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 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’.

The distribution and causes of meiotic recombination in the human genome

2006 ◽  
Vol 34 (4) ◽  
pp. 526-530 ◽  
Author(s):  
S. Myers ◽  
C.C.A. Spencer ◽  
A. Auton ◽  
L. Bottolo ◽  
C. Freeman ◽  
...  
Keyword(s):  
Human Genome ◽  
Local Context ◽  
Rate Variation ◽  
Dna Repeats ◽  
Recombination Rates ◽  
Recombination Hotspots ◽  
Rates Of Evolution ◽  
Recombination Rate Variation ◽  
Very High

Using the statistical analysis of genetic variation, we have developed a high-resolution genetic map of recombination hotspots and recombination rate variation across the human genome. This map, which has a resolution several orders of magnitude greater than previous studies, identifies over 25000 recombination hotspots and gives new insights into the distribution and determination of recombination. Wavelet-based analysis demonstrates scale-specific influences of base composition, coding context and DNA repeats on recombination rates, though, in contrast with other species, no association with DNase I hypersensitivity. We have also identified specific DNA motifs that are strongly associated with recombination hotspots and whose activity is influenced by local context. Comparative analysis of recombination rates in humans and chimpanzees demonstrates very high rates of evolution of the fine-scale structure of the recombination landscape. In the light of these observations, we suggest possible resolutions of the hotspot paradox.

scholarly journals The recombination landscape in wild house mice inferred using population genomic data

2017 ◽  
Author(s):  
Tom R. Booker ◽  
Rob W. Ness ◽  
Peter D. Keightley
Keyword(s):  
House Mouse ◽  
Recombination Rate ◽  
Inbred Lines ◽  
House Mice ◽  
Rate Variation ◽  
Recombination Hotspots ◽  
Population Genomic ◽  
Wild House Mice ◽  
Recombination Rate Variation ◽  
Broad Scale

AbstractCharacterizing variation in the rate of recombination across the genome is important for understanding many evolutionary processes. The landscape of recombination has been studied previously in the house mouse, Mus musculus, and it is known that the different subspecies exhibit different suites of recombination hotspots. However, it is not established whether broad-scale variation in the rate of recombination is conserved between the subspecies. In this study, we construct a fine-scale recombination map for the Eastern house mouse subspecies, M. m. castaneus, using 10 individuals sampled from its ancestral range. After inferring phase, we use LDhelmet to construct recombination maps for each autosome. We find that the spatial distribution of recombination rate is strongly positively between our castaneus map and a map constructed using inbred lines of mice derived predominantly from M. m. domesticus. We also find that levels of genetic diversity in M. m. castaneus are positively correlated with the rate of recombination, consistent with pervasive natural selection acting in the genome. Our study suggests that recombination rate variation is conserved at broad scales between M. musculus subspecies.

scholarly journals PRDM9 forms an active trimer mediated by its repetitive zinc finger array

2018 ◽  
Author(s):  
Theresa Schwarz ◽  
Yasmin Striedner ◽  
Karin Haase ◽  
Jasmin Kemptner ◽  
Nicole Zeppezauer ◽  
...  
Keyword(s):  
Strand Break ◽  
Specific Protein ◽  
Binding Studies ◽  
Recombination Hotspots ◽  
C Terminus ◽  
Dna Binding Site ◽  
Vitro Binding ◽  
Meiotic Initiation

PRDM9 has been identified as a meiosis-specific protein that plays a key role in determining the location of meiotic recombination hotspots. Although it is well-established that PRDM9 is a trans-acting factor directing the double strand break machinery necessary for recombination to its DNA binding site, the details of PRDM9 binding and complex formation are not well known. It has been suggested in several instances that PRDM9 acts as a multimer in vivo; however, there is little understanding about the protein stoichiometry or the components inducing PRDM9 multimerization. In this work, we used in vitro binding studies and mass spectrometry to characterize the size of the PRDM9 multimer within the active DNA-protein complex of two different murine PRDM9 alleles, PRDM9Cst and PRDM9Dom2. For this purpose, we developed a strategy to infer the molecular weight of the PRDM9-DNA complex from native gel electrophoresis based on gel shift assays (EMSAs). Our results show that PRDM9 binds as a trimer with the DNA. This multimerization is catalysed by the long ZnF array (ZnF) at the C-terminus of the protein and 11, 10, 7 or 5 ZnFs are already sufficient to form a functional trimer. Finally, we also show that only one ZnF-array within the PRDM9 trimer actively binds to the DNA, while the remaining two ZnF-arrays likely maintain the multimer by ZnF-ZnF interactions. Our results have important implications in terms of PRDM9 dosage, which determines the number of active hotspots in meiotic cells, and contribute to elucidate the molecular interactions of PRDM9 with other components of the meiotic initiation machinery.

scholarly journals Localization matters: nuclear-trapped Survivin sensitizes glioblastoma cells to temozolomide by elevating cellular senescence and impairing homologous recombination

2021 ◽  
Author(s):  
Thomas R. Reich ◽  
Christian Schwarzenbach ◽  
Juliana Brandstetter Vilar ◽  
Sven Unger ◽  
Fabian Mühlhäusler ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Nuclear Export ◽  
Cell Model ◽  
Chromosome Instability ◽  
Direct Interaction ◽  
High Grade Glioma ◽  
Strand Break ◽  
Γh2ax Foci

AbstractTo clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.

scholarly journals Microglia in Neurodegenerative Events—An Initiator or a Significant Other?

2021 ◽  
Vol 22 (11) ◽  
pp. 5818
Author(s):  
Gaylia Jean Harry
Keyword(s):  
Neurovascular Unit ◽  
Cell Types ◽  
In Vitro Assays ◽  
Significant Other ◽  
Neurodegenerative Process ◽  
Target Sites ◽  
Systemic Factors ◽  
Injury And Repair ◽  
The Brain

A change in microglia structure, signaling, or function is commonly associated with neurodegeneration. This is evident in the patient population, animal models, and targeted in vitro assays. While there is a clear association, it is not evident that microglia serve as an initiator of neurodegeneration. Rather, the dynamics imply a close interaction between the various cell types and structures in the brain that orchestrate the injury and repair responses. Communication between microglia and neurons contributes to the physiological phenotype of microglia maintaining cells in a surveillance state and allows the cells to respond to events occurring in their environment. Interactions between microglia and astrocytes is not as well characterized, nor are interactions with other members of the neurovascular unit; however, given the influence of systemic factors on neuroinflammation and disease progression, such interactions likely represent significant contributes to any neurodegenerative process. In addition, they offer multiple target sites/processes by which environmental exposures could contribute to neurodegenerative disease. Thus, microglia at least play a role as a significant other with an equal partnership; however, claiming a role as an initiator of neurodegeneration remains somewhat controversial.

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