h o w i n g c o m p e t e n c e f o r o v e r t a c t i v i t y ) , a l t h o u g h s t i l li n a c t i v e ; a t a s t i l l l a t e r s t a g e t h e y b e c o m e t r a n s c r i p t i o n a l l y a c t i v e ( S t a l d e r , 1 9 8 0 ;G r o u d i n e & W e i n t r a u b , 1 98 1).

    F o r b o t h v i si b le a n d c r y p t i c re s p o n s e s , t h e r e i s e v i d e n c e t h a t t h e n e w e p i g e n e t i cs t at e o f th e g e n e c a n b e p r o p a g a t e d d u r i n g c el l d i v i si o n . I n t h is r e s p e c t e p i g e n e t i cc h a n g e s b r o u g h t a b o u t b y e n v i r o n m e n t a l st im u l i r e se m b l e D N A s e q u e n c e c h a n g e si n d u c e d b y a m u t a g e n i c a g e n t s . H o w e v e r , t h e r e a re i m p o r t a n t d i f f e re n c e s . T h e s ea r e s u m m a r i s e d i n T a b l e 1.

    T A B L E 1A comparison o f induced her i tab le ep igene tic modi f ica t ions and induced m uta t ions

    I n d u c e d h e r i t a b l e e p i g e n e t i cP r o p e rt y v a r i a ti o n I n d u c e d m u t a t i o n

    t y p e o f v a r i a ti o n d o e s n o t i n v o lv e D N A b a s e i n v o l ve s a c h a n g e i n D N A b a s es e q u e n c e c h a n g e s ; i n v o lv e s a s e q u e n c e

    f r e q u e n c y o f " ' f o r w a r d " v a r i a t i o n

    f r eq u e n c y o f " b a c k w a r d "v a r i a t i o nl o c u s a n d t i s s u e s p e c i f ic i t y

    a d a p t i v e n e s s o f t h e i n d u c e dr e s p o n s e

    t r a n s m i s s i o n t h r o u g h t h eg e r m l i n e

    c h a n g e i n c h r o m a t i n s t r u c t u r ew h i c h i s l i k e ly t o a f f e c t t r a n s c r i p -t i o n a l c o n t r o lv e r y w i d e r a n g e : u p t o 1 0 0 % p e rl o c u sv e r y w i d e r a n g e : u p t o 1 0 0 % p e rl o c u sm a y b e h i g h l y s p e c i fi c ; t h e p r o b a -b i l it y o f a s p e c if i c c h a n g e c o u l db e 1 0 0 % f o r t h e a p p r o p r i a t e g e n ei n t h e r e l e v a n t c e l l t y p e a t t h ea p p r o p r i a t e s t a g e o f d e v e l o p m e n tt h e m o d i f i c a t i o n m a y h a v e n o n -r a n d o m , a l t h o u g h n o t n e c e s sa r i lya d a p t i v e , b i o l o g i c a l s i g n i f i c a n c ed e p e n d s o n t h e n a t u r e o f r ep r o -g r a m m i n g p r oc e s s e s a n d o n t h ee f f i c i e n c y o f r e p a i r a n d c e l ls e l e c t i o n

    m o r e l i m i t e d r a n g e : < 1 0 - 4 p e rl o c u sm o r e l i m i t e d r a n g e : v e r y l o w

    t h e p r o b a b i l i t y o f a p a r t i c u l a rc h a n g e v a r i e s , b u t i s a l w a y se x t r e m e l y l o w

    n o c o n n e c t i o n b e t w e e n t h em o l e c u l a r e v e n t a n d i t s p o t e n -t i a l b i o l o g i c a l s i g n i f i c a n c ed e p e n d s o n t h e e f fi c ie n c y o fr e p a i r a n d c e l l s e l e c t i o n p r o -c e s s e s

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    I N H E R I T A N C E O F A C Q U I R E D V A R I A TI O N S 7 3A S i n d i c a t e d i n t h e T a b l e , m u t a t i o n s a r e u s u a l l y r a n d o m , w i th a n e w m u t a t i o n

    b e i n g u n r e l a t e d t o t h e s t i m u l u s i n d u c i n g i t . I n c o n t r a s t t o t h i s , e p i g e n e t i cm o d i f i c a t i o n s c a n b e e i t h e r r a n d o m o r d i r e c t e d . Random m o d i f i c a t i o n s a r e n o n -s p e c if i c b o t h w i t h r e g a r d t o t h e s ti m u l u s w h i c h i n d u c e s t h e m a n d t h e g e n e w h i c hi s m o d i f i e d . H o l l i d a y ( 1 9 8 5 , 1 9 8 7 ) h a s t e r m e d s u c h m o d i f i c a t i o n s " e p i m u t a t i o n s " .T y p i c a l l y , t h e f r e q u e n c y o f i n d u c t i o n a n d t h e f r e q u e n c y o f re v e r si o n o f e p i m u t a t i o n sa r e h i g h e r t h a n f o r c l as s ic a l m u t a t i o n s . T h e r e d u c t i o n i n t h e l ev e l o f D N A m e t h y l a -t i o n i n d u c e d b y 5 - a z a c y t i d i n e l e a d s t o th i s c la s s o f e p i g e n e t i c v a r i a t io n . T h i s c h e m i c a ld o e s n o t s p e c i f ic a l ly o r p r e f e r e n t i a l l y i n d u c e a c h a n g e i n t h e m e t h y l a t i o n o f ap a r t i c u l a r g e n e , b u t r a t h e r i n d u c e s a g e n o m e - w i d e r e d u c t i o n i n t h e le v el o f D N Am e t h y l a t i o n ; e a c h g e n e w i t h i n a w i d e c a t e g o r y o f g e n e s w h o s e e x p r e s s i o n is r e g u l a t e db y D N A m e t h y l a t i o n h a s a c e rt a in , a n d s o m e t i m e s s u b s ta n t ia l , p r o b a b i l i ty o f b e i n ga c t i v a t e d ( J o n e s , 1 9 8 5 ) . Direc ted e p i g e n e t ic v a r ia t i o n s a re t h o s e p r o d u c e d w h e n t h es t i m u l u s a f f e c t s a s p e c i f i c g e n e i n a p a r t i c u l a r c e l l t y p e a t a p a r t i c u l a r s t a g e o fd e v e l o p m e n t . T h e s t i m u l u s h a s n o c o n s i s t e n t e f fe c t o n o t h e r g e n e s , o r o n t h e s a m eg e n e i n a d i f f e r e n t t i ss u e o r a t a d i f fe r e n t d e v e l o p m e n t a l s t a g e . T h i s c la s s o f e p i g e n e t i cm o d i f ic a t i o n m a y b e i n v o l v e d i n t h e p r o d u c t i o n o f p h e n o c o p i e s , i .e . e n v i r o n m e n t a l l yi n d u c e d p h e n o t y p i c c h a n g e s w h i c h m i m i c t h o s e p r o d u c e d b y c la s si ca l m u t a t io n s .F o r e x a m p l e , i n Drosophila, e t h e r t r e a t m e n t o f v e r y e a rl y e m b r y o s l e a d s t op h e n o c o p i e s o f b i t h o r a x ( W a d d i n g t o n , 1 95 6; C a p d e v i l a & G a r c i a - B e l l i d o , 1 97 4 ).A l t h o u g h m o s t o f t h e d e t e c t a b l e d i re c t e d m o d i f ic a t i o n s w h i c h a r e i n d u c e d e x p e r i-m e n t a l l y a re l i k e ly t o b e d e t r i m e n t a l , t h e r e a r e m a n y e x a m p l e s o f d i r e c t e dm o d i f i c a t io n s w h i c h a r e a d a p t i v e : t h e i n d u c e d m o d i f i c a ti o n i s a d v a n t a g e o u s t o t h ec e ll o r to t h e w h o l e o r g a n i s m b e c a u s e i t is p a r t o f t h e n o r m a l d e v e l o p m e n t a lp r o g r a m m e . F o r e x a m p l e , n u c l e a s e h y p e r s e n s i t i v e s i t e s w h i c h a r e i n d u c e d i n t h ec h i c k e n v i t e l l o g e n i n g e n e b y o e s t r o g e n a n d w h i c h a r e p e r p e t u a t e d i n t h e ce ll l i n e a g ee v e n w h e n t h e h o r m o n e is w i t h d r a w n ( B u t c h & W e i n t r a u b , 1 9 83 ), ar e d i r e c te dm o d i f ic a t i o n s o f c h r o m a t i n s t ru c t u r e w h i c h a r e o f a d a p t i v e i m p o r t a n c e .

    E p i g e n e t i c V a r i a t i o n s i n t h e G e r m L i n e a n d G a m e t e sI n o r d e r f o r a n a c q u i r e d e p i g e n e t i c v a r i a t i o n t o b e t r a n s m i t t e d t o d e s c e n d a n t s , i t

    is n e c e s s a r y f o r t h e v a r i a t i o n t o b e p r e s e n t i n th e g e r m l in e a n d e v e n t u a l l y in t h eg a m e t e s . W h e t h e r o r n o t t h i s i s s o w i l l d e p e n d o n t h r e e p r i n c i p a l f a c t o r s : ( i ) t h eo c c u r r e n c e a n d t im i n g o f t h e s e g re g a t io n b e t w e e n t h e g e rm l in e a n d s o m a d u r i n gd e v e l o p m e n t ; ( ii ) t h e f r e q u e n c y o f e p i g e n e t i c v a r i a t i o n s i n g e r m l i n e c e ll s, o r inc e ll s t h a t c a n c o n t r i b u t e t o t h e g e r m l i n e ; ( ii i) th e f r e q u e n c y o f " r e v e r s i o n " , w h i c hw il l d e p e n d o n t h e a c c u r a c y o f t h e c o p y i n g s y s te m , o n t h e n a t u r e o f r e p r o g r a m m i n ga n d d e d i f f e r e n t i a t i o n p r o c e s s e s , a n d o n t h e e f fi c i en c y o f a n y r e p a i r a n d c e ll se l e c t i o nm e c h a n i s m s .

    ( 1) T H E S E G R E G A T I O N O F S O M A A N D G E R M L I N EF o r b o t h e p i g e n e t i c v a r i a t i o n s a n d c l a ss i ca l m u t a t i o n s , t h e l i k e l i h o o d o f t r a n s -

    m i s s i o n is a f f e c te d b y t h e ti m e a t w h i c h t h e " d e v e l o p m e n t a l b a r r i e r " s e p a r a t i n g

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    7 4 E . J A B L O N K A A N D M . J . L A M Bs o m a t i c a n d g e r m l in e c e ll s is e s ta b l i s h e d , a n d i ts s ta b i li ty . T h e e a r l i e r in d e v e l o p m e n ti t o c c u r s , a n d t h e m o r e i r r e v e r s i b l e i t i s , t h e s m a l l e r t h e c h a n c e t h a t n e w v a r i a t i o n sw i ll b e p r e s e n t i n th e g e r m l in e . T h e t i m i n g a n d r e v e r si b i li t y o f g e r m l i n e - - s o m as e g r e g a t i o n i s d i f f e r e n t f o r d i f f e r e n t o r g a n i s m s ( B u s s , 1 9 83 , 1 98 7 ). I n o r g a n i s m sw i t h o u t a d i s t i n c t g e r m l i n e , g e r m c e l l s c a n d e v e l o p f r o m s o m a t i c s t e m c e l l s .T h e r e f o r e , i f t h e g e n e s o f th e s e " s o m a t i c " c e l ls h a v e b e e n e p i g e n e t i c a l l y m o d i f i e d ,t h e m o d i f i c a t i o n c a n , in t h e o r y , b e t ra n s m i t t e d t o t h e g e r m l i n e a n d t o t h e o r g a n i s m ' sd e s c e n d a n t s . T h e t i m i n g a n d r e v e r si b i li t y o f g e r m l i n e s e g r e g a t io n is o f p a r t i c u l a rr e l ev a n c e w h e n c o n s i d e r i n g w h a t w e h a v e t e r m e d d i r e c t e d m o d i f i c a t io n s . A d i r e c t e dm o d i f i c a t i o n i s , b y d e f i n i t i o n , l i m i t e d t o a p a r t i c u l a r c e l l t y p e a n d p a r t i c u l a r t i m e ,s o i t s t r a n s m i s s i o n t o d e s c e n d a n t s w i l l d e p e n d o n w h e t h e r t h a t c e l l t y p e c a nc o n t r i b u t e to t h e g e r m l i ne . In m a n y a n i m a l g r o u p s , i n c l u d i n g t h e m a m m a l s , g e r ml i n e - - s o m a s e g r e g a t i o n o c c u r s e a r l y i n d e v e l o p m e n t a n d s e e m s t o b e i rr e v e rs i b le .I n s u c h g r o u p s , o n l y c h a n g e s o c c u r r i n g b e f o r e s e g r e g a t i o n , o r t h o s e o c c u r r i n g int h e g e r m l i n e i t s e l f , c a n b e p a s s e d o n t o d e s c e n d a n t s . O n t h e o t h e r h a n d , i n p l a n t s ,f u n g i a n d p r o t i s t s , w h e r e t h e d e v e l o p m e n t a l b a r r i e r d o e s n o t e x i s t , d i r e c t e d a n da d a p t w e v a r i a t i o n s a f fe c t i n g s o m a t i c s t em c e ll f u n c t i o n s c o u l d b e r e p r e s e n t e d i nt h e g e r m l i ne f a ir l y f r e q u e n t l y , a n d h e n c e c o u l d b e o f c o n s i d e r a b l e e v o l u t i o n a r ys i g n i f i c a n c e .

    ( 2 ) T H E F R E Q U E N C Y O F E N V I R O N M E N T A L L Y I N D U C E D E P I G E N E T I C V A R I A T I O N S I NG E R M L I N E C E L L S

    I f t h e e p i g e n e t i c c h a n g e i n d u c e d i n t h e g e r m l in e is a r a n d o m m o d i f i c a t i o n , t h ep r o b a b i l i ty o f i ts o c c u r r e n c e w i ll d e p e n d o n t h e p o t e n c y o f th e i n d u c i n g a g e n t. F o rs o m a t i c c el ls , i t is k n o w n t h a t 5 - a z a c y t i d i n e c a n c a u s e a 3 0 % r e d u c t i o n i n t h e l e ve lo f to t a l g e n o m i c m e t h y l a t i o n ( R a z in e t a l . , 1 9 8 4 ) ; s i l e n t g e n e s a r e r e a c t i v a t e d i n0 . 1 - 3 0 % o f s u r v iv i n g ce l ls ( C o m p e r e & P a l m i t e r , 1 9 81 ; H o r s - C a y l a e t a l . , 1983;K o n i e c z n y & E m e r s o n , 1 9 84 ; H a r r i s, 1 9 8 6 ). U n f o r t u n a t e l y t h e f r e q u e n c y o f a c t iv a -t i o n o r r e p r e s s i o n o f g e n e s i n g e r m l i n e c e ll s b y 5 - a z a c y t i d i n e o r o t h e r a g e n t s i su n k n o w n . F o r a d i r e c t e d m o d i f i c a t i o n , a n i n d u c e r c o u l d , b u t n e e d n o t , a f f e c t 1 0 0 %o f th e g e r m l i n e c el ls . T h u s , i n a n e x t r e m e c a s e , t h e f u n c t i o n a l s t a t e o f a p a r t i c u l a rg e n e c o u l d b e a l t e r e d i n e v e r y g e r m l in e c e il .

    ( 3 ) T H E F R E Q U E N C Y O F " ' R E V E R S I O N " I N G E R M L I N E C E L L ST h e a c c u r a c y o f t h e m e c h a n i s m s r e s p o n s ib l e f o r p r o p a g a t i n g a g e n e ' s p h e n o t y p e

    i n t h e g e r m l i n e i s n o t k n o w n . F o r D N A m e t h y l a t i o n i n s o m a t i c c e l l s i n c u l t u r e ,t h e a c c u r a c y o f c o p y i n g m a y b e o v e r 9 9 % ( H a r l a n d , 1 9 82 ), a l t h o u g h s o m e s t u d ie ss u g g e s t a m o r e s u b s t a n t i a l d r i f t i n m e t h y l a t i o n p a t t e r n s ( S h m o o k l e r R e i s & G o l d s t e i n ,1 9 82 ; W i l s o n & J o n e s , 1 9 83 ). T h e r e i s s o m e e v i d e n c e t h a t m e t h y l a t i o n s t a b i l it yv a r i e s w i t h t h e s i t e , w i t h c r i t i c a l s i t e s b e i n g m o r e s t a b l e ( Y e n e t a l . , 1 9 8 6 ) . I n t h eg e r m l in e , t h e c h a n c e s o f t r an s m i s s io n a ls o d e p e n d o n t h e n a t u r e o f t h e r e p r o g r a m -m i n g p r o c e s se s w h i c h t a k e p l a c e d u r i n g g a m e t o g e n e s i s , o n t h e e f f i c ie n c y o f m e c h a n -i sm s w h i c h r e p a i r e p ig e n e t i c v a r i at i o n s w h i c h d e v i a t e f r o m s o m e r e c o g n i s e d " n o r m " ,

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    I N H E R I T A N C E O F A C Q U I R E D V A R I A T I O N S 75and on detection-elimination mechanisms which preferentially remove cells contain-ing epigenetic variants.

    The molecular mechanisms involved in the reprogramming processes which ensurethe tot ipotency of gametes are not fully understood. It seems likely that the changesin chromatin structure such as replacement of proteins (Grimes, 1986), changes inthe level of DNA methylation (Groudine & Conklin, 1985; Monk e t a l . , 1987;Sanford e t a l . , 1987), etc. which occur during gametogenesis, particularly duringspermatogenesis, play an important role in reprogramming. Since extensive changesin chromatin take place, it could be argued that these changes are likely to eraseinformat ion from previous stages which is encoded in the structure of chromatin.However, Groudine & Conklin (1985) have shown that this need not be so. Theyfound that in the chicken the chromatin structure of all genes in sperm is differentfrom that seen in somatic cells and spermatogonia, and that the general level ofDNA methylation is higher. Nevertheless, the DNA sequences within DNase-Ihypersensitive sites of constitutively expressed genes are marked in sperm by beingpreferentially undermethylated. Thus the undermethylated regions serve as "foot-prints" of the past DNase-I hypersensitive conformation, and could act as"blueprints" for the reconstitution of that conformation in early embryogenesis.Further evidence that blueprints of epigenetic information can be transmittedthrough the germ line comes from recent work by Silva & White (1988). They showedthat in some tissues the pattern of methylation differs at two allelic sites. Thisvariation, which is tissue specific, is inherited in a Mendelian fashion for at leastthree generations. However, in sperm the methylation pattern of these loci wasfound to be uniform and sperm-specific. Thus, the variation cannot be t ransmitteddirectly, but some blueprint of the methylat ion patterns must be established duringgametogenesis. Silva & White suggested that elements such as DNA binding proteinswhich segregate with the chromosomes during meiosis may serve as blueprints.Whatever the molecular nature of the blueprint mechanism, this work, like that ofGroudine & Conklin, shows clearly that, although epigenetic information is nottransmitted unaltered, some characteristics of its structure may be encoded in thechromatin of gametes.

    The role of repair and selection processes in eliminating epigenetic variants isunknown. It has been suggested that meiosis plays an important role in repairingboth defects in DNA (Bernstein, 1977; Martin, 1977) and epigenetic defects resultingfrom loss of methylation (Holliday, 1984). Although it seems highly likely thatmechanisms repairing, eliminating or compensating for epigenetic defects do exist,they are at present unknown, so their efficiency cannot be estimated. It is improbablethat they are perfect.

    Impr int ing and Impr int ing- l ike Inher i tance o f Epigene t i c Var ia t ionsThe evidence outlined above suggests that new, induced, chromatin modifications

    could persist during cell division in the germ line, could affect the restructuring ofchromatin at the reprogramming stage, and could be transmitted as new blueprintsto the next generation. However, in order for this phenomenon to have any evolution-

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    76 E. JAB LONK A AND M. J . LAMBary significance, we have to assume that the chromatin modifications are capableof influencing gene expression during the offspring's development, and that themodifications are transmitted by the offspring to future generations. Evidenceshowing that epigenetic characteristics are not only transmit ted via the gametes, butalso influence the expression o f genes in the offspring, comes from studies o f genomicimprinting. In animal groups as different as mammals and insects, it has been shownthat the genetic contributions of male and female parents are not equivalent: theexpression and transmission of a gene, a chromosome, or a set of chromosomessometimes depends on whether it was inherited from the male or the female parent(reviewed by Monk, 1987; Marx, 1988). The processes which establish the differencesbetween the maternally and paternally derived genetic contributions are known as"imprinting" (Crouse, 1960). The most plausible origin of the phenomenon is inthe differences in chromatin structure in male and female gametes, which areinevitable consequences of the different ways in which the chromatin is packagedin the sperm and egg (Hennig, 1986). At fertilization, the paternal and maternalchromosome sets have different conformations. The differences are normally erasedearly in development (Longo, 1987). However, when they persist for a longer time,phenotypic differences due to the parent-dependent functional state of specific genesor chromosomes become visible, and "parental genomic imprinting" is detected.

    It is not clear how widespread genomic imprinting is, but the diversity of groupsin which it has been found suggests that it may be quite common. In some dipteraand coccids, there is selective elimination or inactivation of the whole haploid setof chromosomes inherited from the male parent (Crouse, 1960; Brown & Chandra,1977). In mammals, in almost all somatic cells of marsupials (Cooper e t a L , 1971;Sharman, 1971) and in the extraembryonic tissues of eutherians (Takagi & Sasaki,1975), the paternally derived X-chromosome is preferentially inactivated. There isalso evidence of functional differences between maternally and paternally derivedautosomes: mouse embryos which inherit both copies of an autosome from a singleparent frequently do not complete development, and if they do, the phenotype ofindividuals inheriting both autosomes from their mother sometimes differs fromthat of those inheriting both from their father (Cattanach & Kirk, 1985; Cattanach,1986). Further evidence of imprinting in mammals comes from the fact that mouseembryos containing two male pronuclei or two female pronuclei do not developmuch beyond the implantation stage (McGrath & Solter, 1984; Surani e t a l . , 1984).What are known as "parental source effects" have long been recognized inD r o s o p h i l a : for example, the extent of position effect variegation, i.e. the mosaicphenotype observed in heterozygotes for some chromosomal rearrangements whichplace euchromatic genes near heterochromatin, depends on the sex of the parenttransmitting the rearrangement (Spofford, 1976). Recently, it has been suggestedthat the effects of imprinting can be seen in a number of human genetic diseaseswhose expression is influenced by the sex of the parent from which they wereinherited (Laird e t a l . , 1987; Reik e t a l . , 1987; Ridley e t a l . , 1988; Wilkins, 1988).

    Imprinting must involve parent-dependent chromatin modifications which arecapable of influencing gene expression in the offspring. Differential DNA methyla-tion may be one of the mechanisms involved (Holliday & Pugh, 1975; Riggs, 1975).Recently, attempts have been made to investigate the molecular nature of imprinting

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    I N H E R I T A N C E O F A C Q U I R E D V A R I A T I O N S 7 7b y u s in g t r a n s g e n i c m i c e . T h e s e s t u d ie s h a v e p r o v i d e d s t ro n g e v i d e n c e t h a t m e t h y l a -t i o n is i n v o l v e d i n s o m e c a s e s o f i m p r i n t i n g ( R e i k e t a l . , 1 9 8 7 ; S a p i e n z a e t a l . , 1 9 8 7 ;S w a i n e t a l . 1 9 8 7 ) . I n o n e s t u d y i t w a s f o u n d t h a t a t r a n s g e n e w a s e x p r e s s e d o n l yw h e n i n h e r i t e d f r o m t h e m a l e p a r e n t ; t h is m a l e - t r a n s m i t t e d t ra n s g e n e w a s u n d e r -m e t h y l a t e d c o m p a r e d w i t h th e m a t e r n a l l y t r a n s m i t t e d g e n e ( S w a in e t a l . , 1987) .

    I n t h e s t u d i es o f m e t h y l a t i o n o f tr a n s g e n e s c i t ed a b o v e , t h e p a t t e r n o f m e t h y l a t i o nw a s r e v e r s e d w h e n t h e t r a n s g e n e w a s t r a n s m i t t e d t h r o u g h t h e o p p o s i t e s ex . T h i s ise x p e c t e d i f m e t h y l a t i o n i s c a u s a l l y r e la t e d t o i m p r i n t i n g . A s o m e w h a t d i f fe r e n t , b u tw e b e li e v e i m p o r t a n t , o b s e r v a t i o n o f a n i m p r i n t in g - l ik e p h e n o m e n o n h a s b e e nd e s c r i b e d b y H a d c h o u e l e t a l . ( 1 98 7 ). T h e i r w o r k s h o w e d t h a t a tr a n s g e n e w h i c hw a s u n d e r m e t h y l a t e d a n d e x p r e s s e d w h e n p a t e r n a l l y t r a n s m i tt e d , b e c a m e i r r e v e r s i b l yr e p r e s se d a n d m o r e h i g h ly m e t h y l a t e d o n c e i t p a s s e d t h r o u g h a f e m a l e ; i t w a si n h e r i t e d i n t h is r e p r e s s e d s t a te f o r s e v e r a l g e n e r a t i o n s , i r r e s p e c t i v e o f t h e s e x o ft h e p a r e n t . T h e w o r k o f S i lv a & W h i t e ( 1 9 8 8 ) s h o w e d t h a t n o r m a l , d i f f e re n t i a l lym e t h y l a t e d , g e n e s c a n b e h a v e i n t h e s a m e w a y a s t h i s t r a n s g e n e , i . e . t h e p a r t i c u l a rm e t h y l a t i o n p a t t e r n o f a n a l le l e c an b e s t a b l y t r a n s m i t te d , i r re s p e c ti v e o f p a r e n t a ls e x . T h i s e v i d e n c e s h o w i n g t h a t e p i g e n e t i c v a r i a t i o n s c a n b e i n h e r i t e d is t h e b a s iso f o u r m o d e l f o r t h e i n h e r i t a n c e o f a c q u i r e d e p i g e n e t i c c h ar a c te r s . W e b e l i e v e t h a tg e n o m i c i m p r i n t in g , i n w h i c h t h e in h e r i t e d c h r o m a t i n m o d i f ic a t io n s d e p e n d o n t h es e x o f t h e p a r e n t , is a s p e c i a l c a s e o f a m o r e g e n e r a l p h e n o m e n o n i n w h i c h e p i g e n e t i ce v e n t s i n o n e g e n e r a t i o n m a y , u n d e r s o m e c i r c u m s t a n c e s , l e a v e a n i m p r e s s i o n , o rm a r k , o n t h e g e n e , w h i c h i n f lu e n c e s i ts a c ti v i ty in t h e n e x t g e n e r a t i o n . I n o r d e r t or e ta i n t h e t e rm " i m p r i n t " f o r a h e r it a b l e c h r o m a t i n m o d i f i c a ti o n w h i c h i s d e t e r m i n e db y t h e s e x o f t h e p a r e n t o f o ri g in , w e w ill u s e th e t e r m " m a r k " f o r a n y c h r o m a t i nm o d i f ic a t i o n w h i c h r e f l ec ts th e f u n c t i o n a l h i s t o r y o f th e g e n e o r c h r o m o s o m e r e g i o ni n t h e p r e v i o u s g e n e r a t i o n .

    T h e M o d e lT h e i n h e r i t a n c e o f a n a c q u i r e d e p i g e n e t i c v a ri a t io n r e q u ir e s th a t :

    ( i) A n e n v i r o n m e n t a l s t i m u l u s i n d u c e s a h e r i t a b l e c h a n g e i n a g e n e ' s p h e n o t y p e .( ii ) T h e s t i m u l u s a f f e c t s e i t h e r g e r m l i n e c e l ls , o r c e ll s w h i c h c a n c o n t r i b u t e t o

    t h e g e r m l i n e .( ii i) T h e c h a n g e i n t h e g e n e ' s p h e n o t y p e is t r a n s m i t t e d t o p r o g e n y .W e a s s u m e t h a t t h e n e w p h e n o t y p e o f t h e g e n e is n o t t r a n s m i t te d t o t h e n e x t

    g e n e r a t i o n u n a l t e r e d . R a t h e r , a s o c c u r s w i t h i m p r i n t i n g , t h e c h r o m a t i n v a r i a t i o n i st r a n s m i t t e d a s a c h a n g e d m a r k o n t h e g e n e i n t h e g a m e t e s . T h i s m a r k c a n i n f l u e n c et h e g e n e ' s e x p r e s s io n i n th e p r o g e n y . H o w e v e r , i n o r d e r f o r th e n e w v a r i a ti o n t oh a v e a n y e v o l u t i o n a r y s i g n if ic a n c e, th e p r o g e n y m u s t a ls o p r o p a g a t e t h e n e w m a r k ,i .e . i t m u s t b e t r a n s m i t t e d t h r o u g h t h e i r g e r m l i n e, b e p r e s e n t i n t h e i r g a m e t e s ,p a s s e d t o th e i r o f fs p ri n g , a n d s o o n . W h e n t h is o c c u r s , th e n e w p h e n o t y p e o f t h eg e n e , w h i c h w a s o r i g in a l l y i n d u c e d b y a n e n v i r o n m e n t a l s t i m u lu s , w i ll b e m a i n t a i n e di n t h e d e s c e n d a n t s w h e t h e r o r n o t t h e s t im u l u s is p r e s e n t . I n o t h e r w o r d s , t h ec h r o m a t i n v a r i a ti o n is s t i m u lu s i n d e p e n d e n t - - a n a c q u i re d c h a r a c t e r ha s b e c o m ei n h e r i t e d .

    N e w c h r o m a t i n v a r i a t i o n s a r e a l w a y s i n i t i a t e d i n g e r m l i n e o r p r e - g e r m l i n e ce l ls ,b u t o n c e t h e y a r e e s t a b l i s h e d i n t h e g e r m l i n e a g e , t h e i r e ff e c ts m a y b e s e e n e i t h e r

    this look so

    similar togeneticassimilation

    which is thedifference?

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    78 E. JABL ONKA AND M. J . LAM Bi n t h e g e r m l i n e i t s e l f , o r i n s o m a t i c c e l l s d e r i v e d f r o m t h e g e r m l i n e , o r i n b o t h .T h e c h a n g e i n t h e g e n e ' s p h e n o t y p e w i l l u s u a l l y r e s u l t i n a c h a n g e i n i t s t i m e o rm o d e o f e x p r e s s i o n . H o w e v e r , e v e n if t h e r e i s n o c h a n g e i n t h e a c ti v i ty o f t h e g e n ea s a r e su l t o f i ts a l t e r e d p h e n o t y p e , t h e n e w v a r i a t i o n c o u l d s ti ll b e o f f u n c t i o n a ls i g n i f i c a n c e s i n c e i t m i g h t m a k e t h e g e n e r e s p o n d t o o t h e r e n v i r o n m e n t a l c h a n g e sm o r e r e a d i l y th a n b e f o r e m o d i f ic a t io n .

    I n t h e o r y , t h e s t i m u l u s l e a d i n g t o a c h a n g e i n t h e g e n e ' s p h e n o t y p e c o u l d b e o fl i m i t e d d u r a t i o n ( e . g . a t e m p e r a t u r e s h o c k ) , o r p e r s i s t t h r o u g h o u t d e v e l o p m e n t ( e . g .a s u st a in e d c h a n g e i n e n v i r o n m e n t a l t e m p e r a t u r e ) . F u r t h e r m o r e , i t c o u l d o c c u r j u s to n c e , o r r e c u r in s e v e r a l g e n e r a t i o n s . A l t h o u g h a s in g l e s ti m u l u s c o u l d a f f ec tc h a r a c t e r s i n d e s c e n d a n t s , t h i s i s p r o b a b l y u n u s u a l , s i n c e s m a l l c h a n g e s i n a g e n e ' sp h e n o . : y p e m a y f a i l t o e s t a b l i s h a n o v e l m a r k i n g a m e t e s , o r m i g h t e s t a b l i s h a n e wm a r k w i t h n e u t r a l e f f e c t s. F o r t h i s r e a s o n , i t s e e m s l i k e l y t h a t a n u m b e r o f s m a l lc h a n g e s i n c h r o m a t i n s t r u c tu r e h a v e t o a c c u m u l a t e b e f o r e t h e c h r o m a t i n i s m o d i f i e ds u f f ic i e n tl y t o c r e a t e a n e w m a r k . T h i s w o u l d r e q u i r e a s u s t a i n e d o r r e c u r r i n ge n v i r o n m e n t a l c h a n g e . A n o t h e r r e a s o n f o r t h i n k i n g t h at p e r s is t e n t e n v i r o n m e n t a lc h a n g e s m a y b e n e c e s s a r y i s t h a t w i t h a s i n g le s t im u l u s , e v e n i f b o t h c o p i e s o f t h eg e n e i n t h e e x p o s e d i n d i v i d u a l a r e m o d i f i e d , it s o f f s p r i n g m a y c a r r y o n l y o n e c o p yo f t h e n e w m a r k . I n t h e g e r m l in e th is " h e t e r o z y g o u s " c o n d i t i o n c o u l d l e a d t o th eg e n e b e i n g d e t e c t e d a s d e v i a n t a n d b e i n g r e p a i r e d , o r it m i g h t e v e n s ig n a l t h ed e s t r u c t i o n o f t h e c e l l.

    T h e e v o l u t i o n a r y i m p o r t a n c e o f n e w e p i g e n e t i c v a r i a ti o n s i s t h r e e - fo l d : ( i)c h r o m a t i n m o d i f ic a t io n s w h i c h a r e t r a n s m i tt e d t o t h e p r o g e n y m a y d i r e c t ly af f ec tt h e t e m p o a n d m o d e o f a d a p t i v e e v o l u t i o n a n d s p e c i a t io n ; ( i i) c h r o m a t i nm o d i f i c a ti o n s in g e rm c el ls m a y h a v e n o n - r a n d o m e ff e ct s o n D N A b a s e s e q u e n c ec h a n g e s ; a n d ( ii i) s i n c e m o s t i n h e r i t e d e p i g e n e t i c v a r i a t i o n s a r e l i k e l y t o h a v ed e l e t e r i o u s e f f e ct s, s e l e c t io n w i ll s t r e n g t h e n s y s t e m s w h i c h m i n i m i z e t h e t r a n s m i s s i o no f i n d u c e d e p i g e n e t i c v a r i a n t s to t h e n e x t g e n e r a t i o n . S u c h s y s t e m s i n c l u d e t h o s ea f f e c ti n g t h e t im i n g a n d s t a b il i ty o f g e r m l i n e - s o m a s e g r e g a t i o n , a n d t h e r e p a i r a n de l i m i n a t i o n p r o c e s s e s o f th e g e r m l in e . T h e s e w e r e c o n s i d e r e d e a r l i e r in th i s p a p e r .I n t h e f o l lo w i n g s e c t io n s w e s h a ll d i sc u s s t h e m o r e d i r e c t e v o l u t i o n a r y c o n s e q u e n c e so f i n h e r i t e d e p i g e n e t i c m o d i f i c a t io n s .

    Adaptive Evolut ion and Speciat ionS i n c e s o m e e p i g e n e t i c v a r i a t i o n s m a y b e d i r e c t e d b y t h e e n v i r o n m e n t , t h e i r

    t r a n s m i ss i o n t o th e n e x t g e n e r a t i o n c a n r e s u lt in a t y p e o f " L a m a r c k i a n " i n h e r it a n c e :a h e r e d i t a r y c h a r a c t e r is t r a n s f o r m e d b y a n e n v i r o n m e n t a l s t i m u l us i n a n o n - r a n d o mw a y . D i r e c t e d h e r i t a b l e v a r i a t i o n s w i l l o c c u r i n t h o s e l o c i w h o s e a c t i v i t i e s c h a n g ei n r e s p o n s e t o c h a n g e s i n t h e e n v i r o n m e n t . T h i s m a y a f f e c t b o t h t h e d i r e c t i o n a n dr a t e o f e v o l u t i o n . L o c i i n v o l v e d i n t w o t y p e s o f p h y s i o l o g i c a l a d a p t a t i o n a r e l ik e l yt o s h o w L a m a r c k i a n i n h e r i t a n c e : ( i) lo c i c o n t r o l l i n g g l o b a l r e s p o n s e s s u c h a sa d a p t a t i o n s t o t e m p e r a t u r e o r s al in i ty , s in c e c h a n g e s i n su c h l o c i a f f e ct a l m o s t a l lc e ll t y p e s ; ( ii ) lo c i d e t e r m i n i n g g e r m l i n e - - s p e c i f i c a d a p t a t i o n s . S i n c e n e w e n v i r o n -m e n t s w i ll i n d u c e m o r e a n d d i f f e re n t c h r o m a t i n m o d i f i c a t i o n s , i n h e r i t e d e p i g e n e t i cc h a n g e s c o u l d c o n t r i b u t e t o r a p i d a d a p t a t i o n t o n e w n i c h e s .

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    I N H E R I T A N C E O F A C Q U I R E D V A R I A T I O N S 7 9Another consequence of epigenetic inheritance is that a variation can become

    fixed in a population fairly rapidly, even if it has no selective advantage. Thishappens because the same directed variation can occur in a number of unrelatedindividuals when the population encounters a new environment. In the case of aseverely detrimental epigenetic variant, if the stimulus is potent and continues forseveral generations, the result could be population extinction because all individualswould soon carry the new variation.

    The effects of a change in the phenotype of a gene will be influenced by the stagein development at which it is expressed. A change in a gene which is expressedearly in development is likely to have extensive detrimental effects and usually itwill be selectively eliminated. Nevertheless, on rare occasions, such a change couldcause alterations in the timing of determination and differentiation events whichwould lead to evolutionary innovations such as various types of heterochrony(Gould, 1977).

    Epigenetic changes in genes which are expressed in the germ line may haveparticularly important evolutionary consequences, because such genes are usuallyinvolved in determining fertility. The accumulation of modifications in these genesmay play an important role in speciation. Speciation involves the development ofreproductive isolation between populations. Frequently, hybrid sterility and hybridinviability, which reduce the success of interspecific crosses, are important isolatingmechanisms. It is possible, particularly in the early stages of divergence betweenpopulations, that such sterility and inviability are the consequences of epigeneticrather than genetic differences between incipient species. This can be illustrated byconsidering how epigenetic changes could be the basis of reproductive isolationbetween populations due to (i) sterility of one sex of the hybrids and (ii) sterilityof both sexes.

    (i) According to Haldane' s rule, if only one sex of the hybrids between two speciesis sterile, it is almost always the heterogametic sex (Haldane, 1922). There are two,probably related, reasons for thinking that epigenetic modifications may be involvedin this sex difference. The first is that in a least some species, imprinting seems tobe particularly marked for sex chromosomes. For example, inactivation of mam-malian X-chromosomes is influenced by their parental origin (Cooper e t a l . , 1971;Sharman, 1971; Takagi & Sasaki, 1975); in S c i a r a , the maternal and paternalX-chromosomes behave differently during embryogenesis and during male meiosis(Brown & Chandra, 1977). The second reason is that in groups in which the sexchromosomes are heteromorphic, the chromosomes in the heterogametic sex undergoextensive conformational changes during gametogenesis. When these conforma-tional changes are impaired, the result is a reduction in fertility or complete sterility(Jablonka & Lamb, 1988). The marked imprinting o f the sex chromosomes and therequirement for precisely regulated conformational changes in these chromosomesduring gametogenesis may mean that t he y are particularly sensitive to changes intheir chromatin conformation. If two populations have diverged and accumulatedepigenetic variations, then the sex chromosomes may not undergo the requiredconformational changes during gametogenesis in the heterogametic sex of hybrids.The resulting sterility may be analogous to the reduced fertility found in theheterogametic sex of many species when chromosome aberrations interfere with the

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    8 0 E . J A B L O N K A A N D M . J . L A M Bconformational changes that sex chromosomes normally undergo duringgametogenesis.

    (ii) In cases where both sexes of the hybrid progeny are sterile, sterility may bedue to the accumulation of epigenetic variations in germ line-specific genes. As wehave already pointed out, adaptive changes are likely to occur in germ line-specificgenes, and these genes probably play an important role in determining fertility. Afurther reason for the sterility of hybrids may be that chromatin restructuring isdefective in the cells of hybrids, and neither autosomes nor sex chromosomesundergo the correct conformational changes. This could result in germ cells beingunable to complete gametogenesis successfully.

    There is some evidence suggesting that chromatin structure does indeed differ inclosely related strains or species, and is involved in hybrid inviability. Crossesbetween some strains of the haplodiploid wasp M o r m o n i e l l a produce no, or few,diploid females. Even though sperm enter the eggs, the chromosomes of paternalorigin appear disorganized and are not incorporated into the zygote nucleus (Ryan& Saul, 1968). Consequently, most of these eggs develop as haploid males ratherthan diploid females. The chromatin from the male parent in these incompatiblestrains presumably carries different imprints from that of compatible strains.Differences in parental imprinting may also be responsible for the allelic repressionfound in hybrids from some interspecific crosses in birds and fish (Castro-Sierra &Ohno, 1968, Whitt e t a l . , 1972). Although for some isozymes hybrids express bothalleles, for others only one of the parental alleles is expressed. We believe that theaccumulation of differences in chromatin structure such as are suggested by theseexamples may be important in speciation. Isolating mechanisms involving inheritedepigenetic differences may explain some of the cases where no significant geneticdivergence has been detected between non-interbreeding populations.

    Epigenetic Modifications and DNA Base Sequence ChangesThe way in which chromatin conformation affects DNA base sequence changes

    has not been explored in depth. However, the evidence outlined below suggests thatthe conformation of a chromosome region may influence the frequency of mutationand recombination in that region.

    ( 1 ) D N A R E P A I R A N D M U T A T I O NIn mammalian cells, the rate of repair of UV-induced damage is higher for actively

    transcribed genes than for inactive genes. It has been suggested that this may beassociated with the more open conformation of DNA in transcriptionally activeregions (Hanawal t, 1987). However, recent work showing that damage to thetranscribed strand of DNA is removed more rapidly than tha t to the non-transcribedstrand indicates that chromatin conformation is not the only factor involved (Mellone t a l . , 1987). Kennedy e t a l . ( 1 9 8 0 ) proposed that malignant transformat ion followingexposure of mouse cells to X-rays involves two steps, one of which is epigenetic.The first step occurs in most cells and involves a change in functional state whichis transmitted to daughter cells. This epigenetic change enhances the probability of

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    I N H E R I T A N C E O F A C Q U I R E D V A R I A T I O N S 81a second, probably mutational, change which results in transformation. Studies ofirradiated mice suggest that similar epigenetic modifications may be induced ingerm line cells and result in a high incidence of tumors in the progeny (Holliday,1987).Recent work by Cairns e t a l . (1988) has shown that some mutat ions in E . c o l i aredirected, i.e. in response to the selection agent, the bacteria mutate in ways whichenhance their own survival. In all the cases studied, the selection agent also partici-pated in the regulation of gene activity by altering the affinity of regulatory proteins.Therefore, the observed local increase in mutation frequency may have been causedby conformational changes influencing the action o f repair enzymes which introducemutations.

    ( 2) T R A N S P O S I T I O N A N D D N A M O D I F I C A T I O N I N P L A N T SSome transposable elements in maize undergo reversible changes in activity which

    have been shown to be correlated with changes in DNA methylation (Chandler &Walbot, 1986; Chomet e t a l . , 1987). In the cases reported, high levels of DNAmethylation were correlated with inability to transpose, whereas low levels wereassociated with the active transposing state. These alterations in the ability totranspose were transmitted through the germ line. McClintock (1984) suggested thatenvironmental stress may initiate transposition and thereby increase genetic variationand reshape the genome. If restructuring of the genome in response to stress doesoccur, it may be initiated by heritable epigenetic modifications (e.g. changes in DNAmethylation) of transposable and other genetic elements which enhance the normalrate of transposition and result in an increased frequency of base sequence changes(Wessler, 1988).

    Transposition is not the only genomic change in plants which appears to beincreased by stress (Walbot & Cullis, 1985). Heritable changes in the DNA contentand number of copies of certain genes have been found in some flax varieties aftergrowing the plants in a different environment for a single generat ion (Cullis, 1984).Cullis (1987) has suggested that chromatin structure rather than DNA sequence isimportant in determining which genes are affected.

    ( 3 ) M E I O T I C R E C O M B I N A T I O NIt has been known for many years that the frequency of recombination in

    heterochromatic regions of chromosomes is lower than that in euchromatin (Brown,1966). Heterochromatin and euchromatin refer to conformational states which canbe reversed (Hennig, 1986) and are associated with differences in the degree ofcondensa tion of the chromatin, differences in functional states, and differences inthe time of DNA replication (Comings, 1972). If changes in chromatin conformationare induced in the germ line, the frequency of recombination in the affected regionmay be changed.

    If the preceding arguments about the effects of chromatin structure on mutationand recombination are correct, they suggest an additional way in which heritableepigenetic variations can have evolutionary significance. If the extent of sequencevariation is partially determined by the gene's phenotype, it means that heritable

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    8 2 E . J A B L O N K A A N D M . J . L A M Be p i g e n e t i c v a r i a t i o n s c a n i n f l u e n c e t h e o p p o r t u n i t i e s f o r D a r w i n i a n s e l e c t i o n o fm u t a t i o n s w i th i n t he s a m e c h r o m o s o m e r e g io n .

    C o n c l u s i o n sO u r h y p o t h e s i s s u g g e s t s t h a t i n h e r i te d e p i g e n e t i c c h a n g e s i n th e s tr u c t u re o f

    c h r o m a t i n m a y p l a y a n i m p o r t a n t r o l e i n e v o l u t i o n . A c c o r d i n g t o t h e h y p o t h e s i s ,a c q u i r e d e p i g e n e t i c c h a r a c t e r s c a n b e i n h e r i t e d a n d a r e i n v o l v e d i n a d a p t i v e e v o l u -t io n a n d i n s p e c i a ti o n . J a c o b e x p r e s s e d a g en e r a l l y a c c e p t e d v i e w w h e n h e s a id :

    "For mod ern biolog y, there i s no m olecular mech anism enabl ing instruct ions from theenvironm ent to be imprinted into D N A directly , that is , wi thout the round abou t routeof natural se lect ion. Not that such a mechanism is theoret ical ly imposs ible . Simply i tdo es not exist" (Ja cob, 1982).T h e a r g u m e n t s w e h a v e p r e s e n t e d s u g g e s t t h a t t h i s v i e w m a y n o t b e e n t i r e ly c o r r ec t .

    Part o f this wo rk was supp orted by a grant from the Edelstein Cen ter to E va Jablonka.We thank Lia Ett inger, R aft Falk, John Ma ynard Smith and Sarah Sel ig for discuss ions andconstructive criticism o f the manuscript.R E F E R E N C E S

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