conrad et al 2007 gene duplication

8/13/2019 Conrad Et Al 2007 Gene Duplication

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Gene Duplication: A Drivefor Phenotypic Diversity andCause of Human Disease

Bernard Conrad1,2 and Stylianos E. Antonarakis1

1Department of Genetic Medicine & Development, University of Geneva MedicalSchool and Geneva University Hospitals, CH-1211 Geneva 4, Switzerland

2Division of Human Genetics, Bern University Childrens Hospital, CH-3010 Bern,Switzerland; email: [email protected]

Annu. Rev. Genomics Hum. Genet. 2007. 8:1735

First published online as a Review in Advance onMarch 26, 2007.

TheAnnual Review of Genomics and Human Geneticsis online at genom.annualreviews.org

This articles doi:10.1146/annurev.genom.8.021307.110233

Copyright c2007 by Annual Reviews.All rights reserved

1527-8204/07/0922-0017$20.00

Key Words

gene duplication, copy number variant, haploinsufficiency, gene

balance hypothesis, insufficient amount hypothesis

Abstract

Gene duplication is one of the key factors driving genetic inno-vation, i.e., producing novel genetic variants. Although the con

tribution of whole-genome and segmental duplications to pheno-typic diversity across species is widely appreciated, the phenotypic

spectrum and potential pathogenicity of small-scale duplications inindividual genomes are less well explored. This review discusses

the nature of small-scale duplications and the phenotypes produced by such duplications. Phenotypic variation and disease phe-

notypes induced by duplications are more diverse and widespreadthan previously anticipated, and duplications are a major class o

disease-related genomic variation. Pathogenic duplications particu-larly involve dosage-sensitive genes with both similar and dissimilar

over- and underexpression phenotypes, and genes encoding protein

with a propensity to aggregate. Phenotypes related to human-specificcopy number variation in genes regulating environmental response

and immunity are increasingly recognized. Small genomic duplications containing defense-related genes also contribute to complex

common phenotypes.

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INTRODUCTION

Ever since Susumu Ohnos insightful sugges-tion 35 years ago that gene duplication is a key

factor shaping evolution, the model and itsgeneral predictions continue to attract much

attention (70). On an evolutionary scale,gene duplication may result in new functions

via different scenarios (Figure 1). Althoughthe most likely outcome is loss of function

in one of the two gene copies (Figure 1a,

Gene loss = nonfunctionalization

Functional divergence

a

b

No functional divergence = genetic robustnessc

Neofunctionalization Subfunctionalization

d

e

Duplication of gene families

Concerted evolution

Gene

conversion

Birth-and-death evolution

Silent nucleotide substitutionsversus

inactivating mutations

Duplication by retrotransposition

Male germline function

Somatic function

Figure 1

Evolutionary fate of single gene duplications (ac), and duplication of multigene families (de). Singlegene duplication most often results in a nonfunctional duplicate gene copy (a, nonfunctionalization).(b) In rare instances, the functional duplicate gene copy and the ancestral gene diverge in function;

neofunctionalization means that one of the two genes retains the original function, while the otherevolves a new, often beneficial function. Subfunctionalization implies that both the original and theduplicate genes mutate and evolve to fulfill complementary functions already present in the original geneDuplication via retrotransposition represents a particular case of sub- or neofunctionalization. Multigenefamilies evolve in a coordinated fashion, such that the DNA coding sequences and function of the singlemembers of a family remain close to that of the ancestral gene (de). (d) Concerted evolution: Aftermultiple rounds of duplication, gene conversion homogenizes the DNA sequences of the individualmembers. (e) Birth-and-death evolution invokes a process of equilibrium between inactivating mutationsand ongoing duplication of functional gene copies.

nonfunctionalization), in rare instances one

gene copy may retain the original functionwhile the other acquires a novel, evolu-

tionarily advantageous (adaptive) function(Figure 1b, neofunctionalization) (30). Al-

ternatively, after duplication, mutations mayoccur in both genes that specialize to per-

form complementary functions (Figure 1b

subfunctionalization) (56, 57). The ques-tion of how duplicate genes are retained

18 Conrad Antonarakis


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in a population remains controversial.

Classical duplication-degeneration-comple-mentation/subfunctionalization models do

not invoke positive selection, but stipulatea higher retention rate of duplicate genes in

small rather than larger populations. Con-siderably more retentions and fewer losses of

duplicate genes in rodents as compared withhumans indicate that positive selection mayplay a more important role than originally

anticipated (91). If two redundant gene copieswere retained in the genome without signifi-

cant functional divergence, the organism mayacquire increased genetic robustness against

harmful mutations (Figure 1c). In multigenefamilies descended from a common ancestor,

individual genes in the group exert similarfunctions and have similar DNA sequences

(67, 68). One concept, concerted evolution,applies particularly to localized and typically

tandem copies of a gene. The concept

posits that all genes in a given group evolvecoordinately, and that homogenization is

the result of gene conversion (Figure 1d).For most multigene families, the currently

favored model is birth-and-death evolution,according to which similarity in protein

sequence among the members of a family isassured by strong purifying selection, such

that individual genes evolve essentially viasilent synonymous nucleotide substitutions

(67, 68) (Figure 1e). Inactivating mutationsin a single member of a multigene family

do not necessarily imply an evolutionary

dead end, as illustrated by the more is lesshypothesis (72). For instance, the human

CASP12 pseudogene located in a clusterof functional Caspase genes shows that a

protein-truncating mutation can be positivelyselected, probably because the variant allele

confers resistance to severe sepsis (105,108). A recently recognized primate-specific

subgroup of duplications generated by retro-transposition was recruited to enhance male

germline function (Figure 1b) (103). Thismechanism thus represents a variation of

neo- or subfunctionalization. Irrespective of

these alternatives, gene duplication is, along

Whole-genomeduplication and 2Rhypothesis:increased complexityand genome size ofvertebrates resulted

from two rounds(2R) ofwhole-genomeduplication duringearly vertebrateevolution

Small-scaleduplications: arecent gene familyexpansion bysegmental or tandemduplication50150 Mya thatmay have followedon one singleprecedent round(1R) of WGD

Gene balancehypothesis: positsthat an imbalance inthe concentration ofindividualcomponents of amultiproteincomplex isdeleterious

with alternative splicing, a major mechanism

of gene diversification (48, 99). For instance,along the lineage leading to humans, 689

genes were gained and 86 genes lost sincethe split from chimpanzees, contributing

to a 6% difference in the complement ofgenes between humans and chimpanzees

(1418 of 22,000 genes), largely outnumber-ing the 1.5% nucleotide difference betweenorthologous sequences of the two species (23).

Whole-Genome versus Small-ScaleDuplications

Recent analysis of eukaryotic genomes showsthat gene duplication is widespread (50, 56).

A series of arguments suggest that currentvertebrate genomes have been shaped by

two rounds of whole-genome duplication (22,100). An alternative hypothesisfavors one sin-gle round of whole-genome duplication plus

continuous small-scale duplications (35). Us-ing Arabidopsis as a model system that un-

derwent several rounds of complete genomeduplication, the fate of small-scale versus

whole-genome duplication was addressed.This analysis not only revealed the dominant

evolutionary impact of whole-genome dupli-cation, but also the important role of small-

scale duplications for gene categories relatedto metabolism, stress responses,and celldeath

(58). The functional gene categories that have

been selectively maintained by the two mech-anisms differ somewhat (20). For instance, a

group of genes also referred to as connectedgenes, encoding among other transcriptional

regulators with limiting downstream part-ners that participate in protein-protein in-

teractions, and interacting proteins that arepart of signal transduction pathways (31), are

consistently underrepresented among small-scale duplications, and overrepresented after

whole-genome duplication (76). Duplicationof such dosage-sensitive genes, required at

stoichiometrically precise levels, may be

tolerated in whole-genome, but not insmall-scale, duplications (20). These findings

comply with the gene balance hypothesis

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Recent segmentalduplications:sequences that are>1 kb in length andthat show>90%sequence identity

Breakpoint inconserved synteny:syntenic segments orblocks 100 kb withbreakpointsidentified as changein orientation orchromosomelocation based onunique regions of thegenome

Copy number

variant (CNV) orcopy numberpolymorphism(CNP): a DNAsegment1 kbpresent at variablecopy numbercompared with areference genome

Copy numbervariable region(CNVR): CNVsidentified in

individuals of theHapMap collection,called in more thanone individual, andreplicated by asecond independentplatform

(9, 10, 31, 76, 102), which posits that con-

nected genes are particularly dosage sensitive,and are expected to be overretained relative

to nondosage-sensitive genes after whole-genome and larger-scale duplications, but not

after local duplications.

Recent Segmental Duplications

Recent segmental duplications comprise

about 5% of the euchromatic portion of thehuman genome (26). Although one current

definition includes sequences that are >1 kbin length and that show>90% sequence iden-

tity (6, 16), other authors use the term vari-ably, giving rise to different numbers of du-

plicated segments in the genome. Segmentalduplications are particularly enriched at peri-

centromeric and subtelomeric regions; sub-telomeric duplications account for 40% (51),and pericentromeric duplications for 33%

of the total (90). A considerable fraction(25%) of the nonpericentromeric and non-

subtelomeric duplications are associated withsyntenic breaks (4, 5), and 98% of primate-

specific breakpoints contain segmental du-plications (66). This was recently confirmed

for the duplication-rich human chromosomes15 (113) and 17 (114) (HSA15, HSA17).

On these chromosomes, the human-specificbreakpoints of conserved synteny (breakpoint

identified as changein orientation or chromo-

some location based on unique regions of thegenome, and for syntenic segments 100 kb)

(5) occur mostly in regions containing dupli-cations; 13 out of 15 breakpoints on HSA15

contain duplications, and 74% of duplicatedbases on HSA17 reside in breakpoints. At least

50% of duplications are strictly intrachromo-somal [50% for HSA15 (110) and 62% for

HSA17 (111)]. Between 3.5% and 11% ofall duplications contain complete genes (110),

and nearly one third of duplicated genes arearrayed in tandem (92). An unexpected fea-

ture of areas with tandem duplications is theirasynchronous replication, suggesting that du-

plicate structures alter the epigenetic state of

a given locus (33). Ultraconserved elements

(UCEs) arerare in segmental duplications and

copy number variants (CNVs), except for theUCE-subclass that overlaps exons (24). The

mechanisticbasis for this exquisite intoleranceto copy number changes of UCEs awaits fur-

ther characterization.At least 30% of the pericentromeric du-

plications were duplicatively transposed fromeuchromatic regions, generating a minimum

of 28 new transcripts that are expressed pri-

marily in the testis (90). The overall propor-tion of duplications is highest close to cen-

tromeres, and gradually diminishes within adistance of5 Mb from centromeres. Con-

versely, gene density increases with distancefrom centromeric -satellite repeats. The

subtelomeres contain 25 small gene familiesorganized in tandemly repeated blocks shar-

ing extensive sequence similarity, and 18 ofthese have at least one functional member

(51). Gene products within these blocks ex-ert highly varied functions, but are predomi-

nantlyodorant-andcytokine-receptors,tubu-

lins, and transcription factors.Several recent studies revealed the

widespread presence of large-scale CNVsin the normal human population (85, 88)

Deletions and insertions were equally rep-resented, often occurring around regions

of chromosomal instability (88). In onestudy, 70 different genes were shown to

vary in copy number within CNVs (85)Similarly, extensive CNVs in subtelomeric

blocks were documented (51). Approxi-mately 1450 copy number variable regions

(CNVRs) encompassing 360 Mbs, or 12%

of the genome, were mapped through thestudy of 270 individuals from the HapMap

collection (80), and 5150 CNVs genome-wide are currently recorded in the available

databases [http://paralogy.gs.washingtonedu/structuralvariation/ (85), http://

projects.tcag.ca/variation/(43), http://www.som.soton.ac.uk/research/geneticsdiv/

anomaly%20register/]. Within humanCNVs, a significant overrepresentation

of genes associated with environmentallyregulated functions and immunity was found



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suggesting an adaptive advantage of dosage

imbalance in these regions (69). Mecha-nistically, duplications that share extensive

sequence similarity, called low copy repeats(LCRs), occur frequently in regions with

large duplicated stretches. One commondefinition of LCRs is sequences that are

10 kb in length, show 95% sequenceidentity, and are separated by 50 kb10 Mbof intervening sequence (97). Such LCRs

serve as substrates for nonallelic homologousrecombination (NAHR) that can result in

duplications, reciprocal deletions, inversions,and reciprocal translocations (83, 89). The

primate-specific burst of Alu-repeats 3540 million years ago (Mya) could have been

one critical event initiating segmental geneduplications (7). Consistent with this, the

generation and structure of LCRs appear tobe associated with Alu-elements (89), and 492

human-specific deletions can be attributed to

this process (87). A detailed analysis of theproximal short arm of HSA17 indicated that

NAHR between LCRs is a major mechanismof recurrent rearrangements, whereas nonho-

mologous end-joining (NHEJ) can, in manyinstances, be responsible for nonrecurrent

rearrangments (54). The prevailing molecularmechanism also depends on the chromosomal

position, because subtelomeric duplicationswere generated almost exclusively via NHEJ

of double-strand breaks (51).Functional, duplicated genes comprise an

important, rapidly evolving euchromatic frac-

tion of our genome that displays extensivepolymorphism; it is therefore importantto ex-

amine their contribution to phenotypic vari-ation and disease.

Evolutionary Forces and Duplicated

Genes

The evolutionary forces acting on duplicatedgenes are diverse. A number of interdepen-

dent variables determine whether a gene will

be retained after duplication; these includeits functional category (46, 61, 76), degree

of conservation (18, 19, 45), sensitivity to

Low copy repeats(LCRs): sequencesthat are 10 kb inlength that show95% sequenceidentity, and are

separated by50 kb10 Mb ofintervening sequence

Haploinsufficientgenes: subset ofgenes experiencing aloss of fitness whenpresent in a singlecopy in diploidspecies

dosage effects (46), as well as its regulatory

and architectural complexity (39). In general,genes encoding proteins that interact with

the environment tend to be more frequentlyretained after duplication than those that

interact with intracellular compartments (50,61). Genes with permanent duplicates in

the Caenorhabditis elegans and Saccharomycescerevisiae genomes are more constrainedbefore duplication than genes that never

duplicated (19). However, human CNVs areconsistently enriched in genes with increased

rates of synonymous and nonsynonymouscodon substitutions (69). Haploinsufficient

genesi.e., genes experiencing a loss offitness when present in a single copy in

diploid specieshave more paralogs thanhaplosufficient genes, supporting the concept

that gene dosage may be critical in fixing du-plications (gene balance hypothesis) (46). In

general, duplicated genes encode for longer

proteins containing more domains and morecis-regulatory elements than singleton genes

(39). These observations indicate that naturalselection created a preferential association of

duplications with certain gene categories.Experiments performed on multiple

species, from unicellular organisms to mam-mals, indicate that genes rapidly diverge

after duplication (Figure 2) (17, 47). Al-though divergence of duplicated genes was

traditionally assessed by comparing the rateof amino acid changes, more recently the

focus was on divergence of gene expres-

sion, of transcriptional networks, and ofprotein-protein interactions. It has been

shown that the protein-coding sequence andcis-regulatory regions of duplicated genes

evolve independently (Figure 2a) (104).Shortly after duplication, expression and

regulatory divergence exceed changes inthe protein sequence (36). In humans and

yeast, protein sequence evolution and geneexpression diversity significantly correlate

and increase with evolutionary time (37, 60).In addition, the mode of duplication and

the functions of the genes involved also play

important roles in expression divergence



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b1 Protein-sequence divergence Regulatory divergencec

Protein-network divergence

cis-regulatory

divergence

t

(Evolutionary time)

acis-regulatory region

Protein-coding region

b2

Figure 2

Functional divergence of duplicated genes. (a) Thecis-regulatory and the protein-coding regions evolveindependently after duplication. Divergence increases with evolutionary distance. (b) Schematicrepresentation of (b1) protein sequence divergence after duplication (green sequence diverges intoblueororange); (b2) protein network divergence, where the protein interaction domains of the original greensequence evolve by maintenance, gain, or loss of interacting partners. (c) Schematic representation ofDNA sequence regulatory divergence after duplication (certain regulatory motifs are lost in one copy ofthe duplicated gene sequence).

(13). Divergence of cis-regulatory motifs in

the promoter-proximal region (Figure 2c) isprobably not the only substrate for expres-

sion divergence, suggesting thattrans-actingfactors could also be important (111). In

humans, genes diverge asymmetrically afterduplication; they rapidly lose their original

coexpressed partners and acquire new ones(Figure 2c) (17). Expression levels of du-

plicate genes diverge significantly duringdevelopment within and between species,

as compared to single-copy genes (37).

Paralogous genes in humans and mice tend tobecome more specialized in their expression

patterns (42).The protein interaction partners

(Figure 2b) change at a slower rate than thetranscription factors shared by duplicated

genes (62). The divergence of protein-protein

interactions after duplication depends on the

connectivity [i.e., number of binding partnersof a protein (8)] of the ancestral gene (112)

Proteins with a higher ancient connectivitytend to display an asymmetrical evolution

of the duplicates, whereas duplicates witha lower connectivity tend to gain and lose

interacting partners at about the same rate. Inconclusion, gene expression divergence is a

key substrate for functional divergence of du-plicate genes, and gene regulatory networks

evolve at a higher rate after duplication than

protein-protein interactions.

The Phenotypic Spectrumof Duplicated Genes

Gene dosage effects. The phenotypic con-

sequence of duplicating large regions or even



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whole chromosomes is at least in part de-

termined by the extent of regulatory imbal-ances. It is a priori expected that duplicate

genes (three copies per diploid genome) willexhibit a 1.5-fold increase in mRNA expres-

sion. Consistent with the prediction, 50%of trisomic genes are overexpressed at the ex-

pected 1.5 level or higher; this is true forgenes overexpressed as a consequence of anadditional whole chromosome copy in hu-

man trisomy 21 and in the respective trisomicmouse models (81). Similarly, a recent com-

parison of chimpanzee and human segmentalduplications revealed that among the human-

specific duplicates (causing trisomies), 56%show a significant difference in gene expres-

sion between the two species, mostly (83%)overexpression in human as compared to

chimpanzee (15).For genes that fail to show such a dose-

dependent increase, compensatory mecha-

nisms are usually involved (i.e., dosage com-pensation). For instance, this can happen

when the regulator controlling transcriptionand the target gene reside together on an

aneuploid segment, canceling dosage imbal-ances (9). Conversely, duplicated regions con-

taining positive or negative regulators canproduce negative effects on target genes lo-

cated outside of the aneuploid area (9, 10).The main conclusion from this is that the

most significant alteration in gene expressioncaused by aneuploidy will be exerted by the

target genes that are not in the aneuploid

region.In aneuploidy, it is generally assumed that

only a restricted set of dosage-sensitive genesis responsible for the phenotype. In a sys-

tematicanalysis of overexpression phenotypesin yeast, 15% of overexpressed genes re-

duced cell growth, and among those, cellcycle-regulated genes, signaling molecules,

and transcription factors were enriched (96).Interestingly, the overexpression phenotypes

differed from the deletion mutant pheno-types, indicating that the underlying mech-

anisms are specific for under- and overex-

pression, respectively, rather than resulting

UNDER- AND OVEREXPRESSIONPHENOTYPES: THE GENE BALANCEHYPOTHESIS VERSUS THE INSUFFICIENT

AMOUNT HYPOTHESIS

Another extrapolation of the gene balance hypothesis is that

under- and overexpression phenotypes are identical, or at leastsimilar, as they both act via the disruption of an identical mul-

timeric, regulatory protein complex (disrupted stoichiometryof protein subunits encoded by connected genes).

The primary mechanism of haploinsufficiency in yeast is

an insufficient protein production, which led to the formula-tion of the insufficient amount hypothesis, contradicting the

predictions of the balance hypothesis. In further support ofthe insufficient amount hypothesis is the fact that under- and

overexpression phenotypes of bona fide connected genes inyeast differ, indicating specific regulatory imbalances, rather

than disrupted stoichiometry (see References 25 and 96).

from a common disruption of protein com-plex stoichiometry. These results contradict

the gene balance hypothesis and are consis-

tent with the insufficient amounts hypothe-sis (25), in which haploinsufficient genes are

needed at abnormally high levels, and there-fore are more sensitive to a reduction in dose

(see sidebar on Under- and OverexpressionPhenotypes: The Gene Balance Hypothesis

versus the Insufficient Amount Hypothesis formore information).

Relationship of gene dosage and fitness

(phenotype). The relationship betweengene dosage and fitness (phenotype) is

complex. Three alternatives have beenproposed, each one characteristic of certain

gene categories (Figure 3) (46). The firstdescribes a linear relationship that is often

found for structural and regulatory proteins(Figure 3a); the second fits a diminish-

ing returns principle typical of enzymesthat function at limiting concentrations

(Figure 3b). Consistent with this, disorderscaused by genes encoding enzymes are pri-

marily recessive, indicating that these genes

are not dosage sensitive (haplosufficient)



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Protein concentration(genotype)

Fitness

(phenotype)

0 0.5 1 2

(aa) (aA) (AA) (AA,AA)


Fitness

(phenotype)

0 0.5 1 2



Fitn

ess

(phen

otype)

0 0.5 1 2



Fitn

ess

(phen

otype)

0 0.5 1 2


Examples

Examples

a

c

Linear function

Stoichiometric titration

Structural-,regulatory-

proteins

Examples

Proteins with pro-

pensity to aggregate(Parkinson/Alzheimerdisease)(see Table 1)

d Aggregation

Examples

b Diminishing returns function

Enzymes(see Table 1)

Dosage-dependent

transcription factors(see Table 1)

Figure 3

Schematic representations of gene dosage and fitness (phenotype). Four different relationships areshown. (a) A linear relationship is typically found for structural and regulatory proteins; (b) a diminishingreturns function classically involves enzymes that show little variation in function over large dose ranges.(c) Certain functional gene classes enriched for transcriptional regulators and signaling molecules causephenotypes both when under- and overexpressed (haploinsufficiency and pathogenic gene duplication).(d) Disease phenotypes caused by protein aggregation. The wild-type protein aggregates at doses beyondthe threshold level of two gene copies. Heterozygous mutations can also cause protein aggregation at onegene copy. Uppercase A depicts the normal allele; lowercase a represents a mutant loss of functionallele.

Haploinsufficiency:a dominantphenotype in adiploid organismthat is heterozygousfor a loss of functionallele

(44). The third alternative corresponds

to a diminished fitness for both increasedand decreased gene dosage, indicating ei-

ther multisubunit complexes with a singlecomponent that has a tight stoichiometry

(46) (gene balance hypothesis), or specificregulatory imbalances as a consequence of

under- (insufficient amount hypothesis) andoverexpression (25) (Figure 3c). Transcrip-

tional regulators can cause phenotypes both

when under- and overexpressed (84), a mech-anism responsible for many developmental/

malformation syndromes (Figure 3c) (Ta-

ble 1). A fourth alternative concerns proteinswith a propensity to aggregate (Figure 3d)

These proteins display a dual behaviorThe wild-type protein aggregates in a

dose-dependent manner once the diploidthreshold dose is exceeded (e.g., gene du-

plication). Alternatively, aggregation occursin the diploid state in the presence of a

dominant mutation (Figure 3d) (49). Genesencoding such proteins include -synuclein

(SNCA), responsible for one rare familial



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form of early-onset Parkinson disease, and

the amyloid precursor protein (APP) thatcauses one form of dominant early-onset

Alzheimer disease (38, 93).

Synopsis of diseases and mechanisms asso-

ciated with duplicated genes. In Table 1,

we summarized the main features of pheno-types and diseases caused by duplicated genes.

Examples of pathogenic duplications in-

volving dosage-sensitive genes. The gen-

eral models discussed predict that among thegenes overexpressed as a result of duplication,

a minor fraction of dosage-sensitive genesenriched for transcription factors, signaling

molecules, and cell cycle-regulated genes willbe critical for the phenotypic features (96).

Competing models stipulate that over- andunderexpression phenotypes of such genes areeither similar (gene balance hypothesis), or al-

ternatively distinct (insufficient amounts hy-pothesis). In Charcot-Marie-Tooth (CMT)

disease, the most frequent inherited disor-der of the peripheral nervous system (55,

65), a 1.4-Mb tandem duplication is foundin 70% of autosomal dominant CMT1A

patients. Although the 1.4-MB interval con-tains 30 genes,PMP22,encoding the major

myelin protein, is responsible for the disorderthrough a gene dosage effect. In the heterozy-

gous duplication state,PMP22trisomy causesa nerve conduction deficit due to demyliniza-

tion (CMT1A), whereasPMP22 monosomy

(deletion) causes a nerve conduction block[hereditary neuropathy with liability to pres-

sure palsies (HNPP)] in its haploinsufficientstate. Because many central and peripheral

demyelinating disorders, such as CMT1A,Pelizaeus-Merzbacher disease (PMD) (27),

and autosomal dominant leukodystrophy(ADLD) (75), can be caused by gene duplica-

tion, it was suggested that myelin formationis particularly susceptible to gene dosage ef-

fects (75). The CMT/HNPP-causing regionshows how two distinct phenotypes can result

from over- and underexpression of a critical

dosage-sensitive gene. Similarly, deletion and

duplication of the Sotos syndrome region and

NSD1gene dosage effects cause contrastingphenotypes (14).

Over- and underexpression phenotypescan also be similar, as shown by the methyl-

CpG-binding protein 2 (MECP2), a chro-matin architectural protein linked to tran-

scriptional repression (52). The progressiveneurodegenerative disorder Rett syndrome,

which in its classical form affects females

almost exclusively, is due to MECP2 hap-loinsufficiency. Severe mental retardation and

neurological symptoms with features of Rettsyndrome in males can also be caused by

MECP2duplications (101). Likewise, abnor-mal neurodevelopmental phenotypes linked

to both MECP2 under- and overexpressionwere described in human and transgenic

mouse models (53). Similarly, X-linked hy-popituitarism can be caused by inactivating

heterozygous SOX3 mutations, or by duplica-tion of a region containing the developmental

transcription factorSOX3(Table 1) (107).

Pathogenic duplications also occur in re-gions of genomic microdeletions, such as

the velocardiofacial, the Williams-Beuren,the Alagille, and the Smith-Magenis syn-

drome regions (Table 1) (64, 79, 95, 109).These examples partially fit the model

that duplication of one or a few dosage-sensitive genes causes overexpression pheno-

types that resemble the underexpression phe-notype (Figure 3c). On the other hand, the

duplication at 1p36 matches an incremental/linear gene-phenotype model for closure of

cranial sutures (Figure 3ab) (32). Hap-

loinsufficiency of genes in this region re-sult in delayed closure of cranial sutures,

whereas increased gene dosage via duplica-tion, for instance, results in craniosynosto-

sis. A heterogenous group of duplications,spanning 0.51-Mb regions, causes pheno-

types (a) for which the corresponding mono-somy has either not yet been reported (split

hand/split foot syndrome, SHFM3) (21);(b) for which duplication and haploinsuffi-

ciency of as-yet-unidentified genes have beenimplicated in a similar/identical phenotype



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Table 1 Duplication phenotypes

Species GeneGene

categoryGenomicalteration Disease Phenotype Mechanism References

Similar under- and overexpression phenotypes

Hs/Mm MECP2 MethylatedDNAbinding

DuplicationMECP2

Progressive neu-rodevelopmentalsyndrome inmales

Mentalretardation,epilepsy

Loss of genefunction due tounder- andoverexpression

(52, 98)

Hs SOX3 Developmentalregulator(TF)

DuplicationSOX3

X-linkedhypopituitarism(XLHP)

X-linkedhypopituitarismand infundibularhypoplasia


(104)

Hs ND (TBX1) ND Duplication22q11.2

Velocardiofacialsyndrome(VCFS)

Variable: normal todevelopmentaldelay andmalformations


(106)

Hs ND (ELN) ND Duplication7q11.23

Williams Beurensyndrome(WBS)

Delay expressivelanguage


(92)

Hs ND

( JAGGED1)

Developmental

regulator(TF)

Duplication

20p11

Alagille syndrome

(AS)

Cardiovascular-,

ocular-, bileduct-, andskeletal anomalies

Loss of gene

function due tounder- andoverexpression

(63)

Hs RAI1 Developmentalregulator(TF)

Duplication17p11.2

Smith-Magenissyndrome (SMS)

Mild mentalretardation anddentalabnormalities


(77)

Hs PLP1 Proteolipidprotein

DuplicationPLP1

Pelizaeus-Merzbacher(PM)

Demyelinationdisorder CNS


(26)

Dissimilar under- and overexpression phenotypes

Hs PMP22 Myelinprotein

DuplicationPMP22

Charcot MarieTooth 1A

(CMT1A)

Peripheral myelinneuropathy

Loss of genefunction due to

under- andoverexpression

(54, 64)

Hs NSD1 Histonemethyltrans-ferase

DuplicationNSD1

Growthretardationsyndrome

Growthretardation


(63)

Hs ND(MMP23)

ND Duplication1p36

Premature closurecranial sutures

Craniosynostosis Incremental genefunction

(31)

Complex, yet unresolved expression phenotypes

Hs LMB1 Laminarnuclearenvelopeprotein

DuplicationLMB1

Autosomaldominantleukodystrophy(ADLD)

Demyelinationdisorder CNS

ND (73)

Hs ND ND Duplication10q24

Split hand/splitfootmalformation 3(SHFM3)

Split hand/splitfoot

ND (21)

Hs ND ND Duplication2q13

Orofacialclefting/cleftpalate only

Mental retardationand orofacialclefting

ND (72)

(Continued)



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Table 1 (Continued)

Species GeneGene

categoryGenomicalteration Disease Phenotype Mechanism References

Hs ND ND Duplication16p13

ATR-X-like X-linked -thalassemia/mentalretardation

ND (2)

Protein aggregation due to overexpression

Hs SNCA Molecular

chaperone

Duplication

SNCA

Parkinson disease Nigrostriatal

neurondegeneration

Protein

aggregation andunderlying genemutations

(91)

Hs APP Amyloidprecursorprotein

DuplicationAPP

Alzheimer disease Parenchymal/vascularamyloiddeposition

Proteinaggregation andunderlying genemutations

(37, 79)

Phenotypes of CNVs related to environment and immunity

Hs CYP2D6 P-450isoenzyme

P-450CNV Altered drugmetabolism

Adverse drug effects Incremental/lineargene functionmodel

(12, 40, 75)

Hs CCL3L1 Chemokinereceptor

CCL3L1CNV Altered HIVsusceptibility

EnhancedHIV/AIDS

susceptibility

Incremental/lineargene function

model

(33)

Common complex phenotypes of CNVs in defense-related genes

Hs/Rn FCGR3B/Fcgr3-rs

Fc receptorfor IgG

FCGR3CNV Glomerulonephritis/systemic lupuserymathosus

Susceptibility toglomerulonephri-tis

Pathogenic un-derexpressionphenotype

(1)

Mm TLR7 Toll-likereceptor

TLR7CNV Systemic lupuserymathosus-likedisease

Autoantibody-elictedautoimmunity

Pathogenicoverexpressionphenotype

(76)

Hs hBD2 Antimicrobialpeptides

hBD2CNV Crohns disease ofthe colon

Inflammatory boweldisease

Pathogenic un-derexpressionphenotype

(28)

(mental retardation/orofacial clefting syn-

drome) (74); and (c) for which haploinsuf-ficiency of a transcription factor (ATRX at

Xq13.3) and duplication of a second regioncontaining candidateATRXtarget genes (re-

gion at 16p13.11-16p13.3 comprising the -

globin gene) result in a similar clinical outcome

(X-linked -thalassemia/mental retardationsyndrome) (2). Although these examples are

more complex than those previously dis-cussed, the last two cases may be compatible

with similar under- and overexpression phen-toypes.

Diseases caused by protein aggregation.

Protein aggregation is particularly associatedwith disease genes (106). Two rare forms of

neurodegenerative disorders, Parkinson and

Alzheimer disease, provide constructive ex-

amples of pathogenic gene dosage effects me-diated via protein aggregation (Figure 3d)

(38, 93). Alpha-synuclein (SNCA) duplicationandtriplicationlead to increased expression of

-synuclein, a small protein thought to playa role as a molecular chaperone in vesicular

transport and/or turnover of synaptic vesicles.The pathology induced by this protein and the

severity of disease both depend on the geneexpression level. Although the mechanism is

not yet fully understood,-synuclein aggre-gation, controlled by mutations in at least

three genes includingSNCAitself, is thought

to promote nigrostriatal neurons for degen-eration (94).

The amyloid precursor protein (APP)can be cleaved into either of two smaller



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peptides, A40 and A42 (38). It is accumu-

lation of the latter causing parenchymal andvascular deposition that is probably responsi-

ble for Alzheimer pathogenesis. The diseasephenotype can be caused by a varietyof mech-

anisms that lead to an increase in APP pro-tein aggregates, namely duplications ofAPP

on chromosome 21 (82), Down syndrome (tri-somy 21) with three APPcopies, or, alterna-tively, mutations inAPPitself or in the gene

encoding the proteases responsible for APPcleavage (38). Similar mechanisms may ac-

count for other neurological diseases that arebased on protein deposition (38).

Modified responses to drugs. Genes en-

coding enzymes are not usually dosage sen-sitive, yet there are examples of such gene

duplications that cause variable pheno-types, particularly those encoding protein

complexes that regulate drug metabolism

(12). The three cytochrome P-450 isoformsCYP2C9, CYP2C19, and CYP2D6, which all

vary in copy number, are responsible for thebiotransformation of about 40% of all drugs

that are metabolized by P-450. Copy num-ber variation among the 80 distinct alleles

of theCYP2D6gene partially defines the in-dividual capacity to metabolize drugs. Four

major phenotypic categories of drug oxida-tion have been recognized to date, namely

poor, intermediate, extensive, and ultrarapidmetabolizers. Because these phenotypic dif-

ferences have clinical consequences, such as

adverse drug reactions or therapeutic failure(77), it will be important to develop accurately

predictive genotyping for these and other en-zymes that appear to display clinically relevant

CNVs (41). CNVs are currently under inves-tigation for their pharmacogenetic relevance

(73).

Altered responses to pathogens. Becausegenes encoding proteins in metabolic path-

ways in unicellular organisms have a higherduplicability rate than other gene categories

(61), this could generally be true for genes

responding to and/or regulated by environ-

mental stimuli. Intriguingly, copy number

variation of the gene encoding CCL3L1a potent human immunodeficiency virus-1

(HIV-1)-suppressive chemokine, influencesthe susceptibilityto HIV-1 infection (34).One

could speculate that CNVs containing genesrelated to immune responses may be involved

in the control of infections. Of relevance inthis regard are CNVs of the novel defensin

gene family that function as chemotactic

activators of the immune response (3, 86). Asdiscussed below, defensin CNVs may cause

inflammatory bowel disease by modulatingthe host response to pathogens (29). Gene

families that constitute the core elementscontrolling infections, namely the T-cel

receptor and immunoglobulin genes, evolvedvia species-specific sequential rounds of dupli-

cations (98). Copy number variation in thesegene families may also play a role in complex

phenotypes such as autoimmune diseases.

Role of copy number variants in complex

diseases. An example of the possible roleof CNVs in common complex phenotypes

is the demonstration that low copy numbersof theFCGR3Bgene encoding the activatory

Fc receptor for IgG predispose patients withsystemic lupus erythematosus to an inflamma-

tory disease of the kidneys (glomerulonephri-tis) (1). Analogous findings in rats corroborate

this observation. Additional examples includeduplication ofTLR7, an innate immune re-

ceptor that predisposes mice carrying it to au-toreactive B-cell responses (78), and low copy

number of the human beta-defensin 2 (hBD2)

gene that predisposes to Crohns disease ofthe colon (29). The importance of CNVs for

complex phenotypes and diseases in genes re-lated to immune defense should therefore be

generally explored.

Disease-causing gene conversion medi-

ated by duplicated pseudogenes. Among

the 1945 nonprocessed pseudogenes locatednear the ancestral gene (out of a total of

3426 nonprocessed pseudogenes), 11 casesof deleterious gene conversion induced by



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the pseudogene were recognized (11). Among

those is the retinitis pigmentosa9 pseudogene(RP9P) carrying a mutation that produces

a nonsynonymous substitution in the wild-type gene associated with the RP9 form

of autosomal dominant retinitis pigmentosa(ADRP). Two other processed pseudogenes

also contain mutations associated with dis-eases, an inosine monophosphate dehydroge-nase 1 pseudogene (IMPDH1P1) that causes

the RP10 form of ADRP, and a phosphoglyc-erate kinase 1 pseudogene (PGK1P1) associ-

ated with phosphoglycerate kinase deficiency.These observations highlight the pathogenic

potential of duplicate gene copies that ac-quired inactivating mutations (pseudogenes)

for the wild-type progenitor gene locatednearby.

Partial phenotype rescue by a duplicated

gene. The second most frequent autosomalrecessive disease in Europeans, spinal muscu-

lar atrophy (SMA), adds an important lessonto the phenotypic consequences of gene du-

plication. The disease, which is usually due

to homozygous mutations in the survival mo-tor neuron 1 gene (SMN1), can be partially

rescued by increasing copy numbers of itsnearly identical and partially functional dupli-

cate SMN2 (28). This example emphasizesthepartial functional redundancy of some dupli-

cate genes (40), and supports the notion thatdeletion of a duplicate gene results in a less

severe phenotype than deletion of a singletongene.

CONCLUSIONS ANDPERSPECTIVES

The frequency and variety of phenotypes in-

duced by gene duplication are diverse, andhave not yet been fully appreciated. Several

fields deserve more investigation, notably therole of gene duplication in (a) monogenic

phenotypes, [particularly disorders implicat-ing haploinsufficient dosage-sensitive genes,

for instance congenital heart disease (71)];(b) polygenic complex multifactorial pheno-

types, as exemplified by the implication of the

FCGR3and hBD2copy number in glomeru-

lonephritis and Crohns disease, and by therole ofTLR7duplications in autoimmunity

elicited by autoantibodies; (c) drug, host,

pathogen, and metabolic responses; (d) dis-eases due to protein aggregation; and (e) gene

regulation, as exemplified by the contributionof microRNA gene duplication to complex

patterns of gene regulation (59), and by du-plication of conserved noncoding regions that

helped diversify expression of developmen-tal regulators (63). Finally, because increased

dosage of genes related to olfaction, immu-nity, and protein secretion may have been

positively selected in humans (69), a possiblymoregeneral contribution to phenotypicvari-

ation of CNVs in genes responding to envi-

ronmental stimuli deserves a more thoroughexploration in the near future. In summary,

this review article discusses and emphasizesthat gene duplication plays an important role

in genome evolution and phenotypic variabil-ity, and can cause disease phenotypes.

ACKNOWLEDGMENTS

We thank Drs. Jacques Beckmann, Samuel Deutsch, and Henrik Kaessmann for reading the

manuscript. B.C. is supported by the SNSF and Helmut Horten Foundation; S.E.A. is sup-

ported by the SNSF, EU, NIH, and Childcare Foundation, and by funds from the Universityof Geneva.

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440:104549



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Annual Review

Genomics and

Human Geneti

Volume 8, 2007Contents

Human Evolution and Its Relevance for Genetic Epidemiology

Luigi Luca Cavalli-Sforza 1

Gene Duplication: A Drive for Phenotypic Diversity and Cause of

Human Disease

Bernard Conrad and Stylianos E. Antonarakis

17

DNA Strand Break Repair and Human Genetic Disease

Peter J. McKinnon and Keith W. Caldecott 37

The Genetic Lexicon of Dyslexia

Silvia Paracchini, Thomas Scerri, and Anthony P. Monaco 57

Applications of RNA Interference in Mammalian Systems

Scott E. Martin and Natasha J. Caplen 81

The Pathophysiology of Fragile X Syndrome

Olga Penagarikano, Jennifer G. Mulle, and Stephen T. Warren

109Mapping, Fine Mapping, and Molecular Dissection of Quantitative

Trait Loci in Domestic Animals

Michel Georges 131

Host Genetics of Mycobacterial Diseases in Mice and Men:

Forward Genetic Studies of BCG-osis and Tuberculosis

A. Fortin, L. Abel, J.L. Casanova, and P. Gros 163

Computation and Analysis of Genomic Multi-Sequence Alignments

Mathieu Blanchette 193

microRNAs in Vertebrate Physiology and Human Disease

Tsung-Cheng Chang and Joshua T. Mendell 215

Repetitive Sequences in Complex Genomes: Structure and Evolution

Jerzy Jurka, Vladimir V. Kapitonov, Oleksiy Kohany, and Michael V. Jurka 241

Congenital Disorders of Glycosylation: A Rapidly Expanding Disease Family

Jaak Jaeken and Gert Matthijs 261

v


21/21

Annotating Noncoding RNA Genes

Sam Griffiths-Jones

Using Genomics to Study How Chromatin Influences Gene Expression

Douglas R. Higgs, Douglas Vernimmen, Jim Hughes, and Richard Gibbons

Multistage Sampling for Genetic Studies

Robert C. Elston, Danyu Lin, and Gang Zheng

The Uneasy Ethical and Legal Underpinnings of Large-Scale

Genomic Biobanks

Henry T. Greely

Indexes

Cumulative Index of Contributing Authors, Volumes 18

Cumulative Index of Chapter Titles, Volumes 18

Errata

An online log of corrections toAnnual Review of Genomics and Human Genetics

chapters may be found at http://genom.annualreviews.org/

conrad et al 2007 gene duplication

Documents