scholarly journals Genome-wide variability in recombination activity is associated with meiotic chromatin organization

2021 ◽  
Author(s):  
Xiaofan Jin ◽  
Geoff Fudenberg ◽  
Katherine S Pollard
Keyword(s):  
Meiotic Prophase ◽  
Three Dimensional ◽  
Strand Break ◽  
Early Prophase ◽  
Recombination Activity ◽  
Homologous Chromosomes ◽  
Genome Wide ◽  
Wide Variability ◽  
Genomic Regions ◽  
Negative Health Outcomes

Background: Recombination enables reciprocal exchange of genomic information between parental chromosomes and successful segregation of homologous chromosomes during meiosis. Errors in this process lead to negative health outcomes, while variability in recombination rate affects genome evolution. In mammals, most crossovers occur in hotspots defined by PRDM9 motifs, though PRDM9 binding sites are not all equally hot. We hypothesize that dynamic patterns of meiotic genome folding are linked to recombination activity. Results: We apply an integrative bioinformatics approach to analyze how three-dimensional (3D) chromosomal organization during meiosis relates to rates of double-strand-break (DSB) and crossover formation at PRDM9 hotspots. We show that active, spatially accessible genomic regions during meiotic prophase are associated with DSB-favoured hotspots, which further adopt a transient locally active configuration in early prophase. Conversely, crossover formation is depleted among DSBs in spatially accessible regions during meiotic prophase, particularly within gene bodies. We also find evidence that active chromatin regions have smaller average loop sizes in mammalian meiosis. Collectively, these findings establish that differences in chromatin architecture along chromosomal axes are associated with variable recombination activity. Conclusions: We propose an updated framework describing how 3D organization of brush-loop chromosomes during meiosis may modulate recombination.

scholarly journals ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

2019 ◽  
Author(s):  
Daniel Wells ◽  
Emmanuelle Bitoun ◽  
Daniela Moralli ◽  
Gang Zhang ◽  
Anjali Gupta Hinch ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein S ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Histone Marks ◽  
Cpg Dinucleotides ◽  
Recombination Hotspots ◽  
Genome Wide

AbstractDuring meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility.Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

scholarly journals Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta

2020 ◽  
Vol 117 (24) ◽  
pp. 13562-13570 ◽  
Author(s):  
Gudrun Meinhardt ◽  
Sandra Haider ◽  
Victoria Kunihs ◽  
Leila Saleh ◽  
Jürgen Pollheimer ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Target Genes ◽  
Three Dimensional ◽  
Pivotal Role ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
Cellular Models ◽  
Genome Wide ◽  
Specific Proteins ◽  
Genomic Regions

Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation of human placental trophoblasts. Progenitors of the latter either develop into invasive extravillous trophoblasts, remodeling the uterine vasculature, or fuse into multinuclear syncytiotrophoblasts transporting oxygen and nutrients to the growing fetus. However, key regulatory factors controlling trophoblast self-renewal and differentiation have been poorly elucidated. Using primary cells, three-dimensional organoids, and CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15. Genome-wide comparisons of primary villous cytotrophoblasts overexpressing constitutively active YAP-5SA with YAP KO cells and syncytializing trophoblasts revealed common target genes involved in trophoblast stemness and differentiation. ChIP-qPCR unraveled that YAP-5SA overexpression increased binding of YAP–TEAD4 complexes to promoters of proliferation-associated genes such asCCNAandCDK6. Moreover, repressive YAP–TEAD4 complexes containing the histone methyltransferase EZH2 were detected in the genomic regions of the STB-specificCGB5andCGB7genes. In summary, YAP plays a pivotal role in the maintenance of the human placental trophoblast epithelium. Besides activating stemness factors, it also directly represses genes promoting trophoblast cell fusion.

scholarly journals The genome-wide rate and spectrum of spontaneous mutations differ between haploid and diploid yeast

2018 ◽  
Vol 115 (22) ◽  
pp. E5046-E5055 ◽  
Author(s):  
Nathaniel P. Sharp ◽  
Linnea Sandell ◽  
Christopher G. James ◽  
Sarah P. Otto
Keyword(s):  
Structural Changes ◽  
Wide Spectrum ◽  
Doubled Haploids ◽  
Rate Variation ◽  
Spontaneous Mutations ◽  
Single Nucleotide ◽  
Homologous Chromosomes ◽  
Genome Wide ◽  
Dna Replication And Repair ◽  
Genomic Regions

By altering the dynamics of DNA replication and repair, alternative ploidy states may experience different rates and types of new mutations, leading to divergent evolutionary outcomes. We report a direct comparison of the genome-wide spectrum of spontaneous mutations arising in haploids and diploids following a mutation-accumulation experiment in the budding yeast Saccharomyces cerevisiae. Characterizing the number, types, locations, and effects of thousands of mutations revealed that haploids were more prone to single-nucleotide mutations (SNMs) and mitochondrial mutations, while larger structural changes were more common in diploids. Mutations were more likely to be detrimental in diploids, even after accounting for the large impact of structural changes, contrary to the prediction that mutations would have weaker effects, due to masking, in diploids. Haploidy is expected to reduce the opportunity for conservative DNA repair involving homologous chromosomes, increasing the insertion-deletion rate, but we found little support for this idea. Instead, haploids were more susceptible to SNMs in late-replicating genomic regions, resulting in a ploidy difference in the spectrum of substitutions. In diploids, we detect mutation rate variation among chromosomes in association with centromere location, a finding that is supported by published polymorphism data. Diploids are not simply doubled haploids; instead, our results predict that the spectrum of spontaneous mutations will substantially shape the dynamics of genome evolution in haploid and diploid populations.

scholarly journals The genome-wide rate and spectrum of spontaneous mutations differs between haploid and diploid yeast

2018 ◽  
Author(s):  
Nathaniel P. Sharp ◽  
Linnea Sandell ◽  
Christopher G. James ◽  
Sarah P. Otto
Keyword(s):  
Structural Changes ◽  
Wide Spectrum ◽  
Doubled Haploids ◽  
Rate Variation ◽  
Spontaneous Mutations ◽  
Single Nucleotide ◽  
Homologous Chromosomes ◽  
Genome Wide ◽  
Dna Replication And Repair ◽  
Genomic Regions

AbstractBy altering the dynamics of DNA replication and repair, alternative ploidy states may experience different rates and types of new mutations, leading to divergent evolutionary outcomes. We report the first direct comparison of the genome-wide spectrum of spontaneous mutations arising in haploid and diploid forms of the budding yeast. Characterizing the number, types, locations, and effects of thousands of mutations revealed that haploids were more prone to single-nucleotide and mitochondrial mutations, while larger structural changes were more common in diploids. Mutations were more likely to be detrimental in diploids, even after accounting for the large impact of structural changes, contrary to the prediction that diploidy masks the effects of recessive alleles. Haploidy is expected to reduce the opportunity for conservative DNA repair involving homologous chromosomes, increasing the insertion-deletion rate, but we found little support for this idea. Instead, haploids were more susceptible to particular single-nucleotide mutations in late-replicating genomic regions, resulting in a ploidy difference in the spectrum of substitutions. In diploids we detect mutation rate variation among chromosomes in association with centromere location, a finding that is supported by published polymorphism data. Diploids are Saccharomyces cerevisiae not simply doubled haploids; instead, our results predict that the spectrum of spontaneous mutations will substantially shape the dynamics of genome evolution in haploid and diploid populations.

scholarly journals Publisher Correction: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

2021 ◽  
Author(s):  
Jakob M. Goldmann ◽  
Vladimir B. Seplyarskiy ◽  
Wendy S. W. Wong ◽  
Thierry Vilboux ◽  
Pieter B. Neerincx ◽  
...  
Keyword(s):  
De Novo ◽  
Strand Break ◽  
Double Strand Break ◽  
De Novo Mutation ◽  
Oocyte Aging ◽  
Genomic Regions

scholarly journals Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

2021 ◽  
Vol 7 (11) ◽  
pp. eabd1239
Author(s):  
Mark Simcoe ◽  
Ana Valdes ◽  
Fan Liu ◽  
Nicholas A. Furlotte ◽  
David M. Evans ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Color Variation ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Melanin Pigmentation ◽  
Eye Color ◽  
Human Eye ◽  
Genome Wide ◽  
Genomic Regions

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

scholarly journals A deformation energy model reveals sequence-dependent property of nucleosome positioning

Chromosoma ◽  
2021 ◽  
Vol 130 (1) ◽  
pp. 27-40
Author(s):  
Guoqing Liu ◽  
Hongyu Zhao ◽  
Hu Meng ◽  
Yongqiang Xing ◽  
Lu Cai
Keyword(s):  
Budding Yeast ◽  
Nucleosome Occupancy ◽  
Nucleosome Positioning ◽  
Deformation Energy ◽  
Energy Model ◽  
Structural Parameter ◽  
High Deformation ◽  
Dna Deformation ◽  
Genome Wide ◽  
Genomic Regions

AbstractWe present a deformation energy model for predicting nucleosome positioning, in which a position-dependent structural parameter set derived from crystal structures of nucleosomes was used to calculate the DNA deformation energy. The model is successful in predicting nucleosome occupancy genome-wide in budding yeast, nucleosome free energy, and rotational positioning of nucleosomes. Our model also indicates that the genomic regions underlying the MNase-sensitive nucleosomes in budding yeast have high deformation energy and, consequently, low nucleosome-forming ability, while the MNase-sensitive non-histone particles are characterized by much lower DNA deformation energy and high nucleosome preference. In addition, we also revealed that remodelers, SNF2 and RSC8, are likely to act in chromatin remodeling by binding to broad nucleosome-depleted regions that are intrinsically favorable for nucleosome positioning. Our data support the important role of position-dependent physical properties of DNA in nucleosome positioning.

scholarly journals Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1984
Author(s):  
Majid Nikpay ◽  
Sepehr Ravati ◽  
Robert Dent ◽  
Ruth McPherson
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Search ◽  
Risk Snps ◽  
Trait Locus ◽  
Genomic Regions ◽  
Eqtl Data

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

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