scholarly journals The impact of recombination on human mutation load and disease

2017 ◽  
Vol 372 (1736) ◽  
pp. 20160465 ◽  
Author(s):  
Isabel Alves ◽  
Armande Ang Houle ◽  
Julie G. Hussin ◽  
Philip Awadalla
Keyword(s):  
Molecular Mechanisms ◽  
Human Genetics ◽  
Strand Break ◽  
Congenital Defects ◽  
Rate Variation ◽  
Disease Evolution ◽  
Ability To Act ◽  
Human Mutation ◽  
Recombination Rate Variation ◽  
The Impact

Recombination promotes genomic integrity among cells and tissues through double-strand break repair, and is critical for gamete formation and fertility through a strict regulation of the molecular mechanisms associated with proper chromosomal disjunction. In humans, congenital defects and recurrent structural abnormalities can be attributed to aberrant meiotic recombination. Moreover, mutations affecting genes involved in recombination pathways are directly linked to pathologies including infertility and cancer. Recombination is among the most prominent mechanism shaping genome variation, and is associated with not only the structuring of genomic variability, but is also tightly linked with the purging of deleterious mutations from populations. Together, these observations highlight the multiple roles of recombination in human genetics: its ability to act as a major force of evolution, its molecular potential to maintain genome repair and integrity in cell division and its mutagenic cost impacting disease evolution. This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.

scholarly journals Variation in recombination frequency and distribution across eukaryotes: patterns and processes

2017 ◽  
Vol 372 (1736) ◽  
pp. 20160455 ◽  
Author(s):  
Jessica Stapley ◽  
Philine G. D. Feulner ◽  
Susan E. Johnston ◽  
Anna W. Santure ◽  
Carole M. Smadja
Keyword(s):  
Recombination Rate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Essential Feature ◽  
Rate Variation ◽  
Evolutionary Processes ◽  
Recombination Rates ◽  
Great Opportunity ◽  
Patterns And Processes ◽  
Recombination Rate Variation

Recombination, the exchange of DNA between maternal and paternal chromosomes during meiosis, is an essential feature of sexual reproduction in nearly all multicellular organisms. While the role of recombination in the evolution of sex has received theoretical and empirical attention, less is known about how recombination rate itself evolves and what influence this has on evolutionary processes within sexually reproducing organisms. Here, we explore the patterns of, and processes governing recombination in eukaryotes. We summarize patterns of variation, integrating current knowledge with an analysis of linkage map data in 353 organisms. We then discuss proximate and ultimate processes governing recombination rate variation and consider how these influence evolutionary processes. Genome-wide recombination rates (cM/Mb) can vary more than tenfold across eukaryotes, and there is large variation in the distribution of recombination events across closely related taxa, populations and individuals. We discuss how variation in rate and distribution relates to genome architecture, genetic and epigenetic mechanisms, sex, environmental perturbations and variable selective pressures. There has been great progress in determining the molecular mechanisms governing recombination, and with the continued development of new modelling and empirical approaches, there is now also great opportunity to further our understanding of how and why recombination rate varies. This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.

scholarly journals The consequences of sequence erosion in the evolution of recombination hotspots

2017 ◽  
Vol 372 (1736) ◽  
pp. 20160462 ◽  
Author(s):  
Irene Tiemann-Boege ◽  
Theresa Schwarz ◽  
Yasmin Striedner ◽  
Angelika Heissl
Keyword(s):  
Strand Break ◽  
Rate Variation ◽  
Sequence Evolution ◽  
Zinc Finger Domain ◽  
Recombination Activity ◽  
Recombination Hotspots ◽  
Rapid Sequence ◽  
Target Sites ◽  
Recombination Rate Variation

Meiosis is initiated by a double-strand break (DSB) introduced in the DNA by a highly controlled process that is repaired by recombination. In many organisms, recombination occurs at specific and narrow regions of the genome, known as recombination hotspots, which overlap with regions enriched for DSBs. In recent years, it has been demonstrated that conversions and mutations resulting from the repair of DSBs lead to a rapid sequence evolution at recombination hotspots eroding target sites for DSBs. We still do not fully understand the effect of this erosion in the recombination activity, but evidence has shown that the binding of trans -acting factors like PRDM9 is affected. PRDM9 is a meiosis-specific, multi-domain protein that recognizes DNA target motifs by its zinc finger domain and directs DSBs to these target sites. Here we discuss the changes in affinity of PRDM9 to eroded recognition sequences, and explain how these changes in affinity of PRDM9 can affect recombination, leading sometimes to sterility in the context of hybrid crosses. We also present experimental data showing that DNA methylation reduces PRDM9 binding in vitro . Finally, we discuss PRDM9-independent hotspots, posing the question how these hotspots evolve and change with sequence erosion. This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.

scholarly journals Effect of Vietnamese Helicobactor pylori strain DN18 on the NF-κB pathway and H2AX activation of the AGS cell line

2020 ◽  
Vol 4 (2) ◽  
pp. First
Author(s):  
Dao Thi Hong Pham ◽  
Trang My Ho Nguyen ◽  
Vy Thuy Nguyen
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Strand Break ◽  
Gastric Carcinogenesis ◽  
Mucosal Cell ◽  
Geographical Regions ◽  
Infected Cells ◽  
H Pylori ◽  
The Impact

Infection with Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain not elucidated. Recent findings indicate that H. pylori infection may promote gastric carcinogenesis by inducing inflammation and genetic instability in gastric epithelial cells. In addition, it is shown that the impact of H. pylori on infected cells is associated with bacterial virulence that is diverse among geographical regions as well as populations. Therefore, we aimed to investigate the effect of H. pylori strain DN18 from Vietnamese subject on the in vitro activity of NF-κB transcription factor, a key regulator of inflammation, and expression of its target genes in this study. Moreover, host genomic instabilities were studied through examining the formation of DNA double-strand break (DSB) by using phosphorylated histone H2AX (γH2AX) as a DSB marker. Our results showed that H. pylori strain DN18 induced activation of NF-kB pathway and increased transcriptional expression of inflammatory mediators in human gastric mucosal cell AGS. We also provided evidence that the H. pylori infection triggered accumulation of  DSBs marker γH2AX. In summary, our study showed the potential ability to cause inflammation and DNA damage to infected cells of H. pylori strains isolated from Vietnamese patients.

scholarly journals Are the effects of elevated temperature on meiotic recombination and thermotolerance linked via the axis and synaptonemal complex?

2017 ◽  
Vol 372 (1736) ◽  
pp. 20160470 ◽  
Author(s):  
Christopher H. Morgan ◽  
Huakun Zhang ◽  
Kirsten Bomblies
Keyword(s):  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Recombination ◽  
Molecular Mechanisms ◽  
Genetic Material ◽  
Rate Variation ◽  
Complex Structures ◽  
Effects Of Temperature ◽  
Structural Failures ◽  
Recombination Rate Variation

Meiosis is unusual among cell divisions in shuffling genetic material by crossovers among homologous chromosomes and partitioning the genome into haploid gametes. Crossovers are critical for chromosome segregation in most eukaryotes, but are also an important factor in evolution, as they generate novel genetic combinations. The molecular mechanisms that underpin meiotic recombination and chromosome segregation are well conserved across kingdoms, but are also sensitive to perturbation by environment, especially temperature. Even subtle shifts in temperature can alter the number and placement of crossovers, while at greater extremes, structural failures can occur in the linear axis and synaptonemal complex structures which are essential for recombination and chromosome segregation. Understanding the effects of temperature on these processes is important for its implications in evolution and breeding, especially in the context of global warming. In this review, we first summarize the process of meiotic recombination and its reliance on axis and synaptonemal complex structures, and then discuss effects of temperature on these processes and structures. We hypothesize that some consistent effects of temperature on recombination and meiotic thermotolerance may commonly be two sides of the same coin, driven by effects of temperature on the folding or interaction of key meiotic proteins. This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.

scholarly journals Genomic Features of Parthenogenetic Animals

2020 ◽  
Author(s):  
Kamil S Jaron ◽  
Jens Bast ◽  
Reuben W Nowell ◽  
T Rhyker Ranallo-Benavidez ◽  
Marc Robinson-Rechavi ◽  
...  
Keyword(s):  
Theoretical Models ◽  
Hybrid Origin ◽  
Rate Variation ◽  
Genomic Features ◽  
Genome Wide ◽  
Single Feature ◽  
Survivorship Bias ◽  
Recombination Rate Variation ◽  
The Impact ◽  
Animal Genomes

Abstract Evolution without sex is predicted to impact genomes in numerous ways. Case studies of individual parthenogenetic animals have reported peculiar genomic features that were suggested to be caused by their mode of reproduction, including high heterozygosity, a high abundance of horizontally acquired genes, a low transposable element load, or the presence of palindromes. We systematically characterized these genomic features in published genomes of 26 parthenogenetic animals representing at least 18 independent transitions to asexuality. Surprisingly, not a single feature was systematically replicated across a majority of these transitions, suggesting that previously reported patterns were lineage-specific rather than illustrating the general consequences of parthenogenesis. We found that only parthenogens of hybrid origin were characterized by high heterozygosity levels. Parthenogens that were not of hybrid origin appeared to be largely homozygous, independent of the cellular mechanism underlying parthenogenesis. Overall, despite the importance of recombination rate variation for the evolution of sexual animal genomes, the genome-wide absence of recombination does not appear to have had the dramatic effects which are expected from classical theoretical models. The reasons for this are probably a combination of lineage-specific patterns, the impact of the origin of parthenogenesis, and a survivorship bias of parthenogenetic lineages.

Factors that influence bidirectional long-tract homozygosis due to double-strand break repair in Candida albicans

Genetics ◽  
2021 ◽  
Author(s):  
Timea Marton ◽  
Murielle Chauvel ◽  
Adeline Feri ◽  
Corinne Maufrais ◽  
Christophe D’enfert ◽  
...  
Keyword(s):  
Dna Repair ◽  
Candida Albicans ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Strand Break ◽  
Genomic Rearrangements ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Break Site ◽  
The Impact

Abstract Genomic rearrangements have been associated with the acquisition of adaptive phenotypes, allowing organisms to efficiently generate new favorable genetic combinations. The diploid genome of Candida albicans is highly plastic, displaying numerous genomic rearrangements that are often the by-product of the repair of DNA breaks. For example, DNA double-strand breaks (DSB) repair using homologous-recombination pathways are a major source of loss-of-heterozygosity (LOH), observed ubiquitously in both clinical and laboratory strains of C. albicans. Mechanisms such as break-induced replication (BIR) or mitotic crossover (MCO) can result in long tracts of LOH, spanning hundreds of kilobases until the telomere. Analysis of I-SceI-induced BIR/MCO tracts in C. albicans revealed that the homozygosis tracts can ascend several kilobases towards the centromere, displaying homozygosis from the break site towards the centromere. We sought to investigate the molecular mechanisms that could contribute to this phenotype by characterizing a series of C. albicans DNA repair mutants, including pol32-/-, msh2-/-, mph1-/- and mus81-/-. The impact of deleting these genes on genome stability revealed functional differences between Saccharomyces cerevisiae (a model DNA repair organism) and C. albicans. Additionally, we demonstrated that ascending LOH tracts towards the centromere are associated with intrinsic features of BIR and potentially involve the mismatch repair pathway which acts upon natural heterozygous positions. Overall, this mechanistic approach to study LOH deepens our limited characterization of DNA repair pathways in C. albicans and brings forth the notion that centromere proximal alleles from DNA break sites are not guarded from undergoing LOH.

scholarly journals Recombination rate plasticity: revealing mechanisms by design

2017 ◽  
Vol 372 (1736) ◽  
pp. 20160459 ◽  
Author(s):  
Laurie S. Stevison ◽  
Stephen Sefick ◽  
Chase Rushton ◽  
Rita M. Graze
Keyword(s):  
Recombination Rate ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Empirical Work ◽  
Lessons Learned ◽  
Model Organisms ◽  
Rate Variation ◽  
Recombination Rates ◽  
Intrinsic Factors ◽  
Recombination Rate Variation

For over a century, scientists have known that meiotic recombination rates can vary considerably among individuals, and that environmental conditions can modify recombination rates relative to the background. A variety of external and intrinsic factors such as temperature, age, sex and starvation can elicit ‘plastic’ responses in recombination rate. The influence of recombination rate plasticity on genetic diversity of the next generation has interesting and important implications for how populations evolve. Further, many questions remain regarding the mechanisms and molecular processes that contribute to recombination rate plasticity. Here, we review 100 years of experimental work on recombination rate plasticity conducted in Drosophila melanogaster . We categorize this work into four major classes of experimental designs, which we describe via classic studies in D. melanogaster . Based on these studies, we highlight molecular mechanisms that are supported by experimental results and relate these findings to studies in other systems. We synthesize lessons learned from this model system into experimental guidelines for using recent advances in genotyping technologies, to study recombination rate plasticity in non-model organisms. Specifically, we recommend (1) using fine-scale genome-wide markers, (2) collecting time-course data, (3) including crossover distribution measurements, and (4) using mixed effects models to analyse results. To illustrate this approach, we present an application adhering to these guidelines from empirical work we conducted in Drosophila pseudoobscura . This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.

The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics

2019 ◽  
Vol 25 (40) ◽  
pp. 5503-5511 ◽  
Author(s):  
Abdulaziz Alhasaniah ◽  
Michael J. Sherratt ◽  
Catherine A. O'Neill
Keyword(s):  
Ultraviolet Radiation ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Transepidermal Water Loss ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Epidermal Barrier ◽  
Positive Effects ◽  
Terrestrial Mammals ◽  
The Impact

A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.

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