Outline
Comptes Rendus

Evolution / Évolution
A prominent role for segmental duplications in modeling Eukaryotic genomes
Comptes Rendus. Biologies, Volume 332 (2009) no. 2-3, pp. 254-266.

Abstracts

Segmental duplications (SDs) are a major element of eukaryotic genomes. Whereas their quantitative importance vary among lineages, SDs appear as a fundamental trait of the recent evolution of great-apes genomes. The chromosomal instability generated by these SDs has dramatic consequences both in generating a high level of polymorphisms among individuals and in originating numerous human pathogenic diseases. However, even though the importance of SDs has been increasingly recognized at the genomic level, some of the molecular pathways that lead to their formation remain obscure. Here we review recent evidences that the interplay between several mechanisms, some conservative, some based on replication, explains the complex SDs patterns observed in many genomes. Recent experimental studies have indeed partially unveiled some important aspects of these mechanisms, shedding interesting and unsuspected new lights on the dramatic plasticity of eukaryotic genomes.

L'objectif de cette revue est de souligner l'importance du rôle structurant joué par les duplications segmentales (DS) au sein des génomes eucaryotes, au regard des découvertes récentes sur leurs mécanismes de formation. Alors que leurs proportions varient suivant les especes, les DS ont joué un rôle majeur dans l'évolution récente des génomes des grands singes. L'instabilité chromosomique associée à ces structures répétées induit un niveau élevé de polymorphisme au sein des populations humaines et est associée à de nombreux cancers et maladies géniques. Les mécanismes de formation des DS sont multiples et certains demeurent méconnus. Les différentes voies permettant de former des DS peuvent être distinguées suivant qu'elles impliquent ou non une étape de réplication et donc un gain net de matériel génétique. Des études récentes ont notamment permis de proposer un nouveau mécanisme basé sur la réplication des chromosomes et a priori susceptible de dupliquer n'importe quel locus, soulignant par là l'impressionnante plasticité des génomes eucaryotes.

Metadata
Accepted:
Published online:
DOI: 10.1016/j.crvi.2008.07.005
Keywords: Segmental duplication, Replication, Replication factory, Genome evolution, Chromosome rearrangements, CNV, Genomic disease
Mot clés : Duplication segmentale, Réplication, Usine de réplication, Évolution génomique, Réarrangements chromosomiques, CNV, Maladies géniques

Romain Koszul 1, 2; Gilles Fischer 3, 4, 2

1 Department of Molecular and Cellular Biology, Harvard University, 7, Divinity Avenue, Cambridge, MA 02143, USA
2 CNRS, URA2171, F.75724 Paris cedex 15, France
3 Unité de Génétique moléculaire des levures, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris cedex 15, France
4 Université Pierre et Marie Curie-Paris, 6, UFR927, F.75005 Paris cedex 05, France
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Romain Koszul; Gilles Fischer. A prominent role for segmental duplications in modeling Eukaryotic genomes. Comptes Rendus. Biologies, Volume 332 (2009) no. 2-3, pp. 254-266. doi : 10.1016/j.crvi.2008.07.005. https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2008.07.005/

Version originale du texte intégral

1 Introduction

From the time chromosomes were shown to be the physical basis of heredity, scientists have expressed interest in the consequences of physical aberrations resulting in loss and gain of genetic material. Most of these early remarkable achievements and hypotheses originated from members of the group of Thomas H. Morgan and were developed through genetic analysis of Drosophila melanogaster mutants. A notable contribution came from Calvin B. Bridges who, soon after publishing his 1916 key PhD article on chromosomes, support of heredity [1], emphasized the interest duplicating of chromosomal regions as a mean to generate copies of identical genes as early as 1918. Such copies would be prone to accumulate independent mutations and thus acquire new functions, eventually contributing to speciation events [2]. Bridges' research on mutant flies eventually converged with his early interest in duplications to a remarkable climax, providing the basis for the discovery of HOX gene clusters [3]. This cluster appeared, indeed, to result from a series of gene and genome duplications [4]. A very early contribution to the study of segmental duplications (SDs) was made by another member of Morgan's group, Hermann J. Muller, who described X-ray irradiated flies in which a segment from the X chromosome had been duplicated and translocated onto chromosome II [5]. By observing apparent innocuousness from the presence in the same genome of these rearranged chromosomes II with intact X chromosomes, he elegantly proposed that such small duplications, eventually associated with translocations, were less likely to be deleterious than full aneuploidies, and therefore were probably an important source of genetic diversity. As we will see, his hypothesis appears amazingly accurate 70 years later. Early genetic works on filamentous fungi also revealed large duplications of chromosome segments resulting from non-reciprocal terminal translocations [6–8].

The importance of redundancy in eukaryotic genomes was nonetheless dramatically underestimated until the advent of genome sequencing and the revolution of the genomic era. Comparative genomic studies have described a diversity of genomic structures reminiscent of a variety of gene duplication mechanisms. Interestingly, whereas most eukaryotic genomes present a relatively homogenous level of genome redundancy (between 40% and 60% of genes in a given genome belong to gene families), these mechanisms appear somehow lineage-specific among species. Whole genome duplication (WGD), or polyploidy, is a phenomena originally proposed to account for the presence of two sets of identical chromosomes in maize [9] and commonly observed in plants lineages [10]. Such events have since been detected in the evolutionary history of many others species (see Jaillon, Aury and Wincker [11], this issue). However, in addition to these dramatic, relatively rare events, other mechanisms have contributed to generate the genetic redundancy observed in most eukaryotic genomes. Tandem gene duplications are easily recognizable by the physical proximity between the repeated gene copies. On the other hand, dispersed duplicates generally result from the retroposition of mRNA with the limitation that this mechanism often results in the formation of pseudogenes. Finally, a large proportion of eukaryotic genomes appear to have been extensively reshaped by duplications of large DNA segments. Initially considered as peculiar features of genome architecture, interest in SDs intensified with the release of complete genome sequences. A remarkable breakthrough occurred when it was established that recent duplications appear to constitute more than 5% of the human genome [12,13].

2 Segmental duplications among eukaryotic genomes

2.1 Segmental duplications and copy number variation regions in the human genome

The recent interest in segmental duplications as structural elements of eukaryotic genomes has without doubt been magnified by the discovery of their abundance in the human genome sequence. By considering the overrepresentation of some regions among whole-genome shotgun sequence reads, Eichler and collaborators identified potential duplicated regions and were thus able to generate the first genomic map of SDs [12]. With a later refinements, the original predictions proved to be close to the actual map, with approximately 5% of the genome consisting in duplications of DNA segments >1–5 kb sharing >90% identity, usually <300 kb although some of them cover hundreds of kb [14,15]. The nature and distribution of these SDs within the human genome present various levels of heterogeneity. Current analyses estimate that SDs cover approximately 150 Mb of the genome, and are distributed between pericentromeric (31%), subtelomeric (2%) and interstitial (e.g. between pericentromeric and subtelomeric regions, 67%; Fig. 1) regions. In addition, both pericentromeric and subtelomeric regions are enriched in inter- versus intra-chromosomal SDs. Also, the global chromosomal distribution is not uniform, with enriched and impoverished whole chromosomes or whole chromosomal arms. Furthermore, SDs in interstitial regions tend to be interspersed, either as interchromosomal or as intrachromosomal but separated by large distances. The tendency towards SD scattering seem to be specific to the hominoid genomes (Human and chimpanzee) given that in most other sequenced species SDs mainly appear as clusters of tandemly duplicated regions.

Fig. 1

Different classes of SDs, as determined from their chromosomal localization and intra- and interchromosomal positions. The original DNA segment is schematized as a large light-grey arrow and the duplicated copies as repeated dark-grey arrows. Centromeres and telomeres are represented by black ovals and series of open triangles, respectively.

The suspected dramatically fluidic nature of the human genome has been recently confirmed by the analysis of deletion/insertion and duplication polymorphism between human individuals. Large changes in stretches of genomic DNA segments, generically labeled copy number variations (CNVs), have been detected through SNP genotyping [16–18] and comparative genomic hybridization (CGH) assays [19–24]. The two latest studies were performed between hundreds of individuals, and led to the first CNV maps in the human genome: polymorphic variations in DNA segments larger than 1 kb are estimated to cover from 2% (conservative estimation [25]) to 12% [20] of the genome. Not surprisingly, there is a strong bias for CNVs to be associated with the SDs characterized in the reference genome (∼25%; [20,24]). A specific mapping of CNVs on human chromosome 22 revealed that >2/3 of the breakpoints intersect with SDs [26]. Although recent SDs, i.e. sharing very similar sequences, are more likely to correspond to CNV regions, this is not always the case: regions of ancient segmental duplications are still prone to exhibit polymorphism within actual populations (for mechanisms of formation, see below). The importance of CNVs, and their association with SDs in human population suggest common mechanisms of formation that still actively reshape our genome.

Both CNVs and SDs are increasingly recognized as a source of genomic diseases. SDs are responsible for numerous gene-dosage imbalances, gene fusions and disruptions events. Also, there is a strong association between SDs and sites of recurrent pathogenic rearrangements such as mental retardation related deletions [27,28]. CNVs are associated with the development of various human cancers [29–32] and the evolution of genetically complex phenotypes including predisposition to autism [33], epilepsy [34], Alzheimer disease [35], glomerulonephritis [36], systemic autoimmunity [37] and susceptibility to HIV/AIDS infections [38]. This strong association between SDs/CNVs and diseases could be the consequence of the significant gene enrichment that is observed in these regions. It is interesting to note that this enrichment is restricted to a small subset of the core segmental duplications. Sequence divergence analysis revealed that the most recent duplications, those that have emerged since the divergence of human and chimpanzee, are centered on this small portion of core SDs [39]. These recent SDs have been fixed despite their association with a large and increasing number of diseases and chromosomal rearrangements. Although some of these SDs may be selectively neutral and be fixed in genomes through genetic drift, it is unlikely that this is the case for all of them: indeed, in some cases, the creation of gene novelties that accompanies their formation may outweighs the negative effects of both chromosomal instabilities and disease appearance.

2.2 SDs in non-human primate species

A FISH analysis and an evolutionary age estimate of SDs from three non-human primates genomes (chimpanzee, baboon and marmoset) supported that bursts in interspersed intra- and interchromosomal duplications occurred during and after the separation of great apes and human lineages from other primates [40]. Old World monkeys genomes nevertheless contain high proportions of SDs, as seen in the sequence of the Rhesus macaque (Macaca mulatta) (SD content of ∼2.5%) or of Macaca fuscata [40–42]. Human, chimpanzee and macaques shared a common ancestor approximately 25 Mya, revealing the important and rapid genomic changes that marked recent primate genome structure evolution. The analysis of the draft sequence of the chimpanzee genome underlined the importance of SDs as a source of genomic diversity between them. Whereas the genomic divergence due to single-nucleotide substitutions between the human and chimp genomes is approximately 1.2% [43], large SDs have had a greater impact (2.7%) in altering genome sequences between the two species [44]. Human and chimp share ∼66% of their duplication and carry a similar amount of sequences duplicated in one but not in the other lineage (32 Mb in human vs. 36 Mb in chimpanzee). However, a significant increase in copy number for shared duplications was identified in the chimpanzee genome (23 Mb vs. 7 Mb in human), mostly representing chimpanzee-specific hyperexpansion of a small number of chromosomal regions. The lineage-specific duplications and expansions induce changes in gene expression that may contribute to the phenotypic differences observed between human and chimpanzee [45,46]. Overviews of duplication polymorphism, corresponding to gain and loss of DNA segments between the genomes of great apes (chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus)) were obtained from CGH onto on human BAC arrays [42,47]. Overall, more than 300 sites of copy number variations, ranging in size from 40 to at least 175 kb, were observed in all chromosomal regions (centromeric, telomeric and interstitial). Most of these CNVs were lineage-specific, the gorilla genome showing the highest frequency of variations and the orangutan, the lowest. Again, human specific CNVs mostly intersect with SDs. Some of these regions also correspond to karyotypic breakpoints, illustrating their importance in promoting chromosomal evolution.

2.3 SD in other organisms

The availability of genome sequences for an expanding number of species allows the depiction of a more precise picture of the role played by segmental duplications in structuring eukaryotic genomes. Compared to the particularly rich and dynamic history among primate species, SD formation and content in other vertebrate genomes is somewhat lower, although can remain important. Rat and mouse genomes comprise ∼2–3% of SDs [14,48,49], whereas the SD content for the dog and cat genomes, whose sequences have been released, has not yet been clearly established [50,51]. In each lineage, SD genealogy is reminiscent of the history of primate's SDs, as it also appears as the combination of more or less steady levels of duplications, eventually associated with periods of sudden activity resulting in a burst of duplicated sequences within a genome [49]. When compared to the human and chimpanzee, SDs in other mammals are similar in size and present the same enrichment at pericentromeric and, to a lesser extent, at subtelomeric regions, thus generating a pattern which seems characteristic of mammalian genome architecture [49,52]. However, some notable differences exist: for instance, the duplications in interstitial regions tend to occur as intrachromosomal tandems in rat and mouse, unlike in humanoids (above).

Other vertebrate genomes sequenced so far are relatively compact compared to mammalian genomes and maybe because of this present a significant lower extent of SDs that appear significantly smaller in size. For instance, segmental duplications in the chicken (Gallus gallus) genome are usually smaller than 10 kb and appear mostly as intrachromosomal tandems [53].

In other species, the proportion and arrangements of detectable SDs present significant variations. For the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, despite a significant SD content of 4.3% and 1.4%, respectively, the proportion of SDs larger than 10 kb is very low (0.7% and 0.1%) [52,54]. In addition, the contribution of recent segmental duplication is relatively limited. For instance, only 10 interspersed and 4 tandem new gene duplications were detectable in the Caenorhabditis briggsae partial genome sequence when compare to C. elegans, whereas 100 My separate the too species [55]. Few interstitial SDs have been detected in the genomes of different yeast species [56] while the vast majority of the duplicated segment characterized in S. cerevisiae relate to the whole genome duplication event that occurred in this lineage [57]. Paradoxically, yeast remains an important tool to analyze SD formation (below), although little recent duplication has been found in genomes sequenced so far.

The global picture emerging from these studies is that, although the proportion of duplicated genes in most genomes remains high, the contribution of SDs to this feature varies among lineages and periods. It is very likely, however, that bursts similar to that observed within the primate lineage will be characterized in other lineages. These studies will probably help understanding the contribution of SDs polymorphism to speciation and phenotypic variations among closely related species.

3 Mechanisms of SD formation

Numerous studies have approached some of the mechanisms by which large DNA segments can get duplicated in eukaryotic genomes. Important contributions result from both genome sequence analysis (e.g. extent of the duplicated segments, genomic localizations and nature of the breakpoints, Fig. 2), that helped to formulate hypotheses about the molecular mechanisms involved, and experimental studies, where the validity of these hypotheses can be actually tested. From these approaches, it appears that the structures pooled under the generic designation of SDs result from a large variety of molecular mechanisms. In addition, there is an important distinction that can be made between SDs according to their respective origins. On the one hand, duplicated segments can result from the unequal re-assortment of the genetic material of a progenitor cell among its offspring, and thus emerges without any effective DNA duplication. On the other hand, large duplicated segments can result from a round of untimely DNA synthesis, leading to a net increase of genetic material. In the latter scenario, an unscheduled DNA replication step must occur. Although conceptually and mechanistically dissociated, these two classes of SD involve multiple and often share similar genetic pathways. Indeed, whatever the class they belong to, an important aspect of duplications is that like for all chromosomal rearrangements, two distant DNA loci have to be rejoined. This result in the formation of a “breakpoint” sequence, whose nature provides important clues about the genetic pathway involved in its generation (Fig. 2A). Classical hypotheses about breakpoint formation imply a DNA double-strand break (DSB) as the initiating event. However, some recent findings suggest that this might not be an absolute pre-requisite ([58]; below).

Fig. 2

SD breakpoints. Symbols are identical to Fig. 1. (A) Characterization. For direct tandem duplications (i), the breakpoint sequence corresponds to the largest DNA sequence common to both extremities of the duplicated segment that overlaps in-between the two duplicated segments (e.g. the ATGC sequence). (ii) Interspersed intra- or interchromosomal duplications. Breakpoints correspond to the sequence shared by the extremities of the duplication and the insertion locus. In the given example both the extremities of the duplicated and the insertion locus have the same ATGC sequence. (B) Characteristic breakpoints structures of SDs resulting either from HR (left) and NHEJ (right) events.

Briefly, two DSB repair pathways coexist in most eukaryotic cells: non-homologous end joining (NHEJ) and homologous recombination (HR, which consists of different categories, [59]). Maintaining an ability to repair DSBs is an essential function for a cell and both pathways are holders of genome integrity and functionality [60]. The fundamental features of HR consist in the interaction (strand invasion) and exchanges between two homologous DNA sequences. The HR pathway can drive non-allelic homologous recombination events (NAHR), i.e. exchanges between non-allelic sequences showing a high or perfect similarity over dozens of base pairs (bp). Sometimes, a replication fork will be reassembled at the site of strand invasion, which then progresses and replicates dozens of kb in a so-called break-induced replication (BIR) reaction. More than 30 genes are involved in the yeast HR repair pathway, including the group epistatic to the pivotal Rad52 protein [59–61]. The involvement of HR in SD formation can be envisioned when the breakpoint sequence shares a large DNA sequence similarity with the two reunified DNA segments (Fig. 2B). On the other hand, NHEJ allows the ligation of two DNA ends exhibiting virtually no sequence identity. In yeast, the Mre11/Rad50/Xrs2 (MRX) complex binds to the two DNA ends of the break, holding them in the vicinity of each other [62,63]. The Ku70/80 heterodimers are then recruited at these ends, until the ligase Lig4 binds the two DNA ends together. If the two ends are cohesive, then the ligation will be perfect with no trace of the damage remaining. However, in some other cases, small deletions and insertions can eventually occur [60]. Therefore, the breakpoint sequence at the borders of SDs can also serve as a footprint to reveal an origin resulting from a NHEJ event.

3.1 Conservative mechanisms: DNA duplications without duplicating DNA

Large segmental polymorphism in a population can result in the emergence of large duplicated regions in some individual, as a direct consequence of meiosis/mitotic recombination and chromosome segregation. For instance, a translocation-based model could explain how NHEJ-mediated translocations were responsible for the segmental polymorphisms observed in human subtelomeres ([64]; Fig. 3A). This model is reminiscent of the translocation events shown to stabilize SDs in the yeast genome [65]. Dynamic subtelomeric plasticity may allow rapid generation of new alleles combinations or amplifications: for instance, Plasmodium falciparum telomeres carry large gene families involved in the adaptation of the parasite to the host [66,67]. Subsequent rearrangements can eventually disperse these regions all over the genome, ending up in the creation of true “hot-spot” of rearrangements undergoing positive selection [39].

Fig. 3

Conservative mechanisms of SD formation. (A) Inherited segmental polymorphism: a translocation of a large DNA segment from chromosome 1 to chromosome 2 can appear as a segmental duplication in offspring. (B) Unequal crossing-over between direct tandem (i) and interspersed (ii) repeats. (C) Break-Fusion-Bridge amplification. Black lightning: DSB formation along a chromatid. (D) NHEJ ligation model: two homologous chromatids each experiencing a DSB at different positions can lead to SD formation if incorrectly repaired by NHEJ.

3.1.1 The unequal crossing-over mantra

In most eukaryotic genomes, SDs consisting of DNA segments repeated as direct tandems are commonly found. Mitotic and meiotic NAHR events, resolved as unequal crossing-over, have been traditionally invoked to account for the presence of these structures within genomes [68,69]. These recombination events occur between identical regions located either within the same chromatid or on sister-chromatids. They can also occur between homologous chromosomes. These regions can be organized as direct tandems (e.g. the clusters of tandem rDNA units [70], Fig. 3B(i)) but also be separated by hundreds of kb (Fig. 3B(ii)). The size of these regions is variable and matters little, as long as they share a high identity. For instance, they can be large SDs generated beforehand, transposable elements or simple DNA regions containing one or more genes.

Larger chromosomal duplications can result from NAHR events [28]. A classical example consists in Type 1A Charcot-Marie-Tooth and Hereditary Neuropathy with liability to Pressure Palsies syndromes that result either from the gain or loss, respectively, of a 1.5 Mb segment from chromosome 17 following a NAHR event between two 24 kb SDs.

Recombination events between the repeated Alu transposable elements (∼300 bp size) have dramatically reshaped the genomic structure of eukaryotic genomes [71]. In humans, NAHR events between dispersed Alu sequences is a source of oncogenic duplications and deletions [72,73]. In the human genome approximately 27% of SDs are bordered by Alu repeats, whereas they constitute 10.6% of the total sequence [74]. As these sequences tend to be fixed within GC rich regions [75], that could explain why SDs have also colonized gene-rich regions of human chromosomes. However, the presence of repeated sequences at duplication breakpoints does not necessary reflect past occurrence of NAHR events: for instance, a study conducted in yeast revealed that the large spontaneous SDs recovered and flanked by dispersed repeated sequences (essentially Long Terminal Repeats (LTRs) from Ty retroposons [76]) actually result from BIR events (see below) [77]. In this assay, NAHR between repeated sequences are probably suppressed by the DNA divergence between LTRs.

3.1.2 Break-fusion-bridge amplification

Break-fusion-bridges (BFB) is a mechanism responsible for dynamic segmental amplification, notably within subtelomeric regions [78]. The amplification results from the fusion of two sister chromatids, after the loss of a telomere by degradation or because of a DSB improperly repaired. Telomeric proteins usually prevent such fusion from occurring, but sometimes a dicentric chromosome will be generated that will undergo a break during segregation because of the forces dragging the two centromeres towards opposite poles. As a consequence, one of the daughter cells will carry a deletion (Fig. 3C). The new break can be repaired through another chromatid fusion, followed by a new cycle, adding another duplicated unit at the end [79]. The resulting structure consists in series of direct/inverted tandems and eventually leads to gene dosage unbalance characterized in numerous tumorigenesis processes [52].

3.1.3 NHEJ

A subset of tandem SDs either observed in sequenced genomes or experimentally isolated present breakpoints made of few nucleotides, suggesting the involvement of a NHEJ event [76,80]. A conservative hypothesis would be that two sister/homologous chromatids, experiencing a DSB each at a different location and escaping integrity maintenance pathways, would be unified together (Fig. 3D). However, this mechanism appears unlikely in light of a recent study: these events are indeed suppressed in the absence of Pol32, a subunit of the major replicative DNA polymerase δ in S. cerevisiae (see below, [77]).

Although these mechanisms can result in duplications of large DNA regions, the resulting structures are not representative of the diversity of inter- and intrachromosomal SDs. Furthermore, despite the attractiveness of Alu- and other repeat-mediated SDs, such events would only effectively represent a subset of all SD junctions characterized so far [74]. In addition, the prerequisite for any NAHR events to occur consists in the initial presence in the genome of two copies of the region between which the recombination event will occur. As stated by Seymour Fogel in 1983 [81], “It is conceivable that the rate limiting step in tandem gene amplification is the very first event leading to the initial duplication. Once two or more copies of the segment are present, the likelihood of tandem amplification is much greater.” Other mechanisms must therefore play an even, if not more important, role for generating SDs so that a sequence could get duplicated without necessitating pre-existing duplicated sequences.

3.2 De-novo duplication: replication-dependant mechanisms

Invoking replication to account for SD formation may seems straightforward although the multiple roles played by replication are only emerging and remain partially unknown. Interestingly, recent data now favor original new models that are discussed below.

3.2.1 A direct, causative role for replication accidents

Only a subset of SDs breakpoints characterized in eukaryotic genomes are associated with repeated sequences (above). Other sequences, presenting the physicochemical properties of “fragile site”, i.e. regions where DSBs of the DNA molecule are more likely to occur, have been shown to be enriched at breakpoints as well [82]. Fragile sites are actually often associated with hotspots of eukaryotic chromosomal rearrangements as revealed experimentally in several studies, conducted notably in S. cerevisiae. The fragility of some of these loci appears directly linked to replication, the DNA molecule being more prone to break when replication progression is altered chemically and/or physically [83–87]. Improperly repaired, the resulting DSB could induce the formation of a chromosomal rearrangement. Interestingly, spontaneous SDs directly selected within the yeast genome also emphasize a fundamental interplay with DNA replication [76,77]. In these studies, more than 300 SDs (direct tandems as well as inter-chromosomal duplications), strongly reminiscent in size to mammalian SDs (∼40 to 600 kb) and with no constraints exerting on the location of their breakpoints, were isolated. More than 20% of the SDs analyzed were bordered by low complexity DNA sequences (poly A/T and trinucleotide repeats) known to interfere with progression of the replication fork. In addition, the frequency of SDs formation is tremendously enhanced when S-phase DNA damages are induced either by a mutation delaying the firing of replication origins [77,88] or in presence of the Top1 inhibitor, camptothecin [77]. A role for replication accidents in the emergence of SDs is thus supported by recurrent and concordant experimental observations.

3.2.2 Recombination-dependant replication

A DSB originating from replication fork collapse generates a single DNA free-end able to invade the allelic homologous locus on the sister chromatid. This recombination-dependant strand invasion can be followed by reassembly of a replication fork and its progression until the chromosome end through a BIR event [89,90]. However, the DNA free-end can also, and sometimes will, invade a homologous locus located at a non-allelic position, either on the sister-chromatid and upstream the break, or on a different chromosome. Replication fork reassembly will then lead either to a direct tandem SD or to a non-reciprocal translocation, respectively (Fig. 4A). This mechanism is dependent on Pol32, a subunit of the major replicative DNA polymerase δ in S. cerevisiae [91]. Interestingly, all of the recombination-mediated (Rad52-dependant) direct tandem SDs recovered in yeast are actually dependent on the presence of this protein [77], revealing a direct implication of inter sister-chromatid BIR events. In addition, some of the SDs observed in drosophila or recovered using an embryonic stem cell system [54,92] were proposed to result from a mechanisms derived from this classical model, the difference consisting in the possibility for the replication fork to disassemble and the DNA free end to reinvade the original chromosome (Fig. 4B). This model is experimentally supported by evidence of multiple rounds of strand invasion/replication progression in yeast [93].

Fig. 4

Replication-based mechanisms. Black squares stand for fragile sites slowing down replication forks. Black lightning represents emergence of a DSB at these fragile sites. Grey areas represent non-allelic homologous sequences (NAHS) or microhomologies dispersed within the genome, and are numbered for convenient reasons. (A) Intra- and interchromosomal BIR models. Following DSB, the 3′-end of the DSB (NAHS 1) invades a non-allelic region located either within the same chromosome (NAHS 2) or onto a different one (NAHS 3). Reassembly of a replication fork at these locations, and progression until the end of the chromosome will lead either to direct tandem or interchromosomal duplications. (B) Reinvasion & dissociation model. Following a DSB (i), a classical BIR event is engaged (ii). The replication fork progress, duplicating a large DNA region until a new dissociation occurs (iii). The 3′-end subsequently reinvades or is religated to the original chromosome (iv). (C) Replication factory switch of template and MMIR model. (i) Two replication forks of a same replicon co-localize within a replication factory (grey disk). Eventually, more than one replicon will be present within a factory. We propose that following stalling (ii), the replication fork disassembles (iii), leaving the lagging strand of one of the replicon bubble free to interact and invade, in a homologous-independent manner (through microhomology interactions, see MMIR [77]), a sequence located upstream along the chromosome in another replicon (iv). Reassembly of the fork at this location then allows duplication of a large region, using the neo-synthesized strand as a template. This mechanism will generate tandem or interchromosomal duplication depending whether the invading and invaded sequences are located on the same or on different chromosomes, respectively. A similar mechanism involving the leading strand can also be invoked (v) but appear less likely in regards to recently unveiled role for the DNA polymerase δ in replicating the lagging strand template [96].

3.2.3 Replication-based duplications: microhomology/microsatellite-induced replication (MMIR)

Interestingly, in yeast, the absence of all known DNA repair pathways (i.e. when HR (rad52Δ) and NHEJ/MMEJ (lig4Δrad1Δ) are suppressed) does not alter the rate of SD formation as compared to WT [77]. Whereas LTR sequences are not involved at the breakpoints, low-complexity as well as short identical sequences are commonly found. Thus, HR homology search is not necessary for distant sequences to interact. Furthermore, when recombination is impaired SDs appear both Pol32-dependant, and smaller and of a size reminiscent of the distance separating two replication origins [77]. These observations may be fundamental. Indeed, in budding yeast, two replication forks originating from the same origin are processed simultaneously at a single position defined as a replication factory [94]. Combined with evidence in fission yeast for a repeated replication factory “pattern” [95], it is possible that transient colocalization of two regions within a factory increases the chance of physical interactions between them without involvement of a HR step. A DNA free-end resulting from a collapsed replication fork will indeed be located in the vicinity of the symmetrical fork originating from the same origin. The 53 DNA strand may be able to spontaneously invade a sequence in its vicinity sharing a low complexity structure (such as polyA/T repeats), followed by the reassembly of a new replication fork (MMIR mechanism described in [77], Fig. 4C). Such replication factory switches of template may occur spontaneously and rather frequently (in yeast SD rate formation for a 1.6 kb locus is 10−7 event/cell/division). A recent report by Lupski and collaborators propose that the large PLP1 encompassing SDs that cause the dysmyelinating PMD disease could result from a DNA replication mechanism relying on template switching between microhomologous sequences [58]. The analysis of the junction sequences leads to the proposal that after the replication fork stalls or pauses, the lagging (or, but less likely, leading [96]) strand serially disengages and switches to another nearby replicating template without involving any DSB as the initiating event. This is consistent with results suggesting that SDs might not necessitate the presence of a DSB DNA free-end to occur: in the absence of all known DSB repair pathways in yeast, SD still form at a level close to the WT [77].

4 Conclusion

The histories of the duplicated structures found in eukaryotic genomes probably result from complex interplays between all these mechanisms. We distinguish replication fork switching of template as a key player leading to the primary amplification of any sequence in the genome. SDs emerge as natural events likely to occur at high frequencies anywhere in the genome, having a dramatic impact both onto eukaryotic genome evolution and chromosome dynamic.

First of all, duplicated regions containing entire genes will eventually become fixed into genomes [64,76]. Duplicated genes are thought to be the main source of new genes (neofunctionalization, subfunctionalization or degeneration-complementation, etc.) [97–100], and to promote genetic robustness [101].

Interestingly, SDs also lead to gene fusions and domain accretion without necessarily altering the pre-existing genes present in the genome (Fig. 2A, compare tandem to interspersed duplications [76,77]), allowing evolutionary “experiments” currently observed within genomes [13,102,103]. The intragenic sequences serving as SD breakpoints sometimes show specific features such as nucleotide repeats, and local amplifications/contraction that can induce protein changes and have important consequences.

SDs contributions to the evolutionary history of primate and other eukaryotic lineages remain a large field of investigation. Their consequences in terms of genome stability are intensively addressed because of their association with numerous human genomic diseases. Paradoxically, one possibility would be that the duplication of some DNA regions would be favored even though the genome stability is compromised by such expansion. The primate lineage would be dramatically affected by the positive selection of a subset of SDs despite the structural instability they generate [39,52]. Without a doubt, the near future will see more bridges thrown between these fields, which will shed new light onto the roles played by SDs in speciation processes and adaptation.

Acknowledgements

We thank Celia Payen and members from the Unité de Génétique moléculaire des levures (Institut Pasteur) for helpful discussions and Beth Weiner (Harvard University) for constructive reading of the manuscript. This work was supported by grants from the Association pour la Recherche sur le Cancer (3266), the Agence nationale de la recherche (ANR-05-BLAN0331) and by CNRS (GDR2354 “Génolevures II”).


References

[1] C.B. Bridges Non-disjunction as proof of the chromosome theory of heredity, Genetics, Volume 1 (1916), pp. 1-52

[2] C.B. Bridges Salivary chromosome maps with a key to the banding of the chromosomes of Drosophila melanogaster, Journal of Heredity, Volume 26 (1935), pp. 60-64

[3] E.B. Lewis A gene complex controlling segmentation in Drosophila, Nature, Volume 276 (1978), pp. 565-570

[4] W. McGinnis; R.L. Garber; J. Wirz; A. Kuroiwa; W.J. Gehring A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans, Cell, Volume 37 (1984), pp. 403-408

[5] H.J. Muller The origination of chromatin deficiencies as minute deletions subject to insertion elsewhere, Genetica, Volume 17 (1935), pp. 237-252

[6] B.W. Bainbridge; J.A. Roper Observations on the effects of a chromosome duplication in Aspergillus nidulans, J. Gen. Microbiol., Volume 42 (1966), pp. 417-424

[7] F. Daud; G.S. Ortori; J.A. Roper Spontaneous IR duplications generated at mitosis in Aspergillus nidulans: further evidence of a preferential site of transposed attachment, Genetics, Volume 110 (1985), pp. 229-245

[8] C.E. Sexton; J.A. Roper Spontaneous duplications and transpositions of a large chromosome segment in Aspergillus nidulans, J. Gen. Microbiol., Volume 130 (1984) no. Pt 3, pp. 583-595

[9] Y. Kuwada Meiosis in the pollen of mother cells in Zea Mays, L. Bot. Mag., Volume 25 (1911), p. 163

[10] G. Blanc; K.H. Wolfe Widespread paleopolyploidy in model plant species inferred from age distributions of duplicate genes, Plant Cell, Volume 16 (2004), pp. 1667-1678

[11] O. Jaillon; J.-M. Aury; P. Wincker “Changing by Doubling”, the impact of Whole Genome Duplication in the evolution of eukaryotes, C. R. Biologies, Volume 332 (2009), pp. 241-253

[12] J.A. Bailey; Z. Gu; R.A. Clark et al. Recent segmental duplications in the human genome, Science, Volume 297 (2002), pp. 1003-1007

[13] E.E. Eichler Recent duplication, domain accretion and the dynamic mutation of the human genome, Trends Genet., Volume 17 (2001), pp. 661-669

[14] J. Cheung; X. Estivill; R. Khaja; J.R. MacDonald; K. Lau; L.C. Tsui; S.W. Scherer Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence, Genome Biol., Volume 4 (2003), p. R25

[15] L. Zhang; H.H. Lu; W.Y. Chung; J. Yang; W.H. Li Patterns of segmental duplication in the human genome, Mol. Biol. Evol., Volume 22 (2005), pp. 135-141

[16] D.F. Conrad; T.D. Andrews; N.P. Carter; M.E. Hurles; J.K. Pritchard A high-resolution survey of deletion polymorphism in the human genome, Nat. Genet., Volume 38 (2006), pp. 75-81

[17] D.A. Hinds; A.P. Kloek; M. Jen; X. Chen; K.A. Frazer Common deletions and SNPs are in linkage disequilibrium in the human genome, Nat. Genet., Volume 38 (2006), pp. 82-85

[18] S.A. McCarroll; T.N. Hadnott; G.H. Perry et al. Common deletion polymorphisms in the human genome, Nat. Genet., Volume 38 (2006), pp. 86-92

[19] A.J. Iafrate; L. Feuk; M.N. Rivera; M.L. Listewnik; P.K. Donahoe; Y. Qi; S.W. Scherer; C. Lee Detection of large-scale variation in the human genome, Nat. Genet., Volume 36 (2004), pp. 949-951

[20] R. Redon; S. Ishikawa; K.R. Fitch et al. Global variation in copy number in the human genome, Nature, Volume 444 (2006), pp. 444-454

[21] J. Sebat; B. Lakshmi; J. Troge et al. Large-scale copy number polymorphism in the human genome, Science, Volume 305 (2004), pp. 525-528

[22] A.J. Sharp; D.P. Locke; S.D. McGrath et al. Segmental duplications and copy-number variation in the human genome, Am. J. Hum. Genet., Volume 77 (2005), pp. 78-88

[23] H.R. Slater; D.K. Bailey; H. Ren; M. Cao; K. Bell; S. Nasioulas; R. Henke; K.H. Choo; G.C. Kennedy High-resolution identification of chromosomal abnormalities using oligonucleotide arrays containing 116,204 SNPs, Am. J. Hum. Genet., Volume 77 (2005), pp. 709-726

[24] K.K. Wong; R.J. deLeeuw; N.S. Dosanjh et al. A comprehensive analysis of common copy-number variations in the human genome, Am. J. Hum. Genet., Volume 80 (2007), pp. 91-104

[25] G.M. Cooper; D.A. Nickerson; E.E. Eichler Mutational and selective effects on copy-number variants in the human genome, Nat. Genet., Volume 39 (2007), p. S22-S29

[26] J.O. Korbel; A.E. Urban; J.P. Affourtit et al. Paired-end mapping reveals extensive structural variation in the human genome, Science, Volume 318 (2007), pp. 420-426

[27] A.J. Sharp; S. Hansen; R.R. Selzer et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome, Nat. Genet., Volume 38 (2006), pp. 1038-1042

[28] P. Stankiewicz; J.R. Lupski Genome architecture, rearrangements and genomic disorders, Trends Genet., Volume 18 (2002), pp. 74-82

[29] I. Lahortiga; K. De Keersmaecker; P. Van Vlierberghe et al. Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia, Nat. Genet., Volume 39 (2007), pp. 593-595

[30] J.R. Pollack; T. Sorlie; C.M. Perou et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors, Proc. Natl. Acad. Sci. USA (2002)

[31] B.A. Weaver; A.D. Silk; C. Montagna; P. Verdier-Pinard; D.W. Cleveland Aneuploidy acts both oncogenically and as a tumor suppressor, Cancer Cell, Volume 11 (2007), pp. 25-36

[32] B.A. Weir; M.S. Woo; G. Getz et al. Characterizing the cancer genome in lung adenocarcinoma, Nature, Volume 450 (2007), pp. 893-898

[33] R. Ullmann; G. Turner; M. Kirchhoff et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation, Hum. Mutat., Volume 28 (2007), pp. 674-682

[34] M.C. Bonaglia; R. Giorda; R. Tenconi; M. Pessina; T. Pramparo; R. Borgatti; O. Zuffardi A 2.3 Mb duplication of chromosome 8q24.3 associated with severe mental retardation and epilepsy detected by standard karyotype, Eur. J. Hum. Genet., Volume 13 (2005), pp. 586-591

[35] A. Rovelet-Lecrux; D. Hannequin; G. Raux et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy, Nat. Genet., Volume 38 (2006), pp. 24-26

[36] T.J. Aitman; R. Dong; T.J. Vyse et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans, Nature, Volume 439 (2006), pp. 851-855

[37] P. Pisitkun; J.A. Deane; M.J. Difilippantonio; T. Tarasenko; A.B. Satterthwaite; S. Bolland Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication, Science, Volume 312 (2006), pp. 1669-1672

[38] E. Gonzalez; H. Kulkarni; H. Bolivar et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility, Science, Volume 307 (2005), pp. 1434-1440

[39] Z. Jiang; H. Tang; M. Ventura; M.F. Cardone; T. Marques-Bonet; X. She; P.A. Pevzner; E.E. Eichler Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution, Nat. Genet., Volume 39 (2007), pp. 1361-1368

[40] X. She; G. Liu; M. Ventura et al. A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications, Genome Res., Volume 16 (2006), pp. 576-583

[41] R.A. Gibbs; J. Rogers; M.G. Katze et al. Evolutionary and biomedical insights from the rhesus macaque genome, Science, Volume 316 (2007), pp. 222-234

[42] V. Goidts; L. Armengol; W. Schempp et al. Identification of large-scale human-specific copy number differences by inter-species array comparative genomic hybridization, Hum. Genet., Volume 119 (2006), pp. 185-198

[43] The Chimpanzee Sequencing and Analysis Consortium Initial sequence of the chimpanzee genome and comparison with the human genome, Nature, Volume 437 (2005), pp. 69-87

[44] Z. Cheng; M. Ventura; X. She et al. A genome-wide comparison of recent chimpanzee and human segmental duplications, Nature, Volume 437 (2005), pp. 88-93

[45] G.M. Wilson; S. Flibotte; P.I. Missirlis; M.A. Marra; S. Jones; K. Thornton; A.G. Clark; R.A. Holt Identification by full-coverage array CGH of human DNA copy number increases relative to chimpanzee and gorilla, Genome Res., Volume 16 (2006), pp. 173-181

[46] T.L. Newman; E. Tuzun; V.A. Morrison; K.E. Hayden; M. Ventura; S.D. McGrath; M. Rocchi; E.E. Eichler A genome-wide survey of structural variation between human and chimpanzee, Genome Res., Volume 15 (2005), pp. 1344-1356

[47] D.P. Locke; R. Segraves; L. Carbone; N. Archidiacono; D.G. Albertson; D. Pinkel; E.E. Eichler Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization, Genome Res., Volume 13 (2003), pp. 347-357

[48] J.A. Bailey; R. Baertsch; W.J. Kent; D. Haussler; E.E. Eichler Hotspots of mammalian chromosomal evolution, Genome Biol., Volume 5 (2004), p. R23

[49] E. Tuzun; J.A. Bailey; E.E. Eichler Recent segmental duplications in the working draft assembly of the brown Norway rat, Genome Res., Volume 14 (2004), pp. 493-506

[50] K. Lindblad-Toh; C.M. Wade; T.S. Mikkelsen et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog, Nature, Volume 438 (2005), pp. 803-819

[51] J.U. Pontius; J.C. Mullikin; D.R. Smith et al. Initial sequence and comparative analysis of the cat genome, Genome Res., Volume 17 (2007), pp. 1675-1689

[52] J.A. Bailey; E.E. Eichler Primate segmental duplications: crucibles of evolution, diversity and disease, Nat. Rev. Genet., Volume 7 (2006), pp. 552-564

[53] L.W. Hillier et al. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution, Nature, Volume 432 (2004), pp. 695-716

[54] A.S. Fiston-Lavier; D. Anxolabehere; H. Quesneville A model of segmental duplication formation in Drosophila melanogaster, Genome Res., Volume 17 (2007), pp. 1458-1470

[55] A. Coghlan; K.H. Wolfe Fourfold faster rate of genome rearrangement in nematodes than in Drosophila, Genome Res., Volume 12 (2002), pp. 857-867

[56] B. Dujon; D. Sherman; G. Fischer et al. Genome evolution in yeasts, Nature, Volume 430 (2004), pp. 35-44

[57] K.H. Wolfe; D.C. Shields Molecular evidence for an ancient duplication of the entire yeast genome, Nature, Volume 387 (1997), pp. 708-713

[58] J.A. Lee; C.M. Carvalho; J.R. Lupski A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders, Cell, Volume 131 (2007), pp. 1235-1247

[59] F. Pâques; J.E. Haber Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae, Microbiol. Mol. Biol. Rev., Volume 63 (1999), pp. 349-404

[60] Y. Aylon; M. Kupiec DSB repair: the yeast paradigm, DNA Repair (Amst), Volume 3 (2004), pp. 797-815

[61] B.O. Krogh; L.S. Symington Recombination proteins in yeast, Annu. Rev. Genet., Volume 38 (2004), pp. 233-271

[62] L. Chen; K. Trujillo; W. Ramos; P. Sung; A.E. Tomkinson Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes, Mol. Cell, Volume 8 (2001), pp. 1105-1115

[63] K. Riha; M.L. Heacock; D.E. Shippen The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology, Annu. Rev. Genet., Volume 40 (2006), pp. 237-277

[64] E.V. Linardopoulou; E.M. Williams; Y. Fan; C. Friedman; J.M. Young; B.J. Trask Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication, Nature, Volume 437 (2005), pp. 94-100

[65] R. Koszul; B. Dujon; G. Fischer Stability of large segmental duplications in the yeast genome, Genetics, Volume 172 (2006), pp. 2211-2222

[66] Q. Cheng; N. Cloonan; K. Fischer; J. Thompson; G. Waine; M. Lanzer; A. Saul Stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens, Mol. Biochem. Parasitol., Volume 97 (1998), pp. 161-176

[67] L.M. Corcoran; J.K. Thompson; D. Walliker; D.J. Kemp Homologous recombination within subtelomeric repeat sequences generates chromosome size polymorphisms in P. falciparum, Cell, Volume 53 (1988), pp. 807-813

[68] T. Ohta Simple model for treating evolution of multigene families, Nature, Volume 263 (1976), pp. 74-76

[69] G.P. Smith Evolution of repeated DNA sequences by unequal crossover, Science, Volume 191 (1976), pp. 528-535

[70] J.W. Szostak; R. Wu Unequal crossing over in the ribosomal DNA of Saccharomyces cerevisiae, Nature, Volume 284 (1980), pp. 426-430

[71] M.A. Batzer; P.L. Deininger Alu repeats and human genomic diversity, Nat. Rev. Genet., Volume 3 (2002), pp. 370-379

[72] B. Burwinkel; M.W. Kilimann Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease, J. Mol. Biol., Volume 277 (1998) no. 3, pp. 513-517

[73] P.L. Deininger; M.A. Batzer Alu repeats and human disease, Mol. Genet. Matabol., Volume 67 (1999) no. 3, pp. 183-193

[74] J.A. Bailey; G. Liu; E.E. Eichler An Alu transposition model for the origin and expansion of human segmental duplications, Am. J. Hum. Genet., Volume 73 (2003), pp. 823-834

[75] E.S. Lander; L.M. Linton; B. Birren et al. Initial sequencing and analysis of the human genome, Nature, Volume 409 (2001), pp. 860-921

[76] R. Koszul; S. Caburet; B. Dujon; G. Fischer Eucaryotic genome evolution through the spontaneous duplication of large chromosomal segments, EMBO J., Volume 23 (2004), pp. 234-243

[77] C. Payen; R. Koszul; B. Dujon; G. Fischer Segmental Duplications arise from Pol32-dependent Repair of Broken Forks through either Classical or Rad52-Independent Break-induced Replication, PLoS Genet., Volume 4 (2008) no. 9

[78] B. McClintock The stability of broken ends of chromosomes in Zea mays, Genetics, Volume 26 (1941), pp. 234-282

[79] J.P. Murnane Telomeres and chromosome instability, DNA Repair (Amst), 5 (2006), pp. 1082-1092

[80] J. Schacherer; J. de Montigny; A. Welcker; J.L. Souciet; S. Potier Duplication processes in Saccharomyces cerevisiae haploid strains, Nucleic Acids Res., Volume 33 (2005), pp. 6319-6326

[81] S. Fogel; J.W. Welch; G. Cathala; M. Karin Gene amplification in yeast: CUP1 copy number regulates copper resistance, Current Genetics, Volume 7 (1983), pp. 347-355

[82] Y. Zhou; B. Mishra Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling, Proc. Natl. Acad. Sci. USA, Volume 102 (2005), pp. 4051-4056

[83] A. Admire; L. Shanks; N. Danzl; M. Wang; U. Weier; W. Stevens; E. Hunt; T. Weinert Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast, Genes Dev., Volume 20 (2006), pp. 159-173

[84] R.S. Cha; N. Kleckner ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones, Science, Volume 297 (2002), pp. 602-606

[85] A. Coquelle; E. Pipiras; F. Toledo; G. Buttin; M. Debatisse Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons, Cell, Volume 89 (1997), pp. 215-225

[86] F.J. Lemoine; N.P. Degtyareva; K. Lobachev; T.D. Petes Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites, Cell, Volume 120 (2005), pp. 587-598

[87] M. Raveendranathan; S. Chattopadhyay; Y.T. Bolon; J. Haworth; D.J. Clarke; A.K. Bielinsky Genome-wide replication profiles of S-phase checkpoint mutants reveal fragile sites in yeast, EMBO J., Volume 25 (2006), pp. 3627-3639

[88] D.G. Gibson; J.G. Aparicio; F. Hu; O.M. Aparicio Diminished S-phase cyclin-dependent kinase function elicits vital Rad53-dependent checkpoint responses in Saccharomyces cerevisiae, Mol. Cell Biol., Volume 24 (2004), pp. 10208-10222

[89] A. Malkova; E.L. Ivanov; J.E. Haber Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication, Proc. Natl. Acad. Sci. USA, Volume 93 (1996), pp. 7131-7136

[90] A.P. Davis; L.S. Symington RAD51-dependent break-induced replication in yeast, Mol. Cell Biol., Volume 24 (2004), pp. 2344-2351

[91] J.R. Lydeard; S. Jain; M. Yamaguchi; J.E. Haber Break-induced replication and telomerase-independent telomere maintenance require Pol32, Nature, Volume 448 (2007), pp. 820-823

[92] C. Richardson; M.E. Moynahan; M. Jasin Double-strand break repair by interchromosomal recombination: suppression of chromosomal translocations, Genes Dev., Volume 12 (1998), pp. 3831-3842

[93] C.E. Smith; B. Llorente; L.S. Symington Template switching during break-induced replication, Nature, Volume 447 (2007), pp. 102-105

[94] E. Kitamura; J.J. Blow; T.U. Tanaka Live-cell imaging reveals replication of individual replicons in eukaryotic replication factories, Cell, Volume 125 (2006), pp. 1297-1308

[95] P. Meister; A. Taddei; A. Ponti; G. Baldacci; S.M. Gasser Replication foci dynamics: Replication patterns are modulated by S-phase checkpoint kinases in fission yeast, EMBO J., Volume 26 (2007) no. 5, pp. 1315-1326

[96] S.A. Nick McElhinny; D.A. Gordenin; C.M. Stith; P.M.J. Burgers; T.A. Kunkel Division of labor at the Eukaryotic replication fork, Mol. Cell, Volume 30 (2008), pp. 137-144

[97] M.A. Nowak; M.C. Boerlijst; J. Cooke; J.M. Smith Evolution of genetic redundancy, Nature, Volume 388 (1997), pp. 167-171

[98] A.L. Hughes The evolution of functionally novel proteins after gene duplication, Proc. R. Soc. Lond. B Biol. Sci., Volume 256 (1994), pp. 119-124

[99] S. Ohno, Springer-Verlag, New York, 1970

[100] G. Wistow; J. Piatigorsky Recruitment of enzymes as lens structural proteins, Science, Volume 236 (1987), pp. 1554-1556

[101] T. Kitami; J.H. Nadeau Biochemical networking contributes more to genetic buffering in human and mouse metabolic pathways than does gene duplication, Nat. Genet., Volume 32 (2002), pp. 191-194

[102] A. Courseaux; J.L. Nahon Birth of two chimeric genes in the Hominidae lineage, Science, Volume 291 (2001), pp. 1293-1297

[103] P. Stankiewicz; C.J. Shaw; M. Withers; K. Inoue; J.R. Lupski Serial segmental duplications during primate evolution result in complex human genome architecture, Genome Res., Volume 14 (2004), pp. 2209-2220


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