mitotic gene conversion
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Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 114
Author(s):  
Cameron Meyer-Mueller ◽  
Mark J. Osborn ◽  
Jakub Tolar ◽  
Christina Boull ◽  
Christen L. Ebens

Epidermolysis bullosa (EB) is a group of genetic blistering diseases characterized by mechanically fragile skin and mucocutaneous involvement. Historically, disease management has focused on supportive care. The development of new genetic, cellular, and recombinant protein therapies has shown promise, and this review summarizes a unique gene and cell therapy phenomenon termed revertant mosaicism (RM). RM is the spontaneous correction of a disease-causing mutation. It has been reported in most EB subtypes, some with relatively high frequency, and has been observed in both keratinocytes and fibroblasts. RM manifests as identifiable patches of unaffected, blister-resistant skin and can occur through a variety of molecular mechanisms, including true back mutation, intragenic crossover, mitotic gene conversion, and second-site mutation. RM cells represent a powerful autologous platform for therapy, and leveraging RM cells as a therapeutic substrate may avoid the inherent mutational risks of gene therapy/editing. However, further examination of the genomic integrity and long-term functionality of RM-derived cells, as well in vivo testing of systemic therapies with RM cells, is required to realize the full therapeutic promise of naturally occurring RM in EB.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Rhys A. Farrer

Abstract Background Identifying haplotypes is central to sequence analysis in diploid or polyploid genomes. Despite this, there remains a lack of research and tools designed for physical phasing and its downstream analysis. Results HaplotypeTools is a new toolset to phase variant sites using VCF and BAM files and to analyse phased VCFs. Phasing is achieved via the identification of reads overlapping ≥ 2 heterozygous positions and then extended by additional reads, a process that can be parallelized across a computer cluster. HaplotypeTools includes various utility scripts for downstream analysis including crossover detection and phylogenetic placement of haplotypes to other lineages or species. HaplotypeTools was assessed for accuracy against WhatsHap using simulated short and long reads, demonstrating higher accuracy, albeit with reduced haplotype length. HaplotypeTools was also tested on real Illumina data to determine the ancestry of hybrid fungal isolate Batrachochytrium dendrobatidis (Bd) SA-EC3, finding 80% of haplotypes across the genome phylogenetically cluster with parental lineages BdGPL (39%) and BdCAPE (41%), indicating those are the parental lineages. Finally, ~ 99% of phasing was conserved between overlapping phase groups between SA-EC3 and either parental lineage, indicating mitotic gene conversion/parasexuality as the mechanism of recombination for this hybrid isolate. HaplotypeTools is open source and freely available from https://github.com/rhysf/HaplotypeTools under the MIT License. Conclusions HaplotypeTools is a powerful resource for analyzing hybrid or recombinant diploid or polyploid genomes and identifying parental ancestry for sub-genomic regions.


PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3001164
Author(s):  
Xianqing Jia ◽  
Qijun Zhang ◽  
Mengmeng Jiang ◽  
Ju Huang ◽  
Luyao Yu ◽  
...  

In contrast to common meiotic gene conversion, mitotic gene conversion, because it is so rare, is often ignored as a process influencing allelic diversity. We show that if there is a large enough number of premeiotic cell divisions, as seen in many organisms without early germline sequestration, such as plants, this is an unsafe position. From examination of 1.1 million rice plants, we determined that the rate of mitotic gene conversion events, per mitosis, is 2 orders of magnitude lower than the meiotic rate. However, owing to the large number of mitoses between zygote and gamete and because of long mitotic tract lengths, meiotic and mitotic gene conversion can be of approximately equivalent importance in terms of numbers of markers converted from zygote to gamete. This holds even if we assume a low number of premeiotic cell divisions (approximately 40) as witnessed inArabidopsis. A low mitotic rate associated with long tracts is also seen in yeast, suggesting generality of results. For species with many mitoses between each meiotic event, mitotic gene conversion should not be overlooked.


Gene Therapy ◽  
2020 ◽  
Vol 27 (6) ◽  
pp. 281-296 ◽  
Author(s):  
Parisa Javidi-Parsijani ◽  
Pin Lyu ◽  
Vishruti Makani ◽  
Walaa Mohamed Sarhan ◽  
Kyung Whan Yoo ◽  
...  

2019 ◽  
Author(s):  
Matthew Hartfield

AbstractGenome studies of facultative sexual species, which can either reproduce sexually or asexually, are providing insight into the evolutionary consequences of mixed reproductive modes. It is currently unclear to what extent the evolutionary history of facultative sexuals’ genomes can be approximated by the standard coalescent, and if a coalescent effective population size Ne exists. Here, I determine if and when these approximations can be made. When sex is frequent (occurring at a frequency much greater than 1/N per reproduction per generation, for N the actual population size), the underlying genealogy can be approximated by the standard coalescent, with a coalescent Ne ≈ N. When sex is very rare (at frequency much lower than 1/N), approximations for the pairwise coalescent time can be obtained, which is strongly influenced by the frequencies of sex and mitotic gene conversion, rather than N. However, these terms do not translate into a coalescent Ne. These results are used to discuss the best sampling strategies for investigating the evolutionary history of facultative sexual species.


2017 ◽  
Author(s):  
Matthew Hartfield ◽  
Stephen I. Wright ◽  
Aneil F. Agrawal

AbstractUnder neutrality, linkage disequilibrium (LD) results from physically linked sites having non-independent coalescent histories. In obligately sexual organisms, meiotic recombination is the dominant force separating linked variants from one another, and thus in determining the decay of LD with physical distance. In facultatively sexual diploid organisms that principally reproduce clonally, mechanisms of mitotic exchange are expected to become relatively more important in shaping LD. Here we outline mathematical and computational models of a facultative-sex coalescent process that includes meiotic and mitotic recombination, via both crossovers and gene conversion, to determine how LD is affected with facultative sex. We demonstrate that the degree to which LD is broken down by meiotic recombination simply scales with the probability of sex if it is sufficiently high (much greater than 1/N for N the population size). However, with very rare sex (occurring with frequency on the order of 1/N), mitotic gene conversion plays a particularly important and complicated role because it both breaks down associations between sites and removes within-individual diversity. Strong population structure under rare sex leads to lower average LD values than in panmictic populations, due to the influence of low-frequency polymorphisms created by allelic sequence divergence acting in individual subpopulations. These analyses provide information on how to interpret observed LD patterns in facultative sexuals, and determine what genomic forces are likely to shape them.


2017 ◽  
Author(s):  
Yee Fang Hum ◽  
Sue Jinks-Robertson

AbstractMitotic recombination between homologous chromosomes can lead to loss-of-heterozygosity (LOH), which is an important contributor to human disease. In the current study, a defined double-strand break (DSB) on chromosome IV was used to initiate LOH in a yeast strain with sequence-diverged chromosomes. Associated gene conversion tracts, which reflect the repair of mismatches formed when diverged chromosomes exchange single strands, were mapped using microarrays. LOH events reflected two broken chromosomes, one of which was repaired as a crossover and the other as a noncrossover. Gene conversion tracts associated with individual crossover and noncrossover events were similar in size and position, with half of the tracts unexpectedly mapping to only a single side of the initiating break. Although the molecular features of DSB-initiated events generally agree with those predicted by current models of homologous recombination, there were unexpected complexities in associated gene conversion tracts.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-42-SCI-42
Author(s):  
Marjolijn C. Jongmans

Abstract Many genetic syndromes are characterized by a wide spectrum of clinical severity. Even within one family clinical presentations can show extreme variation. Mosaic tissue distribution caused by spontaneous correction of a germline pathogenic allele is one of multiple explanations for variety in phenotypic expression of an inherited mutation. This phenomenon, called somatic reversion, is infrequently observed and can be easily overlooked. Reversion needs to be considered if a person presents with a milder than expected clinical course or with a mixture of phenotypically normal and abnormal cells.1 Mechanisms that may explain reversion include mitotic gene conversion, back mutation, intragenic mitotic recombination and the occurrence of compensatory mutations. A mosaic pattern of somatic reversion only becomes apparent if several criteria are met. The non-mutant cells need to have a selective growth advantage over surrounding mutant cells. Furthermore, to facilitate expansion of the revertant clone the affected genes need to be expressed in regenerating organ systems like skin and blood.1 The chance of spontaneous correction of a pathogenic allele is likely increased in diseases with an underlying mechanism resulting in genomic instability or high mutation rates, like Bloom syndrome and Fanconi anemia, which are both caused by gene defects in DNA repair pathways.2,3 In skin disorders an evolving mosaic revertant pattern is easily visible. Ichthyosis with confetti, caused by mutations in KRT10, is an example of a skin disorder displaying multiple events of reversion.4 In this condition, normal skin spots appear early in life and increase in number and size over time. Each normal spot results from a separate event of loss of heterozygosity on chromosome 17q, which harbors KRT10, via mitotic recombination. Also in the genetic skin fragility disorder epidermolysis bullosa revertant mosaicism has been described repeatedly.5,6 We have observed reversion, caused by mitotic recombination of mutant TE RC (telomerase RNA component) alleles in a family affected by dyskeratosis congenita (DC).7 DC is a multisystem disorder characterized amongst others by bone marrow failure and lung fibrosis. The observation of mosaic stretches of uniparental disomy (UPD) of chromosome 3q as an indication of revertant mosaicism encouraged us to develop a highly sensitive method for detecting genomic regions with low mosaic UPD in SNP array data. Indeed this tool supported us in identifying additional cases of DC and a mosaic reversion pattern in blood cells. Revertant mosaicism being a recurrent event in DC related conditions was recently confirmed by others.8 Awareness of revertant mosaicism is important for improving diagnostic testing. In DC for instance it is common practice that analysis of the DC genes is performed on DNA isolated from peripheral blood cells. In case no pathogenic mutation is found, an obvious conclusion can be that the phenotype in the family is caused by an aberration in an as yet to be identified DC gene. Based on our findings, we recommend sequence analysis on DNA extracted from other cells, such as skin fibroblasts, particularly in individuals without bone marrow failure. The observation of reversion in hematological conditions is also of importance for the development of future therapies: Isolation of autologous reverted stem cells can probably circumvent more toxic and harmful therapies, like allogeneic stem cell transplantation, in a subset of individuals. 1. Hirschhorn R. In vivo reversion to normal of inherited mutations in humans. J Med Genet 2003;40 (10):721-728. 2 Ellis NA, Ciocci S, German J. Back mutation can produce phenotype reversion in Bloom syndrome somatic cells. Hum Genet 2001;108 (2):167-173. 3 Waisfisz Q, Morgan NV, Savino M, et al. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet 1999;22 (4):379-383. 4 Choate KA, Lu Y, Zhou J, et al. Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Science 2010;330 (6000):94-97. 5 Jonkman MF, Scheffer H, Stulp R, et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 1997;88 (4):543-51. 6 Kiritsi D, Garcia M, Brander R, et al. Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa. J Invest Dermatol 2014;134 (8):2097-104. 7 Jongmans MC, Verwiel ET, Heijdra Y, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet 2012;90 (3):426-33. 8 Alder JK, Stanley SE, Wagner CL, et al. Exome Sequencing Identifies Mutant TINF2 in a Family With Pulmonary Fibrosis. Chest 2015;147 (5):1361-8. Disclosures No relevant conflicts of interest to declare.


Genetics ◽  
2014 ◽  
Vol 198 (1) ◽  
pp. 181-192 ◽  
Author(s):  
Eunice Yim ◽  
Karen E. O’Connell ◽  
Jordan St. Charles ◽  
Thomas D. Petes

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