Gene Conversion Mechanism Research Articles

Characterization of adaptive immune receptors in hagfish (170.13)

Abstract Instead of the immunoglobulin based antigen receptors of jawed vertebrates, jawless fish use variable lymphocyte receptors (VLRs) comprised of leucine-rich-repeat (LRR) segments for antigen recognition. Two VLR genes, VLRA and VLRB, have been identified in both lampreys and hagfish. A third VLR, so called VLRC was recently discovered in lampreys. An extensive VLR repertoire is generated through the insertion of diverse LRR sequences into an incomplete germline VLR gene by a gene conversion mechanism. Earlier studies of sea lampreys have shown that VLRB lymphocytes resemble B cells of jawed vertebrates, whereas VLRA lymphocytes are similar to T cells. For the present studies, monoclonal and polyclonal antibodies against the invariant stalk regions of hagfish VLRA and VLRB were produced to identify the VLR-bearing lymphocytes and their products. Flow cytometric analysis indicated that VLRA and VLRB are expressed by separate lymphocyte populations, with VLRA lymphocytes being the dominant population. Western blot and gel-filtration analyses indicated that hagfish VLRB antibodies are released into the circulation as multimeric proteins that are formed by non-covalent linkage of four or five disulfide-bonded VLRB dimers. Conversely, soluble VLRA is not detected in hagfish plasma. These findings indicate that distinctive T-like and B-like lineages are a common feature of the adaptive immune system in both lampreys and hagfish, in keeping with their monophyletic relationship.

Mechanisms of Ectopic Gene Conversion

Gene conversion (conversion), the unidirectional transfer of DNA sequence information, occurs as a byproduct of recombinational repair of broken or damaged DNA molecules. Whereas excision repair processes replace damaged DNA by copying the complementary sequence from the undamaged strand of duplex DNA, recombinational mechanisms copy similar sequence, usually in another molecule, to replace the damaged sequence. In mitotic cells the other molecule is usually a sister chromatid, and the repair does not lead to genetic change. Less often a homologous chromosome or homologous sequence in an ectopic position is used. Conversion results from repair in two ways. First, if there was a double-strand gap at the site of a break, homologous sequence will be used as the template for synthesis to fill the gap, thus transferring sequence information in both strands. Second, recombinational repair uses complementary base pairing, and the heteroduplex molecule so formed is a source of conversion, both as heteroduplex and when donor (undamaged template) information is retained after correction of mismatched bases in heteroduplex. There are mechanisms that favour the use of sister molecules that must fail before ectopic homology can be used. Meiotic recombination events lead to the formation of crossovers required in meiosis for orderly segregation of pairs of homologous chromosomes. These events result from recombinational repair of programmed double-strand breaks, but in contrast with mitotic recombination, meiotic recombinational events occur predominantly between homologous chromosomes, so that transfer of sequence differences by conversion is very frequent. Transient recombination events that do not form crossovers form both between homologous chromosomes and between regions of ectopic homology, and leave their mark in the occurrence of frequent non-crossover conversion, including ectopic conversion.

The ribosomal basis of diamond-blackfan anemia: mutation and database update

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.

Genome Copy Numbers and Gene Conversion in Methanogenic Archaea

Previous studies revealed that one species of methanogenic archaea, Methanocaldococcus jannaschii, is polyploid, while a second species, Methanothermobacter thermoautotrophicus, is diploid. To further investigate the distribution of ploidy in methanogenic archaea, species of two additional genera-Methanosarcina acetivorans and Methanococcus maripaludis-were investigated. M. acetivorans was found to be polyploid during fast growth (t(D) = 6 h; 17 genome copies) and oligoploid during slow growth (doubling time = 49 h; 3 genome copies). M. maripaludis has the highest ploidy level found for any archaeal species, with up to 55 genome copies in exponential phase and ca. 30 in stationary phase. A compilation of archaeal species with quantified ploidy levels reveals a clear dichotomy between Euryarchaeota and Crenarchaeota: none of seven euryarchaeal species of six genera is monoploid (haploid), while, in contrast, all six crenarchaeal species of four genera are monoploid, indicating significant genetic differences between these two kingdoms. Polyploidy in asexual species should lead to accumulation of inactivating mutations until the number of intact chromosomes per cell drops to zero (called "Muller's ratchet"). A mechanism to equalize the genome copies, such as gene conversion, would counteract this phenomenon. Making use of a previously constructed heterozygous mutant strain of the polyploid M. maripaludis we could show that in the absence of selection very fast equalization of genomes in M. maripaludis took place probably via a gene conversion mechanism. In addition, it was shown that the velocity of this phenomenon is inversely correlated to the strength of selection.

TURNIP: tracking unresolved nucleotide polymorphisms in large hard-to-assemble regions of repetitive DNA sequence

TURNIP comprises a suite of Perl scripts and modules that facilitates the resolution of microheterogeneity within hard-to-assemble repetitive DNA sequences. TURNIP was originally developed for the Saccharomyces Genome Resequencing Project (SGRP) within which the ribosomal DNA (rDNA) of 36 strains of S.cerevisiae were analysed to investigate the occurrence of potential polymorphisms. Here, 'partially resolved SNPs', or pSNPs, as well as indels, were found to be far more prevalent than previously suspected. More generally, the TURNIP software ascertains degrees of variation between large tandem repeats within a single locus, offering insights into mechanisms of genome stability and gene conversion in any organism for which genome sequence data are available. The TURNIP source code, results files and online help are available at http://www.ncyc.co.uk/software/turnip.html.

Mosaic gene conversion after a tandem duplication of mtDNA sequence in Diomedeidae (albatrosses)

Although the tandem duplication of mitochondrial (mt) sequences, especially those of the control region (CR), has been detected in metazoan species, few studies have focused on the features of the duplicated sequence itself, such as the gene conversion rate, distribution patterns of the variation, and relative rates of evolution between the copies. To investigate the features of duplicated mt sequences, we partially sequenced the mt genome of 16 Phoebastria albatrosses belonging to three species (P. albatrus, P. nigripes, and P. immutabilis). More than 2,300 base pairs of tandemly-duplicated sequence were shared by all three species. The observed gene arrangement was shared in the three Phoebastria albatrosses and suggests that the duplication event occurred in the common ancestor of the three species. Most of the copies in each individual were identical or nearly identical, and were maintained through frequent gene conversions. By contrast, portions of CR domains I and III had different phylogenetic signals, suggesting that gene conversion had not occurred in those sections after the speciation of the three species. Several lines of data, including the heterogeneity of the rate of molecular evolution, nucleotide differences, and putative secondary structures, suggests that the two sequences in CR domain I are maintained through selection; however, additional studies into the mechanisms of gene conversion and mtDNA synthesis are required to confirm this hypothesis.

Genome-wide computational prediction of tandem gene arrays: application in yeasts

BackgroundThis paper describes an efficient in silico method for detecting tandem gene arrays (TGAs) in fully sequenced and compact genomes such as those of prokaryotes or unicellular eukaryotes. The originality of this method lies in the search of protein sequence similarities in the vicinity of each coding sequence, which allows the prediction of tandem duplicated gene copies independently of their functionality.ResultsApplied to nine hemiascomycete yeast genomes, this method predicts that 2% of the genes are involved in TGAs and gene relics are present in 11% of TGAs. The frequency of TGAs with degenerated gene copies means that a significant fraction of tandem duplicated genes follows the birth-and-death model of evolution. A comparison of sequence identity distributions between sets of homologous gene pairs shows that the different copies of tandem arrayed paralogs are less divergent than copies of dispersed paralogs in yeast genomes. It suggests that paralogs included in tandem structures are more recent or more subject to the gene conversion mechanism than other paralogs.ConclusionThe method reported here is a useful computational tool to provide a database of TGAs composed of functional or nonfunctional gene copies. Such a database has obvious applications in the fields of structural and comparative genomics. Notably, a detailed study of the TGA catalog will make it possible to tackle the fundamental questions of the origin and evolution of tandem gene clusters.

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

BackgroundDepending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts.MethodsThe main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes.ResultsWe found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region.ConclusionLGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.

Inter- and intra-genomic heterogeneity of the intervening sequence in the 23S ribosomal RNA gene of Campylobacter jejuni and Campylobacter coli

An intervening sequence (IVS) can be present or absent in the 23S rRNA of Campylobacter jejuni and Campylobacter coli. As part of a survey, we used a polymerase chain reaction (PCR) assay to detect the presence of the IVS in 43 isolates of C. coli and 82 isolates of C. jejuni. An IVS was present in 40 (93.0%) of the C. coli and only 34 (41.5%) of the C. jejuni isolates. Twelve (27.9%) of the C. coli isolates and seven (8.5%) of the C. jejuni isolates resulted in two polymerase chain reaction products, indicating heterogeneity in the presence of the 23S rRNA IVS. Fourteen of the isolates with two products were evaluated by pulse-field gel electrophoresis; 13 different patterns were observed. The total band size of one isolate was substantially greater than the expected 1.7 Mb, possibly indicating a mixed culture. Southern blot analyses demonstrated the expected three rRNA operons in all tested isolates. Nested PCR reactions with operon-specific primers followed by primers for the IVS confirmed that the strains of interest contained either one or two operons carrying the IVS and the remaining operon(s) did not. Sequence analysis of the IVS and flanking regions of the 23S rRNA genes did not discriminate C. jejuni and C. coli as distinct populations. These results indicate horizontal transfer of 23S rRNA genes or portions of the genes between C. jejuni and C. coli. Also, data showing sequence polymorphisms between the three 23S rRNA loci outside of the IVS region suggest that the isolates with intra-genomic heterogeneity appear to be members of clones that have an ancient defect in gene conversion mechanisms needed for concerted evolution of the ribosomal operons.

Repetitive sequence variation and dynamics in the ribosomal DNA array of Saccharomyces cerevisiae as revealed by whole-genome resequencing.

Ribosomal DNA (rDNA) plays a key role in ribosome biogenesis, encoding genes for the structural RNA components of this important cellular organelle. These genes are vital for efficient functioning of the cellular protein synthesis machinery and as such are highly conserved and normally present in high copy numbers. In the baker's yeast Saccharomyces cerevisiae, there are more than 100 rDNA repeats located at a single locus on chromosome XII. Stability and sequence homogeneity of the rDNA array is essential for function, and this is achieved primarily by the mechanism of gene conversion. Detecting variation within these arrays is extremely problematic due to their large size and repetitive structure. In an attempt to address this, we have analyzed over 35 Mbp of rDNA sequence obtained from whole-genome shotgun sequencing (WGSS) of 34 strains of S. cerevisiae. Contrary to expectation, we find significant rDNA sequence variation exists within individual genomes. Many of the detected polymorphisms are not fully resolved. For this type of sequence variation, we introduce the term partial single nucleotide polymorphism, or pSNP. Comparative analysis of the complete data set reveals that different S. cerevisiae genomes possess different patterns of rDNA polymorphism, with much of the variation located within the rapidly evolving nontranscribed intergenic spacer (IGS) region. Furthermore, we find that strains known to have either structured or mosaic/hybrid genomes can be distinguished from one another based on rDNA pSNP number, indicating that pSNP dynamics may provide a reliable new measure of genome origin and stability.

Second-End Capture in DNA Double-Strand Break Repair Promoted by Brh2 Protein of Ustilago maydis

Brh2 plays a central role in the homologous recombination system of Ustilago maydis, mediating delivery of Rad51 to single-stranded DNA. Here we report that Brh2 can pair the displaced strand of a D loop with a complementary single-stranded DNA to form a duplexed, or double, D loop. The reaction emulates the second-end capture step envisioned in models of DNA double-strand break repair. This second-end capture reaction promoted by Brh2 proceeds efficiently when performed in the presence of Rad51 under conditions that block annealing by Rad52, or when the second single-stranded DNA substrate is replaced by double-stranded DNA. In a coupled reaction that requires extension of the D loop more than 200 nt by DNA synthesis in order to reveal a complementary region, Brh2 was also able to promote second-end capture and thus model a synthesis-dependent strand-annealing mechanism.

Enhanced heterogeneity of the LR2 segment in the human ribosomal intergenic spacer

Human ribosomal intergenic spacer (rIGS) contains in its central part two highly homologous 2 kb repeats, LR1 and LR2. In this paper, we investigate heterogeneity of the variable LR2 segment (LR2 var) in the human rIGS. More than 500 LR2 var copies from ten unrelated human genomes have been cloned and sequenced. Prolonged (G) n (AG) m compound microsatellite clusters with ‘ n’ and ‘ m’ notions fluctuating in random manner span central parts of almost all LR2 var variants. Nucleotide sequences flanking the central microsatellite clusters are represented by more than 30 structural groups, with the two major (A and B) and six minor (C–H) ones. The analysis of sequencing data let us propose that the LR2 var variability can be derived by various ways, including microsatellite DNA slip-strand mispairing during replication, non-equal crossover and segmental DNA exchange between LR1 var and LR2 var through the mechanism of gene conversion.

Structure and Specificity of Lamprey Monoclonal Antibodies

The adaptive immune system of the extant agnathans (lamprey and hagfish) is comprised of clonally diverse lymphocytes that express variable lymphocyte receptors (VLRs) created by the combinatorial assembly of leucine‐rich repeat (LRR) gene segments. During the development of lymphocyte lineage cells, components of the flanking LRR modular units are sequentially inserted into the incomplete germline VLR gene via a gene conversion mechanism to create a potential repertoire of > 1014distinct VLR‐B antibodies. To generate VLR‐B antibody‐secreting cells, we developed a heterologous expression system consisting of HEK‐293T cells transfected with VLR‐B cDNAs. Antigen‐specific VLR‐B antibody clones were isolated by screening VLR‐B cDNA libraries, derived from the lymphocytes of immunized lamprey, for antigen binding. The recombinant VLR‐B antibodies consisted of 8 – 10 uniform subunits arranged into disulfide‐linked tetramers and pentamers of dimers that collectively bind antigen with high avidity. Sequence analysis, mutagenesis, and modeling of antigen‐specific VLR‐B antibodies demonstrated that the primary antigen‐binding site resides in the β ‐sheets of the LRR subunits lining the VLR‐B concave surface. The remarkable antigen‐binding specificity, avidity, and stability of these unusual LRR‐based monoclonal antibodies suggest they will find many biomedical uses.

Mitochondrial Genome of the Colorless Green Alga Polytomella capuana: A Linear Molecule with an Unprecedented GC Content

One common observation concerning mitochondrial genomes is that they have a low guanine and cytosine content (GC content); of the complete mitochondrial genome sequences currently available at the National Center for Biotechnology Information (NCBI) (July 2007), the GC content ranges from 13.3% to 53.2% and has an average value of 38%. Here, we present the GC-rich mitochondrial genome (57% GC) of the colorless green alga Polytomella capuana. The disproportion of GC among the different regions of the P. capuana mitochondrial DNA (mtDNA) suggests that a neutral process is responsible for the GC bias. We propose that a biased gene conversion mechanism resulted in the GC-rich state of the P. capuana mtDNA. In addition, our analysis indicates that the P. capuana mitochondrial genome is a single 13-kb linear molecule with telomeres, which have a closed (hairpin-loop) conformation: a novel terminal structure among described linear green-algal mtDNAs. Furthermore, using a series of GC-rich inverted repeats found within the P. capuana mitochondrial genome, we describe recombination-based scenarios of how intact linear mtDNA conformations can be converted into the fragmented forms found in other Polytomella taxa.

A mechanism for gene conversion in fungi

A mechanism for gene conversion is proposed which overcomes many of the difficulties that any copy choice model encounters. It is suggested that along with general genetic pairing of homologous genomes at meiosis, effective pairing over short regions of the genetic material occurs at the molecular level by the separation of the strands of the DNA double helices, followed by the annealing of strands from two homologous chromatids. If the annealed region happens to span a heterozygous site, mispairing of bases will occur. Such a situation may be analogous to that in DNA which is damaged by mutagens; the same or similar repair mechanisms may operate, and these, by adjusting the base sequences in order to restore normal base pairing, would bring about gene conversion in the absence of any genetic replication. The model indicates how precise breakage and rejoining of chromatids could occur in the vicinity of the conversion, so that conversion would frequently be accompanied by the recombination of outside markers. The model also proposes that the distance between two mutant sites on a fine structure map depends not so much on the frequency of a recombinational event occurring between them, but rather on the degree of inhibition of the processes of genetic pairing by the mutants themselves. The model will explain almost all the data in a formal way, and it has the advantage over copy choice mechanisms for gene conversion in (1) being compatible with semi-conservative replication of DNA, (2) not invoking DNA synthesis during or after genetic pairing, (3) providing a molecular mechanism for close specific pairing, (4) making it unnecessary to postulate sister strand exchange or a process akin to this, (5) suggesting why rates of gene conversion in opposite directions are sometimes unequal and (6) providing an explanation of the clustering of mutant sites, a basis for map expansion and for the apparently capricious departure of fine structure maps from additivity. Although the model proposed is a general rather than a specific one, it suggests that the process of conversion and intragenic recombination is more complex than is usually believed, since it depends on several interacting factors. Nevertheless, it is hoped that the introduction of a model with this complexity will help to stimulate specific experiments, and that these will provide definitive information which would never be obtained if simpler models of conversion and intragenic recombination were believed to explain the genetic data sufficiently well.

Holliday junctions, heteroduplex DNA and map expansion: a commentary on ‘A mechanism for gene conversion in fungi’ by Robin Holliday

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Sequence diversity and evolution of multigene families in Trypanosoma cruzi

Several copies of genes belonging to three multigene families present in the genome of Trypanosoma cruzi were sequenced and comparatively analyzed across six different strains of the parasite belonging to the T. cruzi I lineage (Colombiana, Silvio X10 and Dm28c), the T. cruzi II lineage (Esmeraldo and JG) and a hybrid strain (CL Brener). For all three gene families analyzed, our results support the division in T. cruzi I and II lineages. Furthermore, in agreement with its hybrid nature, sequences derived from the CL Brener clone clustered together with T. cruzi II sequences as well as with a third group of sequences. Paralogous sequences encoding Amastin, an amastigote surface glycoprotein and TcAG48, an antigenic RNA binding protein, which are clustered in the parasite genome, present higher intragenomic variability in T. cruzi II and CL Brener strains, when compared to T. cruzi I strains. Paralogous sequences derived from the TcADC gene family, which encode various isoforms of adenylyl cyclases and are dispersed throughout the T. cruzi genome, exhibit similar degree of variability in all strains, except in the CL Brener strain, in which the sequences were more divergent. Several factors including mutation rates and gene conversion mechanisms, acting differently within the T. cruzi population, may contribute to create such distinct levels of sequence diversity in multigene families that are clustered in the T. cruzi genome.

Maintenance of Antibody to Pathogen Epitopes Generated by Segmental Gene Conversion Is Highly Dynamic during Long-Term Persistent Infection

Multiple bacterial and protozoal pathogens utilize gene conversion to generate rapid intrahost antigenic variation. Both large- and small-genome pathogens expand the size of the variant pool via a combinatorial process in which oligonucleotide segments from distinct donor loci are recombined in various combinations into expression sites. Although the potential combinatorial diversity generated by this segmental gene conversion mechanism is quite large, the functional variant pool depends on whether immune responses against the recombined segments are generated and maintained, regardless of their specific combinatorial context. This question was addressed by tracking the Anaplasma marginale variant population and corresponding segment-specific immunoglobulin G (IgG) antibody responses during long-term infection. Antibody was induced early in A. marginale infection, predominately against the surface-exposed hypervariable region (HVR) rather than against the invariant conserved flanking domains, and these HVR oligopeptides were most immunogenic at the time of acute bacteremia, when the variant population is derived via recombination from a single donor locus. However antibody to HVR oligopeptides was not consistently maintained during persistent infection, despite reexpression of the same segment, although in a different combinatorial context. This dynamic antibody recognition over time was not attributable to the major histocompatibility complex haplotype of individual animals or use of specific msp2 donor alleles. In contrast, the position and context of an individual oligopeptide segment within the HVR were significant determinants of antibody recognition. The results unify the genetic potential of segmental gene conversion with escape from antibody recognition and identify immunological effects of variant mosaic structure.

Neural logic molecular, counter-intuitive

A hypothesis is proposed that multiple “ LOGIC” genes control Boolean logic in a neuron. Each hypothetical LOGIC gene encodes a transcription factor that regulates another LOGIC gene(s). Through transcription regulation, LOGIC genes connect into a complex circuit, such as a XOR logic gate or a two-input flip–flop logic circuit capable of retaining information. LOGIC gene duplication, mutation and recombination may result in the diversification of Boolean logic gates. Creative thinking may sometimes require counter-intuitive reasoning, rather than common sense. Such reasoning is likely to engage novel logic circuits produced by LOGIC somatic mutations. An individual's logic maturates by a mechanism of somatic hypermutation, gene conversion and recombination of LOGIC genes in precursor cells followed by selection of neurons in the brain for functional competence. In this model, a single neuron among billions in the brain may contain a unique logic circuit being the key to a hard intellectual problem. The output of a logic neuron is likely to be a neurotransmitter. This neuron is connected to other neurons in the spiking neural network. The LOGIC gene hypothesis is testable by molecular techniques. Understanding mechanisms of authentic human ingenuity may help to invent digital systems capable of creative thinking.

Template switching during break-induced replication

DNA double-strand breaks (DSBs) are potentially lethal lesions that arise spontaneously during normal cellular metabolism, as a consequence of environmental genotoxins or radiation, or during programmed recombination processes. Repair of DSBs by homologous recombination generally occurs by gene conversion resulting from transfer of information from an intact donor duplex to both ends of the break site of the broken chromosome. In mitotic cells, gene conversion is rarely associated with reciprocal exchange and thus limits loss of heterozygosity for markers downstream of the site of repair and restricts potentially deleterious chromosome rearrangements. DSBs that arise by replication fork collapse or by erosion of uncapped telomeres have only one free end and are thought to repair by strand invasion into a homologous duplex DNA followed by replication to the chromosome end (break-induced replication, BIR). BIR from one of the two ends of a DSB would result in loss of heterozygosity, suggesting that BIR is suppressed when DSBs have two ends so that repair occurs by the more conservative gene conversion mechanism. Here we show that BIR can occur by several rounds of strand invasion, DNA synthesis and dissociation. We further show that chromosome rearrangements can occur during BIR if dissociation and reinvasion occur within dispersed repeated sequences. This dynamic process could function to promote gene conversion by capture of the displaced invading strand at two-ended DSBs to prevent BIR.