REVIEW ARTICLES Genetic Background of Phenotypic Variation

PROGRESS IN NATURAL SCIENCE Vol .17 , No .10 , October 2007

REVIEW ARTICLES

Genetic background of phenotypic variation

Zsolt Boldogköi ＊ (Department of Biology , Faculty of Medicine , University of Szeged , Somogyi Bela st .4 , H-6720 Szeged , Hungary)

Accepted on May 25 , 2007

Abstract A notew orthy featu re of the living w orld is its bew ildering variability .A key issue in several biological disciplines is the achievement of an understanding of the hereditary basis of this variability .Tw o opposing , but not necessarily irreconcilable conceptions at- tempt to explain the underlying mechanism .The gene function paradigm postulates that phenotypic variance is generated by the polymorphism in the coding sequences of genes.How ever , comparisons of a great number of homologous gene and protein sequences have revealed that they predominantly remained functionally conserved even across distantly related phylogenic taxa.Alternatively , the gene regulation paradigm assumes that differences in the cis-regulatory region of genes do account for phenotype variation w ithin species.An extension of this latter concept is that phenotypic variability is generated by the polymorphism in the overall gene expression profiles of gene netw orks. In other w ords, the activity of a particular gene is a system property determined both by the cis-regulatory sequences of the given genes and by the other genes of a gene network , w hose expressions vary among individuals, too .Novel proponents of gene function paradigm claim that functional genetic variance w ithin the coding sequences of regulatory genes is critical for the generation of morphological polymorphism .Note , however , that these developmental genes play direct regulatory roles in the con trol of gene expression .

Keywords: evolution, gene network, gene regulation, genetic variance, phenotype variation.

Diversity , the fundamental hallmark of living paradox , we have to decode the mechanism w hereby sy stem s, is m anifested at all levels of biological hier- the genetic blueprint co ntrols the development and archy , including nucleic acids , proteins , biochemical operation of phenotypic characters .It w as earlier be- and physiological processes, mo rphology and behav- lieved that phenoty pic poly morphism w as produced by ior .The anim al body plan is specified by the genetic the variance in the coding regions of genes , implying material in a very rigid manner that is , mo rphogene- that variations exist in the effectiveness or functions sis in most cases is hig hly resistant to environmental of pro teins .How ever , it w as show n that protein disturbance .Consequently , the polymorphism of function is highly conserved even across large evolu- morphological traits m ust be encoded by likew ise di- tionary distances[ 1] .In the past few years a broad verse genetic material .The major question that arises consensus has emerged that it is not the functions of is the o rigin of this genetic variatio n .The answer to proteins , but their expressions that vary among indi- this leads beyond our mere curiosity concerning an viduals in a population .This cis-regulatory poly mor- understanding of the principles of genetic organiza- phism model holds that phenotypic variance is gener- tion .Deciphering of the algorithm underlying the op- ated by the polymo rphism in the controlling regions of eration of genetic material will be , among others , a genes .This hypothesis is based on the observation central issue of future medicine .Insight into the ge- that genes exhibit ex tensive intraspecific allelic varia- netic basis of phenotypic variation among individuals tions in their regulatory sequences[ 2, 3] .Alternatively , w ill provide us w ith a better understanding of com- the trans-regulatory polymorphism model hypothe- plex diseases and a guiding principle fo r therapy de- sizes that phenotypic variation is generated by the sign , w hich will be especially important in individual- variance in the coding regions of DNA-binding protein centered healthcare in the not too far future .The genes (developmental transcription factor genes[ 4] ) theoretical clarification of the mechanism of evolution and protein-binding protein genes (components of cel- is strictly linked to this issue .Natural selection acts lular signaling pathw ay s[ 5] ).Further , the recently on traits and behaviors, while evolutionary changes discovered reg ulatory RNAs are supposed to play a proceed in DNA sequences .To resolve this apparent no t yet ascertained role as trans-acting facto rs in gene

＊ E-mail:boldog@sb4 .szote .u-szeged .hu 1120 www .tandf .co .uk/ journals Progress in N atural Science V ol.17 No .10 2007 regulation .Thus , it appears that variance in the ge- weight) used the same explanatory scheme ;these netic reg ulato ry machinery , rather than in the func- traits were reg arded as the sums of individual gene ef- tion of physiological genes , underlies phenoty pic vari- fects (polygenic inheritance).Conversely , it w as as- ation.The question is the relative ex tents to w hich sumed that each gene m ade a specific , quantifiable these tw o reg ulato ry mechanisms contribute to the contribution to a particular quantitative trait , and anatomical and physiological polymo rphism of organ- that genes exerted their effects independently of each isms .A further subject of debate is w hether intraspe- other .In other wo rds , in this Mendelian w orld it was cific pheno typic polymo rphism can be generated by considered that an allele was not only a necessary , but single gene variants (or equivalently , by the variance also a sufficient requirement fo r the determination of a in the simple sums of individual gene effects in the pheno type or a piece of phenotype .The work on case of polygenic traits in population genetics), o r model o rganisms including fruit fly , viruses and bac- w hether alternatively , it is produced by the variation teria that gave birth to molecular biology strengthened in gene netw orks (GNs).The classic M endelian- the earlier dogma of one gene , one phenotype of the M organian view holds that polymorphism in a single early Mendelians .In recent decades , molecular ge- gene alone can account for the variance of a certain neticists have contributed to this misconception , e .g . phenoty pic character .Acco rding to ano ther view , through the ways they named their genes on the basis phenoty pic variance is generated by the polymorphism on the phenotypic effects they cause if mutated (espe- in GNs , w hich is m ainly encoded in the cis-regulato- cially in the case of Drosophila).This semantic im- ry regions (CRSs)of GN components .Acco rding to precision has had an unfo rtunate effect on the percep- the gene network-based concepts, the expression of a tion of gene action :it has contributed to the belief particular gene is a system property in that it is deter- that the invariance observed between the mutation of mined not merely by the regulatory architecture of a gene and the resulting phenoty pe can be extrapolat- this gene , but also by the expression profiles of other ed as though the function of a gene is to ensure the members of a GN w hose regulatory sequences display no rmal function abolished by the mutation ;and that v ariation , too .Coding variance in transcription fac- pheno type is due to the ex clusive function of a partic- tors further increases gene ex pression polymorphism . ular gene .Although , this over-simplistic view is apparently contradictory to com mon sense , it served for 1 The genetic architecture of phenotype a long time not only as the research paradigm , but also as the conceptual basis of modern genetics and evo- For an understanding of how genes produce phe- lutionary biology .Even today , the aim in a consider- notypic variance in a population , w e first have to un- able proportion of genetic investigations is to find a derstand the machinery w hereby the pheno type itself correspondence between a pheno type and a particular is determined . gene .Tw o basic approaches can be distinguished :In fo rw ard genetic research random mutations induced in 1 .1 One gene , one phenoty pe or one piece of phe- the genome of a model organism are follow ed by at- notype —the view of the 20th century genetics tempts to identify the mutant gene accounting for the The brilliant experiments by G rego r Mendel altered phenotype .In contrast , reverse genetics seeks shed lig ht on some important aspects of the architec- to explore the function of a single gene by deleting it ture and inheritance of genetic material .Mendel or by altering its expression , w ith a subsequent search demonstrated that the hereditary material is com- fo r the phenoty pe obtained .In gain-of-function mod- prised of discrete entities (later called genes);each els of reverse genetics , a transgene is over-expressed trait in an individual is controlled by tw o hereditary by inserting it into an ectopic genomic location ;in factors , w hich can be either identical (homozygous) loss-of-function approaches , an endogenous gene is o r different (heterozyg ous);depending on their rela- knocked out via gene targeting , or its expression is tionship one v ariant of a gene (allele)can be domi- dow n-regulated by antisense blocking or is knocked nant over another variant (s)or recessive .Mendel dow n by RNA interference .The stereo typic conclu- utilized a pea system , where each allelic variant could sion of these studies is that the particular gene is re- be unambiguously correlated to a particular phenoty p- sponsible fo r the normal development of the pheno- ic character .This type of inheritance w as later con- ty pe altered by the genetic manipulation , w hich is the veyed as monogenic inheritance .The genetic determi- typical reductionist stance .Nevertheless , as yet no nation of quantitative traits (such as heig ht o r case has been demonstrated w here the lines of causali- Prog ress in Natural Science Vol.17 No .10 2007 www .tandf .co .uk/ journals 1121 ty could be mapped from a sing le gene to a phenotypic 1 .2 Interacting genes specify the phenotypes —the character .M olecular biological investigations , how- view of the post-genome era ever , have produced a huge number of data on the It w as developmental biologists who first ex plic- pleio tropic effects exerted by the modified gene func- itly declared that life is more complicated than a 1∶1 tion on the operation of other genes and o n epitasis , relationship betw een genoty pe and phenotype .In- the multifactorial determination of a trait or behav- [ 6 —8] stead , genes create products that interact w ith one ior .In the interpretation framew ork of reverse another and the environment in complex , hierarchical genetics , pleiotropy disturbs the pure effect of an ex- w ays , to establish phenotypes .The result of genetic amined gene on the pheno type presumed to be deter- interplay is the continuous remodeling of gene expres- mined by this gene .This interpretation is in most sion profiles during development (e .g ., in Ref . cases apparently erroneous.The extent of error de- [ 11] )and in the adult body .One gene affects several pends on how far the examined phenoty pe is from the pheno typic characters (pleio tropy), and the reverse is gene product in the hierarchy of regulation .In the also true :a phenotype is determined by several genes case of blood groups , the stringent correspondence (epistasis).From another aspect , a sing le gene af- between gene and the phenotype is acceptable since fects the expressions of several other genes o r , con- blood groups are distinguished on the basis of protein versely , the expression of a gene is determined by the v ariants , which are the products of genes .Similarly , effects of m any other genes .Thus , it is not sufficient if the phenotype is a direct biochemical function of a to investigate the expressions of individual genes protein , the direct relationship between genes and w ithout analy zing the expressions of o ther members phenoty pe could be co rrect .How ever , if we make a of a GN .Additionally , the expressions of genes are g reat jum p in the regulatory hierarchy and correlate a also influenced by o ther factors, including the envi- gene to , for example , a higher-order mental process ronment , the internal milieu , epigenetic mecha- such as depression[ 9] , or speech[ 10] , w e fall into the nisms , etc .Recent technical advances allow examina- trap of oversimplification in the interpretation of the tions of the ex pression profiles of a huge number of results obtained .Ablation of a gene function can genes at the same time .Structural genomics (large cause rearrangement of the ex pression profiles of oth- scale-DNA sequencing ), functional genomics (tran- scriptomics), pro teomics (protein chip arraying ), er genes to such an ex tent that it is impossible to un- and bioinformatics make it po tentially possible to map ravel the contribution of the given gene to a particular the mechanisms underlying genetic and phy siological phenoty pe from the muddled web of causes and ef- processes and to explore the machinery thereby these fects;which is due not only to the complexity , but molecular events give rise to phenotype .How ever , also to the epistatic and pleiotropic effects of interact- large-scale gene expression profiling techniques have ing genes .Alternatively , the phenotypic effect of a some limitations .First of all , raw expression data re- malfunctioned gene can be masked by compensatory veal only the co-occurrence of particular gene expres- mechanism s exerted by other genes (robustness). sion patterns , but do no t provide information on The major problem w ith the investigation attitude of causal relationships and regulato ry hierarchies .Sec- reductionist genetics is that it restricts its focus to the ondly , a change in transcription has a multifactorial effects of gene deletion on the structure and function background for which cis-sequence variation is only presupposed to be altered , and neg lects the interrelat- one of the facto rs . edness of this gene w ith other systems .This view has led to adverse long-term consequences in the research 2 The genetic basis of phenotype variation paradigm of modern genetics by generating a false fo- The term “phenotype” is used in tw o different cus of investigation and improper interpretations of senses:a particular trait , such as eye color , and a obtained results .Of course , most geneticists were certain variant of a trait , such as blue eye color .In aw are of the importance of the interactive nature of order to make a clear distinction between these tw o genes ;how ever , they neglected this situation for sev- meanings, w e use the term “ phenotype variant” for eral reasons , including the need for a simplistic ex- the latter case .While a gene obviously does not en- planatory framework and the unavailability of suitable code a phenoty pe , the one allele , one phenoty pe vari- techniques for the investigation of intricate genetic in- ant correlation is not necessarily incorrect , which does teractions . no t mean that the allele in question encodes the given 1122 www .tandf .co .uk/ journals Progress in N atural Science V ol.17 No .10 2007 phenoty pe variant .Instead , this relationship merely took place by means of the classic spontaneous muta- indicates their invariant co-occurrence .A specific al- tion/selection scheme .Nevertheless , there are some lele —pheno type variant correlation can be a conse- rare exam ples that lend support to the role of g radual quence of a lack of recognizable polymorphism in oth- adaptive changes in some kinds of phenotypic varia- er members of a GN , or the masking of genetic vari- tions .For instance , the affinity of hemoglobin to ance due to the robustness of a GN , or it may result oxygen in goose species living in high mountains is from the contribution of the particular gene to the higher than that of geese living at low er altitudes, phenoty pe sig nificantly ex ceeding the contributions of w hich indicates adaptatio n to poo rer oxygen con- the rest of the GN components .The question to be tent[ 14] .Ano ther ex ample is the additive effects of considered is the proportion of the phenotypes inherit- certain amino acid changes at critical sites of opsins, ed in this Mendelian-like fashion to those that do not w hich ex plain the red-green colo r vision in certain fit this scheme . species[ 15] .Further , it has been show n that mutations in the melanocortin-1 receptor gene are associat- 2 .1 The gene function paradig m —Coding variance ed with differential pigmentation in a w ide range of in physiological genes species[ 16] .How ever , these examples represent inter- It was earlier believed that the major , if not the specific differences .Other exceptions are the paralo- exclusive source of variability lies in the sequences of gous genes ;follow ing gene duplication , these may genes encoding physiological proteins , including en- find a novel “physiological niche” that they can fill by zy mes, structural pro teins, receptors, ion channels , co-opting new functions , although changing of regulation of new ly duplicated genes is much more com- etc .This concept w as fostered by the facts that genes [ 17] and proteins are functional units , and therefore must mon than their functional alterations .Other ex- have undergone positive selection events ;and that ceptions are genes that have acquired novel domains mutation of genes often results in characteristic phe- by exon duplication or exon shuffling .How ever , notypes.The questions to be answ ered are w hether these processes are only of macroevolutionary signifi- gene functions are still evolving today , or w hether cance and hardly ever , if at all contribute to the in- this process occurred in the early phase of life' s histo- traspecific variance w ithin species . ry and w as arrested a long time ago .It has been 2 .2 The gene regulation paradig m show n that a hig h deg ree of poly morphism exists in v arious enzy mes , w hich are called allelozy mes .Fo r 2 .2 .1 cis-regulatory polymorphism example , more than 50 genetic variants of human g lucose-6-phosphate dehy drogenase have already been The developmental program s of o rganisms as dif- described .However , the vast m ajority of allelic vari- ferent as fruit fly and human share a common set of ants fo r most genes in a population do not represent genes .What varies is the amount and the spatio-tem- functional poly morphism either .Defective genes are poral patterns of gene ex pression during development . exceptions , but they do not contribute to the adaptive Although , only sporadic data are av ailable at present , v ariation of a population ;in fact , they are subject to it appears that a large-scale functional polymo rphism purifying selection .Nonetheless , it is no t alw ays easy in gene regulation exists among individuals within to distinguish dy sfunctional alleles from normal gene species.For example , a recent analysis (see Ref . v ariants .As ano ther example , Schmid and Tautz[ 12] [ 18] ), w hich compared the upstream regions of sev- compared the sequences of several pro tein sequences eral genes of 4 inbred mouse strains, indicated exten- of three Drosophila species and found that the fly sive variance in the level and tissue-specificity of gene genomes harbor substantial propo rtions of genes with expression .Similarly , by analy zing the regulatory a very high divergence rate (one-third of the exam- segments of several genes of a fish species , a substan- ined genes w ere poly morphic), w hich led to the con- tial poly morphism has been found (see Ref .[ 19] )in clusion that this kind of variation could be a majo r both the regulato ry sequences and gene ex pression reservoir for the generation of evolutionary novel- levels among individuals .It has also been described ties[ 13] .Current sequence data however , do not sup- that cis-regulatory variation in MHC class II promot- po rt the existence of evolutionary processes that ers in both human and mouse is clearly more frequent w ould result in gradual improvements in gene func- than polymorphism in the coding regio ns of these tion (including the more efficient cataly tic function o r genes[ 19] .Extensive poly morphism has likewise been improved substrate specificity of a protein)w hich detected in the promoters of genes associated w ith im- Prog ress in Natural Science Vol.17 No .10 2007 www .tandf .co .uk/ journals 1123 mune defense[ 18] .Studies (see Ref .[ 21] )examining than that of those of longer repeats to convert these the regulato ry sequences of 313 hum an genes of 82 conformation variants to functio nal protein .An inter- unrelated individuals , detected a high variability in esting co rrelation has been observed[ 24] betw een the them .In another survey of regulatory poly morphism , 51 bp deletion in the repeat region of the Alx-4 gene Rockman and Wray likew ise reported a w idespread and the presence of an ex tra digit in the Great Py re- functional cis-regulatory variance in the human neese breed .They examined a five-toed Great Py re- genome[ 22] .They identified 140 ex perimentally vali- neese and found that it had a full complement of bases dated cis-regulatory polymorphisms , resulting in a in the Alx-4 gene , w hich w as considered verificatio n tw o-fold o r greater variation in transcription rate and of their hypothesis .However , dog is a special case [ 23] subsequent gene ex pression .Other studies ana- since dog breeds display sharply differing pheno types lyzed the diversity of proximal promo ter polymor- due to being artificially selected by man .Further in- phisms on a genome-w ide scale of fruit fly genes and vestig ations are needed to establish w hether tandem showed that they did no t differ between strains with repeat polymorphism in o ther genes is also correlated divergent gene ex pressio n .They concluded that the w ith phenoty pe variation in dogs , and w hether this trans sequences might cause differential gene ex pres- kind of poly morphism is common and behaves in a sion .The key question is w hether these trans effects similar manner in o ther species .Interestingly , tan- are caused by structural differences in regulatory dem repeat expansion and contraction occurs at genes o r by variation in the ex pressio n of other GN 100000 times higher frequency than point mutations. components, including regulatory genes .At the mo- In addition , due to the involvement of transcription ment , w e practically , have no data on the cis-reg ula- factors , this process can in principle , result in a sud- tory polymorphism of transcription factors and reg ula- den emergence of specific mo rphological fo rms during tory RNAs within species . speciation .

2 .2 .2 trans-regulatory polymo rphism —Coding (2)Variance in regulato ry RNAs .Recent inves- v ariance in reg ulato ry genes tigations show ed that the majority of mammalian genome is transcribed , commonly from bo th DNA (1 ) Coding variance in transcription facto r [ 26 , 27] genes.It has been recently conducted a comparative strands .Antisense reg ulatory RNAs are emerg- study[ 24] on 142 domestic dog s from 92 different ing as the key players in cellular regulation , taking on active roles in multiple regulatory lay ers .Until now breeds, and looked at 37 different tandem repeats in [ 28] 17 genes in each .The selected genes were develop- over 1000 micro (mi)RNAs has been described . mental transcription factors that play a role in the for- Micro RNAs can recognize mo re than one target mation of specific morphologies .Fifteen of the 17 genes , and a particular gene can be regulated by sev- genes proved to have multiple alleles varying in the eral miRNAs , therefore , a large number of the genes leng th of their repeats .A closer investigation of the appear to be under intricate control by these noncod- Runx-2 gene revealed that it is highly poly morphic ing messages .The type of regulation (degradation among breeds (it encodes 18 —20 glutamines and through RNA interference pathw ay or translational 12 —17 alanines).The Gln-to-Ala ratio in the alleles repression)by these noncoding RNAs is dependent on of this gene co rrelated with tw o craniofacial parame- the extent of homology between the mRNA and the ters :the length of the midface and the angle at w hich complementary miRNA .The structure of miRNAs [ 28] the nose bends .Three possible mechanism s have been w as found highly conserved betw een species . proposed in an attem pt to ex plain the im pact of repeat However , miRNAs are mainly discovered by compu- leng th on transcriptional activity[ 25] .Follow ing earli- tational means o n the basis of sequence homology er repo rts hinting that strings of glutamines drive (conservatio n), thus , it is possible that a much larger transcription w hile polyalanines repress it , it can be number of miRNAs exist with lower level of sequence hypo thesized that high polyGln/polyAla ratios imply conservation .Another surprising discovery is that a strong transcription . Another possibility is that large po rtion of mam malian genes are regulated by pathological polyAla expansions could induce mislocal- overlapping (cis-)antisense RNAs[ 29] .Due to their ization and ag gregation , w hich cannot be efficiently complementarity w ith the sense DNA strand (encod- resolved by chaperones .Finally , shorter polyAla re- ing m RNA)their structural variations is dependent peats may be associated w ith higher transcriptional on the sense strand variation .How ever , the splicing activity due to the higher efficiency of the chaperones pattern and the leng th of overlap betw een m RNAs 1124 www .tandf .co .uk/ journals Progress in N atural Science V ol.17 No .10 2007 and cis-antisense RNAs might vary within species . on the sy stem , allow ing it to buffer perturbations (developmental noise or mutations)and maintain a Although very little is know n of the variability in specific range of activity , often admitting changes in both the structure and the expression of these noncod- its components without altering its functionalities ;al- ing messages , it m ay be envisaged that accumulating ternatively , in specific circumstances this sy stem is data will lead to a fundamental revision of our percep- capable of major transitions from one state to ano ther tion of the global gene regulatory circuitry of an or- one , even in a single step .A GN possesses a hierar- g anism . chical structure in w hich the component genes exhibit varying deg rees of interconnectivity thereby co nfer- Together , physiological pro teins do not exhibit ring on the GN a scale-free topology[ 38] , w hich im- significant functional v ariation w ithin populations . plies the existence of “Hubs” (the most interconnect- Regulatory pro teins (and possibly no n-coding RNAs) ed genes)that might reg ulate and integ rate the global appear to be ex ceptions ;they m ay play an important expression of the GN .GNs are no t isolated entities; role in the generation of morphological polymorphism they crosstalk w ith and receive feedback from o ther w ithin species .This concept seemingly contradicts genetic pathw ays .Gene netw orks operate as mod- w ith the popular view , w hich holds that sex is origi- ules , display ing higher-o rder collective behavio r of the nated and maintained to produce genetic variation as a interacting genes .The poly morphism generated by defence mechanism against parasites .It is possible the GNs is dynamic in two senses :the genetic com- that , althoug h proteins are conserved in their func- position of a particular GN in a population undergoes tion , specific receptor proteins may vary in their re- continuous alteration due to the mixing of genetic ma- sponses to parasites (e .g .certain receptor configura- terial by sexual reproduction and in response to evolu- tions are not suitable for virus entry to cells). tionary fo rces ;further , genes exert their effects 2 .3 The gene netw ork paradigm through a series of dynamically reg ulated steps via a mutually interdependent interplay betw een the GN The modular arrangement of living systems is components.The expression profile of a particular typical at all levels of biological organizatio n .In a gene is multifacto rial , involving the architecture of its general sense , a “module” can be defined as a certain ow n cis-regulatory sequences (C RSs), the structure , type of dy namic pattern of couplings among the con- amount and spatiotemporal distribution of trans-reg- stituents of a process, w hich ex hibit a hig h density of ulatory elements (transcription factors and regulatory internal interactions and sparse connection to the RNAs)directly controlling gene expression , and the rest .The autonomous genetic modules are termed expression profiles of other components of GNs exert- v ariously :gene expression netw orks , regulatory net- ing their effects through multi-step feedback mecha- w orks , gene nets , gene networks, genetic pathways , nisms .Additionally , gene expression is dependent on transcriptional regulatory circuits , etc ., see Refs . the interplay w ith other GNs and the environment . [ 30 —35] .Gene netwo rks can be considered the key 2 .4 Epigenetic variation modules since they control the formation and operation of anatomical, biochemical , cellular and phy sio- Pheno type v ariation can also be produced w ith- logical sy stems , they are passed on from generation to out a poly morphism in the nucleotide sequence of generation , and they evolve .Furthermore , they are DNA .Alteration of epigenetic info rmation is mani- the most basic modules since they canno t dissect fur- fested in chromatin remodelling , which affects gene ther w ithout losing modularity .Gene netw orks are expression.The polymorphism of epigenome can be dynamic sy stem s:their compositions undergo contin- generated by both inherited and environmental fac- uous reorganization in response to the shuffling effect to rs .Genetic imprinting and maternal effect are of sexual reproductio n and to the nonstop alterations means thereby information is transmitted from par- in their overall expression profiles as a result of both ents to offspring , w hile epigenetic alterations during the interplay between the elements and the influence em bryogenesis leading to tissue differentiation are ge- of the internal milieu and environment[ 36] .A GN can netically prog rammed cascades of events w ithin the be regarded as a complex dy namic system that pos- body of an individual.In a recent article Frag a and sesses self-org anizing features since it contains control colleagues[ 39] examined the epigenetic differences be- mechanism s (positive and negative feedback loops). tw een a large coho rt of identical twins.The authors These mechanisms can confer a robust pheno type[ 37] found that , although the tw ins were epigenetically in- Prog ress in Natural Science Vol.17 No .10 2007 www .tandf .co .uk/ journals 1125 distinguishable during the early period of life , at older 4 Fondon JW and Garner HR.Molecular origins of rapid and contin- age twins exhibited significant differences in their uous morphological evolution .Proc Natl Acad S ci USA , 2004 , 101 :8053 —8058 DNA methylation and histone acetylation pattern . 5 O' Dushlaine CT , Edw ards RJ, Park SD, et al.Tandem repeat These findings signify the importance of epigenetic copy- number variation in protein-coding regions of human genes. processes in the generation of phenoty pe variation . 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