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Evolution of GenomeOrganizationWolfgang Stephan, University of Rochester, NewYork, USA

Several features of chromosomes, such as chromosome number, polyploidy and the

accumulation of repetitive DNA sequences near centromeres, reflect the evolutionary

forces acting on eukaryotic genomes.

Introduction

The purpose of this article is to review the populationprocesses that are likely to be most important in theevolution of genome organization and that have beenexplored theoretically by well-formulated models. Thepoint of view consistently adopted here is that mostevolutionary change at the genome level is the consequence

of changes of gene and chromosome frequencies in naturalpopulations, which result fromthe interaction of mutation,recombination, random genetic drift and natural selection.Some unconventional forces, such as meiotic drive andgene duplication, are also discussed. The role of recombi-nation in determining certain features of the genome, suchas chromosome number and the accumulation of repetitiveDNA near centromeres and telomeres, is particularlyemphasized. The question of why the genome is usuallysubstructured into multiple chromosomes will be dealtwith first. Then the evolution of special regions of theeukaryotic chromosome (i.e. centromeres and telomeres) isdiscussed, followed by the evolution of genome size, with

particular reference to gene duplication and polyploidiza-tion.

Evolutionary Forces AffectingChromosome Number

The number of chromosomes in a cell changes by at leasttwo processes: centric fusion and centric fission (White,1973). Centric fusion, in which two acrocentric chromo-

somes undergo a spontaneous translocation in the regionof their centromere, reduces chromosome number. Thisprocess produces a metacentric chromosome with twolarge arms. Subsequent pericentricinversions can convert alarge metacentric into an acrocentric chromosome. Evolu-tionary reduction in chromosome number due to centricfusions has been documented in both plants and animals(Stebbins, 1971; White, 1973). The converse process,centric fission, increases chromosome number. Thisprocess is thought to be less common than centric fusion.

Which evolutionary forces influence the spread of centrifusions and fissions?

The importance of recombination

It has been suggested that natural selection favouring reduction in recombination will favour a centric fusiobetween two chromosomes, provided that there ar

suitable epistatic fitness interactions between loci on thchromosomes concerned, sufficiently strong to generatlinkage disequilibrium between unlinked genes (Charlesworth, 1985). On the other hand, selection for centrifissions could be generated by any mechanism leading tincreased recombination (Charlesworth, 1985). To betteunderstand these hypotheses, we will outline here threlevant parts of the theory of the evolution of recombination (reviewed in Otto and Michalakis, 1998) and theapply it to the evolution of chromosome number.

There is a large body of literature dealing with thpopulation genetics of systems in which a selectiopressure exists for reducing the rate of recombinatio

between loci. The case usually studied is that of a largerandom-mating, diploid population segregating for a paof loci with alleles A, a and B, b, respectively, which arunder the control of natural selection. In a constanenvironment, lower recombination rates usually evolvwhen the population is near an equilibrium (with respect tselection) and there is linkage disequilibrium between thespolymorphic loci. This is because parents who survive treproduce have a genotype that works under locaenvironmental conditions; tinkering with their offspringgenotypes by recombination risks making the situatioworse, with little chance of making it better. If epistatifitness interactions between polymorphic loci are a wide

spread phenomenon, it seems likely that the mechanismoutlined above would favour genomes in which recombnation is virtually absent. This is not the case, howeverConsequently, a good deal of effort has been put into thinvestigation of theoretical models that generate selectiofor increased recombination.

Increased recombination can evolve in a large population experiencing positive directional selection for beneficial mutations (so that the population is far fromequilibrium), but only if epistasis between loci is negativ

Article Contents

Secondary article

. Introduction

. Evolutionary Forces Affecting Chromosome Number

. Chromosome Architecture and Evolutionary Trends

in Specific Chromosomal Regions

. Evolution of Genome Size (Gene Number)

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(that is, when the fitness effects of different loci contribut-ing to a phenotypic trait are less than additive) and if thisepistasis is not too strong. For increased recombination toevolve, relatively weak negative epistasis is also needed inthe case of purifying (negative) selection against deleter-ious mutations. In smaller populations, in which randomgenetic drift plays an important role, recombination may

be favoured in situations in which it protects rarebeneficial alleles from loss due to drift. Recent results onthe effect of recombination on the fate of new beneficialalleles are particularly important in this context. Theaverage probability of fixation of a new beneficial allele israised by recombination as long as there is genetic variancefor fitness at other loci. This occurs because, with tightlinkage between fitness loci, selection acts on thelevel of thehaplotype and therefore the dynamics of a beneficial allelewill be governed more by the genomic background onwhich it arises and less by its own selective advantage. Withloose linkage, however, selection at the locus itself becomesmore important and drowns out the noise caused by

selection at other loci.Furthermore, increased recombination rates may be

favoured in temporally fluctuating environments. Ifconditions change from time to time in such a way thatthe combinations of genes favoured by selection varyacross generations, it is reasonable to suppose thatincreased recombination will facilitate the passage of thepopulation into a newstate when the environment changes.However, under fluctuating selection, the conditions forincreased recombination to evolve appear to be morerestrictive than under directional selection. As the direc-tion of selection changes, selection weakens relative to thestrength of epistatic interactions, reducing the advantage

of recombination.These models enable the strength of selection on

chromosome number to be studied. A centric fusionbetween two chromosomes of equal length behavesformally as a dominant gene that reduces the frequencyof crossing-over between pairs of loci that were formerlylocated on two different chromosomes; a fission behaveslike a recessive gene increasing recombination (Charles-worth, 1985). Calculations (based on models with negativeepistasis) suggest that centric fusions are weakly selectedagainst (Charlesworth, 1990), particularly in systems withlarge chromosome numbers, so that the effects of selectionare probably overcome by random genetic drift. This may

explain why centricfusions are a major mode of karyotypicevolution in a variety of taxonomic groups (White, 1973).

The effects of random genetic drift

In small populations, chromosome rearrangements, suchas centric fusions or fissions, may rise in frequency and besubsequently fixed by random genetic drift. The problem iscomplicated by the fact that most chromosome rearrange-

ments cause a loss of fertility when heterozygous, owing tthe production of unbalanced gametes as a result odisturbances to normal segregation. Since a new mutatioin a random-mating population is present predominantlin heterozygotes, the chance is small that a rearrangemenassociated with such fertility loss can rise to high frequencin a local population, except with very restricted popula

tion size. Migration between populations lowers thchance of establishment of new arrangements within local population but increases the rate at which they caspread through the species. The most favourable population structure for rapid chromosomal evolution by thmechanism is when there is a high degree of subdivisiointo small, partially isolated populations, with a high ratof extinction and recolonization from adjacent areas. As result of the recolonization process, there is a finite chancthat, at some future date, each local population will bdescended from just one of the populations present in given generation, by analogy with the process of randomfixation of genes by drift in a single population. A

alternative pathway is the origination of a newspecies froma small isolated population; if the isolate becomes fixed foa new arrangement, this will obviously come to characterize the whole species (Charlesworth, 1985).

It seems likely that this process of random fixation ochromosomal rearrangements has played a major role ithe alteration of chromosome number by centric fusions ofissions. The apparent preponderance of fusions ovefissions in many taxonomic groups could be explained bthe greater ease with which fusions originate by mutatio(White, 1973). Inbreeding may play an important role ithis process. Extreme inbreeding, such as self-fertilizationwill accelerate this mode of chromosome evolution, sinc

fewer heterozygotes occur. This may explain why derivedself-fertilizing plant taxa have generally smaller chromosome numbers than their more outcrossing ancestor(Charlesworth, 1985). However, it should be noted thaselective factors influencing recombination and chromosome numbers may also be affected by inbreedingAssociations between inbreeding and rapid karyotypevolution do not, therefore, constitute strong evidence fothe role of random genetic drift.

The effects of meiotic drive

A completely different mechanism that can promote thspread of chromosome rearrangements is meiotic driveExamples of cytologically detectable chromosome changethat are associated with meiotic drive are known in variety of plants and animals. It has been suggested thameiotic drive can fix deleterious chromosome rearrangements in organisms with moderate population size (King1993), but the overall importance of this process in causinspecies differences is not clear. Drive is, however, of majosignificance in maintaining supernumerary chromosome

Evolution of Genome Organization

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These chromosomes are usually heterochromatic, withdeleterious effects on the fitness of their carriers, and arenot homologous with members of the normal complement.They display a variety of drive mechanisms by which theycan maintain their presence in populations despite counter-selection at the individual level.

Chromosome Architecture andEvolutionary Trends in SpecificChromosomal Regions

In this section, we discuss some evolutionary hypotheses toaccount for two major features of the genetic andmolecular evolution of the chromosomes of eukaryotes.The first such feature is the reduced frequency ofrecombination in the neighbourhood of centromeres andtelomeres. A lowered probability of genetic exchange in

meiosis in the centromere region has been most clearlydocumented in Drosophila melanogaster, but a relativecontraction of the genetic map near centromeres isobservable also in several other well-studied organisms,such as tomatoes. The situation in the telomere regions isless clear, but a reduction of meiotic recombination hasbeen found in many organisms. It has been suggested thatthis reduction in crossing-over frequencies is the conse-quence of natural selection for a lower frequency ofunequal exchange between repeated sequences of func-tional significance that are located in these chromosomalregions. The other phenomenon that we will discuss is thetendency for highly repeated DNA sequences of no

apparent functional significance (satellite DNA) and oftransposable elements to accumulate in regions of re-stricted crossing-over (Charlesworth et al., 1986).

Restricted crossing-over near centromeresand telomeres

The structure of centromeres of eukaryotes with very smallchromosomes, suchas yeast, is apparently very simple. Theyeast centromere lacks an identifiable structure such as thekinetochore, and each chromosome is attached to a singlemicrotubule. In contrast, the chromosomes of mammalsand most other higher eukaryotes possess a highly

differentiated kinetochore, through which many micro-tubules attach to a large stretch of specialized chromatin.Although very small chromosomes often show differen-tiated kinetochores, it is usuallythe casethat chromosomeswithout differentiated kinetochores are small (e.g. thechromosomes of Physarum, various yeasts, Neurosporaand the microchromosomes of birds). It is likely that thedisjunction of large chromosomes requires a greater forcethan is necessary for small chromosomes; hence, moremicrotubules per chromosomes are needed. The evolution

of larger chromosomes presumably led to the multitubulspindle fibre and to multiple centromeric microtubulebinding sites (Charlesworth et al., 1986).

Unequal exchange between these repeated sites woullead to variation in the number of binding sites pechromosome. Chromosomes with a number that deviatefrom the optimum may suffer an imbalance of spindl

forces at disjunction, leading to nondisjunction events ananeuploidy, with a consequentreductionin fitness.Naturaselection will therefore favour a reduction in crossing-ovein the centromere region. If the kinetochore found at thcentromere of most animal chromosomes is organizearound an optimal number of microtubule-binding sitethen it is not surprising from the above considerations thacrossing-over is restricted in these regions. The onloptimum number of binding sites that would not favouthe evolution of restricted recombination would be one. Iis interesting to note that yeast has only one binding sitand does not exhibit a centromeric reduction in crossingover comparable in magnitude to that of Drosophila.

There is now clear molecular evidence for the presence ospecialized tandemly repeated sequences in the telomerregions of most species. If there were an optimum numbeof repeats for efficient telomeric replication, the argumenused above for centromeres would apply, and reducerecombination in the telomeric regions would be favoureby natural selection. There is, however, clear evidence thathe size of the block of telomeric repeats is under thcontrol of replicative mechanisms. This probably reduceany effect of unequal exchange on the number of copies othe repeats. In Drosophila, however, restricted recombination near telomeres may be favoured by selection. Icontrast to most organisms, the proper replication o

Drosophila telomeres is ensured by transposable elementhat insert preferentially at the ends of chromosomeTherefore, there may be selective pressure in favour oreduced rates of crossing-over in telomeric regions tprotect these elements from removal by ectopic exchang(see below for more details).

Accumulation of repetitive DNA sequencesin regions of restricted recombination

It has been suggested that the association between highlrepeated DNA sequences, such as satellite arrays, an

regions of restricted crossing-overmay be a consequence oevolution rather than an inherent functional property othese sequences (Charlesworth et al., 1986). This hypothesis is based on a population genetic model thaincorporates the following processes: amplification, describing a sudden increase in array length by one or morrepeat units; unequal exchange between tandem arrays ohomologous chromosomes; random genetic drift; annatural selection against too high copy numbers. Analysiof this model shows that mean array size will be very larg




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when Ng! 1 and selection against total array length isweak (where N is the population size and g is therecombination rate per array). Thus, in regions withrestricted recombination and very weak selection pressureagainst array size, such as in the centromere region, whichis devoid of functional genes, highly repeated sequencesmay accumulate. In contrast, in more distant regions where

the functional genes are located and recombination ratesare generally higher, highly repeated sequences, such assatellite sequences, are only rarely found. The tandemarrays that are usually located in these latter regions havemuch smaller sizes, and are accordingly called microsa-tellites or minisatellites. Severalother properties of tandemarrays of noncoding DNA sequences, including repeatlength and higher-order structure of arrays, seem tocorrelate with rates of recombination along chromosomes.Models accounting for these characteristics have beendiscussed elsewhere (Stephan, 1997).

A similar model has been proposed to account for theaccumulation of transposable elements in regions of

reduced recombination. Recombination between elementsat nonhomologous insertion sites (ectopic exchange) cancause deletions and duplications of genetic material, whichare expected to have dominant deleterious effects in manycases. This canoppose increase in transposable elements byreducing the fertility of individuals with high element copynumbers. There is direct evidence for the occurrence ofectopic exchange between element sequences in Drosophilamelanogaster (Montgomery et al., 1991) and in otherspecies including humans. Survey data from D. melanoga-ster indeed show that transposable elements are signifi-cantly overabundant in chromosomal regions in whichthe rate of recombination is reduced, as expected if

ectopic exchange is reduced parallel with regular meioticrecombination.

Evolution of Genome Size(Gene Number)

The mechanisms discussed earlier contribute to changes inthe arrangement of the genetic material as opposed tochanges in its quantity. Alterations of quantity can proceedby the processes of duplication of entire genomes (poly-ploidization), complete and partial duplication of chromo-

somes, and gene duplication. These will be discussed inturn.

Genome duplication

Genome duplication occurs as a consequence of lack ofdisjunction between the daughter chromosomes followingDNA replication. Polyploidy is a widespread phenomenonin plants, in particular in flowering plants (Stebbins, 1971).The reasons for the prevalence of polyploidy in plants are

not clear. Artificially produced autopolyploids (polyplodization of homologous chromosomes) are generallinferior to their diploid ancestors. The inferiority expressed in lower fertility and a lower ability to competwith diploids. These experimental results and the fact thathe performance of induced polyploids as agriculturacrops has consistently fallen short of expectations have le

most researchers to believe that genome duplication per sis selectively disadvantageous. The widespread success opolyploidy in flowering plants has therefore been attributed to hybridization between individuals from differenpopulations (allopolyploidy). Hybridization increasegenetic diversity and may enable the polyploids to competwith their progenitors or to colonize new habitats. Icontrast, polyploidy is extremely rare in bisexuallreproducing animals, presumably because the two sexeare strongly differentiated with regard to the mechanism ochromosome segregation and combination, and polyplody invariably disturbs this process. In amphibians and fishhowever, many tetraploidspecies have beenfound. In thes

species, genome duplication does not result in sexuaimbalance because the chromosomal determinants of thopposite sexes are still in a rather early state of differentiation so that the sex chromosomes (usuallylabelled as X anY, or Z and W) can substitute for each other (Li, 1997).

Chromosome duplication

The duplication of a chromosome or part of a chromosomis likely to cause a severe imbalance in gene product. Itchance of being fixed in a population and its evolutionarsignificance are thus very small.For example, in Drosophil

the viability of terminal triploids declines with the amounof the triplicated material, generally becoming lethal whemore than one-half of an autosomal arm is present in thredoses. In humans, trisomies can be lethal or can caussterility. Well-known examples are the Down syndrom(trisomy 21) and trisomy of chromosome 18 (Li, 1997).

Gene duplication

Gene duplication seems to play a very important role iincreasing genome size. The evolutionary significance ogene duplication was already recognized in the 1930s, wheHaldane and Muller suggested that a redundant duplicat

of a gene may acquire divergent mutations and eventuallemerge as a new gene. Once a duplication has become fixein a population, the way is open for evolutionardivergence of the two duplicates, if an advantageoumutation conferring a new function becomesfixed in one othe two copies.

Duplicated genes can be divided into two types: varianand invariant repeats. Invariant repeats are (nearlyidentical in sequence to one another. In several cases, threpetition of identical sequences can be shown to b


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correlated with the synthesis of increased quantitites of agene product that is requiredfor the normal function of theorganism (dosage repetition). Representative examplesinclude the genes for tRNAs and rRNAs required fortranslation. Other examples are the amplification of anesterase gene in a Californian Culex mosquito, leading toinsecticide resistance, and the tandem duplication of the D.

melanogaster metallothionein gene involved in heavy metaldetoxification. Variant gene copies differ in their sequenceto various degrees. Depending on their degree of diver-gence, they form multigene families (with weakly tointermediately divergent members) or superfamilies (withvery divergent members). The members of a multigenefamily, such as various types of isozymes, may differ tosome extent in function or regulation, so that they cancontribute to the fine-tuning of physiological processes ofan organism. Members of a superfamily have, however,diverged a long time ago and may have quite distinctfunctions. A well-known example is that of trypsin andchymotrypsin, which diverged about 1500 million years

ago. These two digestive enzymes have acquired distinctfunctions: trypsin cleaves polypeptide chains at arginineand lysine residues, whereas chymotrypsin cleaves atphenylalanine, tryptophan, and tyrosine residues(Li, 1997).

A much more likely fate for a redundant duplicate genethan evolution into a new gene is that it accumulatesdeleterious mutations and becomes nonfunctional. This isbecause deleterious mutations occur far more often thanadvantageous ones. This process produces so-calledpseudogenes. Most multigene families or superfamilies,such as the globin superfamily, contain a rather highpercentage of pseudogenes.

References

Charlesworth B (1985) Recombination, genome size and chromosom

number. In: Cavalier-SmithT (ed.)Natural Selectionand GenomeSiz

pp. 489513. Chichester, UK: Wiley.

CharlesworthB (1990) Mutationselectionbalanceand theevolutiona

advantage of sex and recombination.Genetical Research 55: 19922

Charlesworth B, Langley CH and Stephan W (1986) The evolution

restricted recombination and the accumulation of repeated DNsequences. Genetics 112: 947962.

King M (1993) Species Evolution: The Role of Chromosome Chang

Cambridge, UK: Cambridge University Press.

Li W-H (1997) Molecular Evolution. Sunderland, MA: Sinau

Associates.

Montgomery EA, Huang S-M, Langley CH and Judd BH (199

Chromosome rearrangement by ectopic recombination inDrosophi

melanogaster: genome structure and evolution. Genetics 129: 1085

1098.

Otto SP and Michalakis Y (1998) The evolution of recombination

changing environments.Trends in Ecology and Evolution 13: 14515

Stebbins GL (1971) Chromosomal Evolution in Higher Plants. Londo

Edward Arnold.

Stephan W (1997) Tandem-repetitive noncoding DNA sequences. I

Meyers RA (ed.) Encyclopedia of Molecular Biology and MoleculaMedicine, vol. 6, pp. 110. Weinheim, Germany: Verlagsgesellschaf

White MJD (1973)Animal Cytology and Evolution, 3rdedn. Cambridg

UK: Cambridge University Press.

Further Reading

Cavalier-Smith T (ed.) (1985)The Evolution of Genome Size. Chicheste

UK: Wiley.

Charlesworth B, Sniegowski P and Stephan W (1994) The evolutiona

dynamics of repetitive DNA in eukaryotes. Nature 371: 215220.

John B and Miklos GLG (1988) The Eukaryote Genome in Developmen

and Evolution. London: Allen and Unwin.

Ohno S (1970) Evolution by Gene Duplication. Berlin: Springer-Verlag



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