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PubMed2026

Age-related distribution of homologous recombination deficiency in advanced ovarian carcinoma: a large real-world French cohort.

OBJECTIVE: Tumor genetic testing for BRCA and homologous recombination repair is essential for guiding maintenance therapy in high-grade non-mucinous ovarian carcinomas. While clinical trials (PAOLA-1, PRIMA, ATHENA-MONO, PRIME) have reported homologous recombination deficiency rates of 44% to 67% in cohorts with a median age of 61, real-world data suggest age-related variations. We aimed to evaluate homologous recombination deficiency prevalence in a large French population and hypothesized a distribution pattern similar to the recent German findings published in 2022, in which older age correlated with lower homologous recombination deficiency rates. METHODS: We retrospectively analyzed advanced ovarian carcinoma cases referred to the Dijon Cancer Center from 191 care centers between 2022 and 2024 for Myriad MyChoice homologous recombination deficiency testing. Data collected included age, histologic type, homologous recombination deficiency status, homologous recombination proficiency status, and genomic instability scores. We compared the distribution of homologous recombination deficiency and HRP tumors in women <60 and ≥60 years using the χ2 test. RESULTS: In 1322 advanced ovarian carcinoma cases with a median age of 70.1 years, the overall rates were 35.3% homologous recombination deficiency and 64.7% homologous recombination proficiency. A sub-analysis of 1226 high-grade cases (median age 70.4; including high-grade serous carcinoma, clear-cell carcinoma, undifferentiated carcinomas, and carcinosarcoma) showed 36.5% homologous recombination deficiency and 63.5% homologous recombination proficiency. Notably, patients aged ≥60 years had a significantly higher likelihood of presenting with a homologous recombination proficiency tumor compared with those aged <60 years (65.8% vs 53.2%, p < .001). Among 42 clear-cell carcinoma cases, 97.6% exhibited homologous recombination proficiency status. CONCLUSIONS: In this large real-world cohort of advanced ovarian carcinoma, we observed a notably higher prevalence of homologous recombination proficiency tumors compared to the 4 clinical trials reported in the literature, with homologous recombination proficiency incidence increasing significantly with age. Given that older patients predominantly present with homologous recombination proficiency tumors, which are associated with poorer survival, treatment strategies should be adjusted to better address the specific needs of this demographic.

Humans↗

PubMed2001

Crossing over is rarely associated with mitotic intragenic recombination in Schizosaccharomyces pombe.

Chromosomal rearrangements can result from crossing over during ectopic homologous recombination between dispersed repetitive DNA. We have previously shown that meiotic ectopic recombination between artificially dispersed ade6 heteroalleles in the fission yeast Schizosaccharomyces pombe frequently results in chromosomal rearrangements. The same recombination substrates have been studied in mitotic recombination. Ectopic recombination rates in haploids were approximately 1-4 x 10(-6) recombinants per cell generation, similar to allelic recombination rates in diploids. In contrast, ectopic recombination rates in heterozygous diploids were 2.5-70 times lower than allelic recombination or ectopic recombination in haploids. These results suggest that diploid-specific factors inhibit ectopic recombination. Very few crossovers occurred in ade6 mitotic recombination, either allelic or ectopic. Allelic intragenic recombination was associated with 2% crossing over, and ectopic recombination between multiple different pairing partners showed 1-7% crossing over. These results contrast sharply with the 35-65% crossovers associated with meiotic ade6 recombination and suggest either differential control of resolution of recombination intermediates or alternative pathways of recombination in mitosis and meiosis.

Alleles↗

PubMed1989

Fibroblast interleukin 1 beta: synergistic stimulation by recombinant interleukin 1 and tumor necrosis factor and posttranscriptional regulation.

To understand the role fibroblasts play in mediating and amplifying the effects of inflammatory cytokines, we determined whether recombinant interleukin 1 (IL-1) and recombinant tumor necrosis factor (TNF), alone and in combination, stimulated fibroblasts to produce IL-1 beta. Recombinant IL-1 (alpha and beta) stimulated fibroblast IL-1 beta mRNA accumulation, whereas recombinant TNF did not. In addition, simultaneous stimulation with recombinant IL-1 (alpha or beta) and recombinant TNF resulted in a synergistic increase in IL-1 beta mRNA levels. However, in all cases, IL-1 beta mRNA accumulation was not associated with fibroblast production of soluble IL-1 beta protein. Lysates of unstimulated, recombinant IL-1-stimulated, and recombinant TNF-stimulated fibroblasts did not contain IL-1 beta prohormone. In contrast, IL-1 beta prohormone was detected in lysates of fibroblasts incubated simultaneously with recombinant IL-1 and recombinant TNF. These studies demonstrate that recombinant IL-1 stimulates fibroblast IL-1 beta mRNA accumulation and that recombinant IL-1 and recombinant TNF synergize to further up-regulate IL-1 beta mRNA levels. In addition, they show that IL-1 beta production by human lung fibroblasts is inhibited at a posttranscriptional level. Translational control appears to be important in recombinant IL-1-stimulated fibroblasts and posttranslational control is important in fibroblasts stimulated simultaneously with recombinant IL-1 and recombinant TNF.

Antibodies↗

PubMed2006

Influence of sequence identity and unique breakpoints on the frequency of intersubtype HIV-1 recombination.

BACKGROUND: HIV-1 recombination between different subtypes has a major impact on the global epidemic. The generation of these intersubtype recombinants follows a defined set of events starting with dual infection of a host cell, heterodiploid virus production, strand transfers during reverse transcription, and then selection. In this study, recombination frequencies were measured in the C1-C4 regions of the envelope gene in the presence (using a multiple cycle infection system) and absence (in vitro reverse transcription and single cycle infection systems) of selection for replication-competent virus. Ugandan subtypes A and D HIV-1 env sequences (115-A, 120-A, 89-D, 122-D, 126-D) were employed in all three assay systems. These subtypes co-circulate in East Africa and frequently recombine in this human population. RESULTS: Increased sequence identity between viruses or RNA templates resulted in increased recombination frequencies, with the exception of the 115-A virus or RNA template. Analyses of the recombination breakpoints and mechanistic studies revealed that the presence of a recombination hotspot in the C3/V4 env region, unique to 115-A as donor RNA, could account for the higher recombination frequencies with the 115-A virus/template. Single-cycle infections supported proportionally less recombination than the in vitro reverse transcription assay but both systems still had significantly higher recombination frequencies than observed in the multiple-cycle virus replication system. In the multiple cycle assay, increased replicative fitness of one HIV-1 over the other in a dual infection dramatically decreased recombination frequencies. CONCLUSION: Sequence variation at specific sites between HIV-1 isolates can introduce unique recombination hotspots, which increase recombination frequencies and skew the general observation that decreased HIV-1 sequence identity reduces recombination rates. These findings also suggest that the majority of intra- or intersubtype A/D HIV-1 recombinants, generated with each round of infection, are not replication-competent and do not survive in the multiple-cycle system. Ability of one HIV-1 isolate to outgrow the other leads to reduced co-infections, heterozygous virus production, and recombination frequencies.

Base Sequence↗

PubMed1995

Experimental spinal fusion with recombinant human bone morphogenetic protein-2.

STUDY DESIGN: Lumbar intertransverse process arthrodesis using recombinant human bone morphogenetic protein-2 was performed in a previously established rabbit model for posterolateral spinal fusion and compared with fusions achieved using autogenous bone graft. OBJECTIVES: To qualitatively compare different recombinant human bone morphogenetic protein-2 dosages and carriers and to determine the efficacy of recombinant human bone morphogenetic protein-2 as a bone graft substitute to produce lumbar intertransverse process fusion in a validated rabbit model for posterolateral spinal fusion. SUMMARY OF BACKGROUND DATA: Autogenous bone was considered the most successful bone graft material used for spinal arthrodesis. Problems with its use may occur in 25-30% of patients and prompted the search for and investigation of bone graft substitutes and osteoinductive growth factors, such as bone morphogenetic proteins. Recombinant human bone morphogenetic protein-2 was used successfully in orthotopic sites to generate bone in animal mandibular and long bone defect models. METHODS: Posterolateral intertransverse process arthrodeses were performed at L5-L6 in 56 rabbits using recombinant human bone morphogenetic protein-2 or autogenous bone graft. Rabbits were killed either 5 weeks later to qualitatively compare fusions achieved using different recombinant human bone morphogenetic protein-2 dosages and carriers or 4 weeks later to compare the efficacy of recombinant human bone morphogenetic protein-2 in achieving spinal fusion compared with using autogenous bone graft. Inspection, manual palpation, radiography, histology, and biomechanic testing were used to assess the fusion. RESULTS: All rabbits implanted with recombinant human bone morphogenetic protein-2 achieved solid spinal fusion by manual palpation and were fused radiographically, whereas only 42% of the autograft control fusions were solid. More mature fusions with greater trabecular bone formation were shown radiographically and histologically in rabbits implanted with the high-dose recombinant human bone morphogenetic protein-2 than with the low-dose recombinant human bone morphogenetic protein-2. Fusions achieved using recombinant human bone morphogenetic protein-2 delivered in the collagen carrier were more remodeled and homogeneous compared with using recombinant human bone morphogenetic protein-2 delivered in autograft +/- collagen carrier. Fusions achieved with recombinant human bone morphogenetic protein-2 were biomechanically stronger and stiffer than fusions achieved using autogenous bone graft. CONCLUSIONS: Recombinant human bone morphogenetic protein-2 successfully and reliably achieved lumbar intertransverse process fusion in a validated rabbit model for posterolateral spinal fusion. Radiographically and histologically, greater and more rapid bone formation, consolidation, and remodeling were shown with recombinant human bone morphogenetic protein-2 compared with autogenous bone graft. Fusions achieved with recombinant human bone morphogenetic protein-2 were biomechanically stronger and stiffer than autograft fusions.

Animals↗

PubMed2026

Homologous recombination-deficient high-grade serous ovarian cancers exhibit distinct morphological features.

OBJECTIVE: Access to homologous recombination testing remains limited in many centers. We aim to correlate the morphology and immunophenotype of high-grade serous ovarian carcinoma with homologous recombination statuses. METHODS: A retrospective analysis of a high-grade serous ovarian carcinoma tumors with known homologous recombination status. A pathological review of morphology was performed for each tumor, along with immunohistochemical profiling. Tumor morphology was classified as (1) solid, pseudo-endometrioid, or transitional (2) micropapillary or nested. RESULTS: Overall, 81 tumors were included. The median age was 62 (interquartile range; 52-71). Of those, 27 (33.3%) tumors were BRCA1mut, 19 (23.5%) were BRCA2mut, 15 (18.5%) tumors had no BRCA1 or BRCA2 mutations but exhibited a genomic instability score ≥42 and were classified as BRCA1/2-wild-type with homologous recombinant deficient. The remainder 20 (24.7%) cases were homologous recombinant proficient. The proportion of tumors with solid transitional-like morphology was higher in BRCA1 (12/21, 57%) and BRCA2 (12/18, 67%) compared to the tumors with homologous recombinant proficient (3/17, 18%), p =.019. When stratified by genomic instability score, tumors with low score (genomic instability score <26) exhibited 0% solid transitional-like morphology versus 43% solid transitional-like morphology in high-score (genomic instability score >26), p =.03. PAX8 diffuse expression was detected in 71% of BRCA1, 65% of BRCA2, 92% of BRCA-wild-type homologous recombinant deficient tumors, and 100% of homologous recombinant proficient tumors, p =.071. The proportion of diffuse expression was higher in homologous recombinant proficient (100%) versus BRCA2 (65%) (Bonferroni-adjusted pairwise comparisons). CONCLUSIONS: Homologous recombinant deficient tumors are associated with the solid transitional-like morphology, with the BRCA1/2-mutated homologous recombinant deficient cases showing the strongest correlation. Genomic instability score alone may not fully capture the spectrum of homologous recombinant deficient-related phenotypes. The variation in solid transitional-like morphology features among BRCA1- or BRCA2-mutated, BRCA1/2- wild-type with homologous recombinant deficient, and homologous recombinant proficient cases may reflect the diverse biological spectrum of different homologous recombination alterations.

Humans↗

PubMed2002

Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I have been postulated as possible disease modifying therapies for amyotrophic lateral sclerosis. Randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis to date have yielded conflicting results. OBJECTIVES: The main objective of this review was to examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Occurrence of adverse events has also been reviewed. SEARCH STRATEGY: A search was carried out using the Cochrane Neuromuscular Disease Group register for randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Enquiries were also made of authors of randomised clinical trials as well as the manufacturers of recombinant human insulin-like growth factor I regarding any other randomised clinical trials which had not yet been published. SELECTION CRITERIA: Types of studies: all randomised controlled clinical trials involving recombinant human insulin-like growth factor I treatment of amyotrophic lateral sclerosis. TYPES OF PARTICIPANTS: Adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. Types of interventions: Treatment with recombinant human insulin-like growth factor I or placebo. Types of outcome measures: Primary: Change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score with 0.1mg/kg/day of recombinant human insulin-like growth factor I after nine months treatment. Secondary: Change in AALSRS with recombinant human insulin like growth factor I 0.1mg/kg/day and 0.05mg/kg/day at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: We identified two randomised clinical trials. Each reviewer graded them for methodological quality. Data were extracted and entered by the lead reviewer and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs. MAIN RESULTS: The primary outcome measure was change in disease progression as determined by the Appel ALS Rating Scale total score with 0.1 mg/kg/day of recombinant human insulin-like growth factor I subcutaneously after nine months treatment. The level of significance was lower in the European trial which compared 59 patients on placebo with 124 on insulin-like growth factor I 0.1 mg/kg/day (weighted mean difference -3.30, 95%CI -8.68 to 2.08) than in the North American trial which compared 90 patients on placebo with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day 89 patients and 87 patients on 0.1mg/kg/day (weighted mean difference -6.00, 95%CI -10.99 to -1.01). The combined analysis from both randomised clinical trials showed a weighted mean difference of -4.75 (95% CI -8.41 to -1.09) favouring the treated group. The secondary outcome measures showed similar trends favouring recombinant human insulin-like growth factor I but these did not reach significance at the five per cent level. Similarly the data with the 0.05mg/kg/day dose showed trends favouring recombinant human insulin-like growth factor I at all time points but did not reach significance at the five per cent level at any point. Evaluation of adverse events showed an increased risk of injection site reactions/inflammation with recombinant human insulin-like growth factor I (relative risk 2.53, 95% CI 1.40 to 4.59). The drug was otherwise safe and well tolerated. REVIEWER'S CONCLUSIONS: Recombinant human insulin-like growth factor I may be modestly effective but the evidence currently available is insufficient for a definitive assessment. Further randomised clinical trials need to be done.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey.

OBJECTIVE: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-beta carboxyterminal peptide (recombinant hFSH-CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH-CTP after SC injection in female rhesus monkeys. DESIGN: Rhesus monkey study. SETTING: Academic research environment. ANIMAL(S): Ten female rhesus monkeys. INTERVENTION(S): Recombinant hFSH and recombinant hFSH-CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and n = 4 for SC recombinant hFSH and recombinant hFSH-CTP, respectively; for IV dosing, n = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH-CTP after confirmation of pituitary suppression. MAIN OUTCOME MEASURE(S): Plasma disappearance rate of recombinant hFSH and recombinant hFSH-CTP and serum estradiol levels. RESULT(S): The elimination half-life of recombinant hFSH-CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH-CTP than for recombinant hFSH after SC administration. Recombinant hFSH-CTP stimulates estradiol secretion for 5-7 days after an isolated SC dose. CONCLUSION(S): Addition of the hCG-beta carboxyterminal peptide to hFSH-beta results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.

Absorption↗

PubMed1999

Emerging recombinant human immunodeficiency viruses: uneven representation of the envelope V3 region.

OBJECTIVE: To determine whether the envelope V3 region from HIV-1 subtypes A, C or D had the same probability of being present in intersubtype recombinant genomes. MATERIALS AND METHODS: The envelope C2-C5 and the gag p24-p7 regions from one hundred infants infected perinatally in Tanzania were compared using phylogenetic and recombination analysis. Exact binomial and Fisher's exact tests were used to assess if various genomic regions were more likely to be overrepresented in intersubtype recombinants. RESULTS: Of one hundred HIV-1 positive infants analyzed, twenty-two (22%) showed exclusively subtype A sequence in gag and env. Subtype C accounted for twenty-two infants (22%) whereas nineteen infants (19%) were infected by HIV-1 subtype D. Intersubtype recombinant genomes accounted for thirty-seven infections (37%). The V3 region from subtype A was found in all fifteen A-D recombinants (P = 0.00003) and the V3 region from subtype C was found in all twelve C-D recombinants (P = 0.0002). Conversely, subtype D gag sequences were preferentially represented in the gag of A-D recombinants (P = 0.0003) as well as C-D recombinants (P = 0.002). In A-D recombinants, the V3 region of subtype A was generally surrounded by subtype A C3-C5 sequences. In contrast, the V3 region from subtype C was surrounded by subtype D C3-C5 sequences in C-D recombinants. Significant differences were not found in the number of subtype A or subtype C sequences in A-C recombinants. CONCLUSION: We have shown that several recombinant HIV-1 viruses have been generated and efficiently transmitted to infants in Tanzania. The recombination patterns showed that the V3 region of subtypes A or C was always selected in A-D and C-D recombinants. This selection suggests that the fitness of subtype D-V3 in perinatal transmission may be reduced with respect to V3 from subtype A and/or subtype C. The elevated number of recombinants transmitted perinatally suggests that co-infection or super-infection by two HIV-1 subtypes is not uncommon in this population.

Amino Acid Sequence↗

PubMed2004

A novel reporter for intrachromosomal homoeologous recombination in Arabidopsis thaliana.

A reporter system using engineered introns as recombination substrates in the uidA (GUS) gene has been developed and characterized in Arabidopsis thaliana. The non-coding nature of the recombination substrate has allowed us to monitor recombination events between duplicated copies of the intron that are either identical (homologous recombination) or harbour sequence polymorphisms (homoeologous recombination). The effects of substrate length and divergence on the frequency of recombination events were examined. A positive correlation between substrate length and somatic recombination frequency was found as the frequency of recombination increased 183-fold when the recombination substrate was lengthened from 153 to 589 bp. The existence of 11 polymorphisms in a 589-bp recombination substrate (1.9% sequence divergence) led to an almost 10-fold reduction in the frequency of recombination. This result demonstrates that relatively modest levels of sequence divergence can substantially reduce the frequency of recombination in plants. A molecular analysis of recombination products revealed that the recombination junctions are more frequent in the central segment of the recombination substrate.

Arabidopsis↗

PubMed1990

Transduction of cellular neo mRNA by retrovirus-mediated recombination.

Transduction of cellular oncogenes by retroviruses is thought to be a multistep process, involving transcriptional activation of a cellular gene by upstream proviral integration and joining of cellular DNA to retroviral transcriptional signals, followed by copackaging and recombination with a helper virus genome during reverse transcription. To examine the molecular mechanism of the reverse transcriptase-mediated recombination, we introduced into mouse fibroblast cells a variety of constructs in which the neo selectable marker was joined to flanking retroviruslike or cell-like sequences. After superinfection and copackaging with a replication-competent Mo-MuLVsupF virus, the formation of recombinant neo transducing viruses was assessed in a second round of virus infection by the ability to confer G418 resistance to infected cells. Our results showed that recombinant neo proviruses were generated from neo RNA containing either a 5' or 3' retroviral end, implying that one recombination event with helper virus RNA was sufficient to incorporate the neo gene into proviral DNA. Recombination occurred with an apparent frequency of 10(-4) to 10(-5) per replication cycle in the absence of homology between the two recombining partners. This frequency, however, increased at least 100-fold if homology was provided at the site of recombination. Our results support the hypothesis that neo-transducing viruses arise via reverse transcriptase-mediated recombination of RNA rather than by recombination proceeding through DNA intermediates. Unexpectedly, removal of the retroviral packaging site psi reduced the number of neo recombinants only slightly. Our data indicated that although RNAs lacking the psi site are poorly packaged into virions, those RNAs that are included in the virions undergo frequent recombination, even if there is no selection for recombination. Many of the neo recombinants formed with the psi- constructs had undergone additional recombinations and often incorporated the psi site from the helper RNA.

DNA, Viral↗

PubMed2004

Genetic and physical mapping of homoeologous recombination points involving wheat chromosome 2B and rye chromosome 2R.

Wide hybrids have been used in generating genetic maps of many plant species. In this study, genetic and physical mapping was performed on ph1b-induced recombinants of rye chromosome 2R in wheat (Triticum aestivum L.). All recombinants were single breakpoint translocations. Recombination 2RS-2BS was absent from the terminal and the pericentric regions and was distributed randomly along an intercalary segment covering approximately 65% of the arm's length. Such a distribution probably resulted from structural differences at the telomeres of 2RS and wheat 2BS arm that disrupted telomeric initiation of pairing. Recombination 2RL-2BL was confined to the terminal 25% of the arm's length. A genetic map of homoeologous recombination 2R-2B was generated using relative recombination frequencies and aligned with maps of chromosomes 2B and 2R based on homologous recombination. The alignment of the short arms showed a shift of homoeologous recombination toward the centromere. On the long arms, the distribution of homoeologous recombination was the same as that of homologous recombination in the distal halves of the maps, but the absence of multiple crossovers in homoeologous recombination eliminated the proximal half of the map. The results confirm that homoeologous recombination in wheat is based on single exchanges per arm, indicate that the distribution of these single homoeologous exchanges is similar to the distribution of the first (distal) crossovers in homologues, and suggest that successive crossovers in an arm generate specific portions of genetic maps. A difference in the distribution of recombination between the short and long arms indicates that the distal crossover localization in wheat is not dictated by a restricted distribution of DNA sequences capable of recombination but by the pattern of pairing initiation, and that can be affected by structural differences. Restriction of homoeologous recombination to single crossovers in the distal part of the genetic map complicates chromosome engineering efforts targeting genes in the proximal map regions.

Chromosome Mapping↗

PubMed1984

Molecular mechanisms of recombination in Saccharomyces cerevisiae: testing mitotic and meiotic models by analysis of hypo-rec and hyper-rec mutations.

Recombination in the yeast Saccharomyces cerevisiae has been the subject of extensive genetic studies documenting the general properties of intragenic and intergenic recombination and the differences between mitotic and meiotic gene conversion and reciprocal exchange. Spontaneous mitotic and meiotic events differ in the time of onset of recombination relative to chromosomal replication, symmetry versus asymmetry of putative heteroduplex DNA regions, polarity of conversion of intragenic markers, and the lengths of DNA segments that undergo coincident conversion. The differences observed and the properties of yeast rec mutations provide evidence for multiple modes or pathways of mitotic and meiotic recombination. Several molecular models of recombination have been proposed to account for the basic parameters of genetic recombination and the differences between mitotic and meiotic recombination. Since the models differ with respect to the partial reactions comprising recombination they predict the isolation of different classes of hypo-recombination and hyper-recombination rec mutants. We have isolated a broad spectrum of yeast REC gene mutations that includes both hyper-rec and hypo-rec mutants. Five phenotypic classes of rec variants have been identified based upon their effects on spontaneous mitotic gene conversion and intergenic recombination. Their characteristics demonstrate that mitotic gene conversion and intergenic recombination are under independent as well as coordinate genetic control. Four gene mutations affecting recombination rad50, rad52, rem1 and spo11 have been extensively examined in several laboratories and illustrate the information that can be obtained by characterization of double mutant strains, detailed genotypic analysis of recombinants, and studies of meiotic recombination in cells in which the reductional division of meiosis has been bypassed by the spo13 mutation.

DNA↗

PubMed1991

Random nature of coronavirus RNA recombination in the absence of selection pressure.

RNA-RNA recombination is thought to occur preferentially at certain selected sites and in only a few RNA viruses; the mechanism for these restrictions is unknown. In this paper we report the development of a recombination assay for coronavirus, using polymerase chain reaction, in the absence of selection pressure. Our results showed that within a 1-kb region of the peplomer gene, RNA recombination occurred at almost every potential crossover site. Thus, coronavirus RNA recombination appears to be more random than previously realized. However, after serial passages of the recombinant viruses in tissue culture, the recombination sites among the progeny viruses became clustered in the region which contains the previously reported "hot spot" for coronavirus recombination. These results suggest that RNA recombination is common and random in nature, but only certain recombinants can be selected. Thus, the presence of recombinational "hot spots" for coronavirus or other RNA viruses most likely resulted from selection of certain recombinant viruses and not restriction on the occurrence of RNA recombination. The failure to detect recombinants in other RNA viruses may therefore be due to unfavorable properties of recombinant viruses. This approach can be used to detect recombinants in these viruses.

Animals↗

PubMed2026

Evolution of maize recombination landscape during domestication.

Despite the plethora of knowledge about the benefits of meiotic recombination and numerous theoretical studies examining how recombination rates evolve, there is a general lack of empirical support and consensus across species. To fill this knowledge gap, we characterized the evolution of recombination landscape in maize during its domestication from teosinte and related the observed changes to established theoretical frameworks. Through examining recombination in experimental populations of maize and teosinte and the population genomics approach of identifying historical recombination events using ancestral recombination graph inference to generate saturated maize and teosinte recombination maps, we found that during domestication, maize experienced a 12% increase in its genome-wide recombination rate. Furthermore, maize evolved higher recombination rates on the long arms of chromosomes in regions closer to centromeres, where recombination is generally very low. The repatterning of crossover events came from changes in global crossover positioning rather than alterations in cis-acting chromatin factors. Consequently, we found evidence of selection acting on trans-acting recombination modifiers affecting crossover interference and controlling the interference-dependent class I crossover pathway. We show that CO repatterning was likely beneficial for maize fitness, as significant recombination rate increases were predominantly in gene-rich regions, which harbor domestication-related variation. This work suggests genomic and mechanistic processes leading to the evolution of meiotic recombination landscape in response to directional selection pressure and provides evidence for the evolutionary advantage of recombination.

Zea mays↗

PubMed2025

Comparative Phylogenetics Reveal Clade-specific Drivers of Recombination Rate Evolution Across Vertebrates.

Meiotic recombination is an integral cellular process, required for the production of viable gametes. Recombination rate is a fundamental genomic parameter, modulating genomic responses to selection. Our increasingly detailed understanding of its molecular underpinnings raises the prospect that we can gain insight into trait divergence by examining the molecular evolution of recombination genes from a pathway perspective, as in mammals, where protein-coding changes in later stages of the recombination pathway are connected to divergence in intra-clade recombination rate. Here, we leverage increased availability of avian and teleost genomes to reconstruct the evolution of the recombination pathway across two additional vertebrate clades: birds, which have higher and more variable rates of recombination and similar divergence times to mammals, and teleost fish, which have much deeper divergence times. Rates of molecular evolution of recombination genes are highly correlated between vertebrate clades and significantly elevated compared to control panels, suggesting that they experience similar selective pressures. Avian recombination genes are significantly more likely to exhibit signatures of positive selection than other clades, unrestricted to later stages of the pathway. Signatures of positive selection in genes linked to recombination rate variation in mammalian populations and those with signatures of positive selection across the avian phylogeny are highly correlated. In contrast, teleost fish recombination genes have significantly less evidence of positive selection despite high intra-clade recombination rate variability. Gaining clade-specific understanding of patterns of variation in recombination genes can elucidate drivers of recombination rate and thus, factors influencing genetic diversity, selection efficacy, and species divergence.

Animals↗

PubMed1996

Homologous recombination in variants of the B16 murine melanoma with reference to their metastatic potential.

Genomic instability has been accepted as providing a phenotypic variety of malignant cells within a developing tumour. Defects in genetic recombination can often lead to phenotypic differences; therefore, it is possible that metastatic variant cell lines exhibit their particular phenotype as a result of an altered ability to catalyse homologous recombination. We have investigated recombination efficiency in B16 melanoma metastatic variants, using a plasmid, pDR, as a recombination substrate. The plasmid contains two truncated, nontandem but overlapping segments of the neomycin resistance gene (neo 1 and neo 2), separated by the functional gpt gene unit. Only a successful recombination of the two neo segments will generate a functionally intact neomycin gene. Extrachromosomal recombination here was a transient measure of the cells to recombine the neo fragments in an intra- or intermolecular manner. Extrachromosomal recombination frequencies were higher in the high metastasis variants (BL6, ML8) compared with the low metastatic F1 cells. On the other hand, the frequency of chromosomal recombination (after plasmid integration) was higher for the low metastasis (F1) cell line compared with the highly metastatic variants, BL6 and ML8. Since the recombination assay measures only successful recombination events, we have interpreted the observed higher incidence of chromosomal recombination in the low metastatic variant line as indicative of a more stable genome. Similarly, a higher inherent instability in the genome of the high metastasis variants would render these less efficient at producing and maintaining successful recombination events, and this was found to be true by Southern analysis. The results presented show that frequency of recombination may be adduced as evidence for implicating genomic instability in the generation of variant cell populations during metastatic spread. Such an interpretation is also compatible with the Nowell hypothesis for tumour progression.

Animals↗

PubMed1985

Extent of sequence homology required for bacteriophage lambda site-specific recombination.

Bacteriophage lambda integration and excision occur by reciprocal recombination within a 15-base homologous core region present in the recombining attachment (att) sites. Strand exchange within the core occurs at precise nucleotide positions, which define an overlap region in which the products of recombination contain DNA strands derived from different parents. In order to define the role of sequence homology during recombination we have constructed point mutations within the core and assayed their effects in vivo and in vitro on site-specific recombination. Two of the mutations are located at position -3 of the core, which is one base-pair outside of the overlap region where strand exchange occurs. These mutations do not affect integrative or excisive recombination, thereby suggesting that homology outside the overlap region is not required for recombination. Two other mutations are located at position -2 of the core, which is one base-pair within the overlap region. These mutations show severely depressed integrative and excisive recombination activities in vitro and in vivo when recombined against wild-type att sites. However, the -2 mutations show normal recombination activity when recombined against att sites containing the homologous mutation, thereby suggesting that homology-dependent DNA interactions are required within the overlap region for effective recombination. In vitro recombination between homoduplex attP sites and heteroduplex attB sites demonstrated that the DNA interactions require only one strand of the attB overlap region to be homologous to attP in order to promote recombination.

Attachment Sites, Microbiological↗