scholarly journals Epigenetic conflict on a degenerating Y chromosome increases mutational burden in Drosophila males

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin H.-C. Wei ◽  
Lauren Gibilisco ◽  
Doris Bachtrog
Keyword(s):  
Y Chromosome ◽  
Early Development ◽  
Defense Mechanisms ◽  
De Novo ◽  
Genome Integrity ◽  
Selfish Dna ◽  
Mutational Burden ◽  
Y Chromosomes ◽  
Genome Wide ◽  
Eukaryotic Genomes

Abstract Large portions of eukaryotic genomes consist of transposable elements (TEs), and the establishment of transcription-repressing heterochromatin during early development safeguards genome integrity in Drosophila. Repeat-rich Y chromosomes can act as reservoirs for TEs (‘toxic’ Y effect), and incomplete epigenomic defenses during early development can lead to deleterious TE mobilization. Here, we contrast the dynamics of early TE activation in two Drosophila species with vastly different Y chromosomes of different ages. Zygotic TE expression is elevated in male embryos relative to females in both species, mostly due to expression of Y-linked TEs. Interestingly, male-biased TE expression diminishes across development in D. pseudoobscura, but remains elevated in D. miranda, the species with the younger and larger Y chromosome. The repeat-rich Y of D. miranda still contains many actively transcribed genes, which compromise the formation of silencing heterochromatin. Elevated TE expression results in more de novo insertions of repeats in males compared to females. This lends support to the idea that the ‘toxic’ Y chromosome can create a mutational burden in males when genome-wide defense mechanisms are compromised, and suggests a previously unappreciated epigenetic conflict on evolving Y chromosomes between transcription of essential genes and silencing of selfish DNA.

scholarly journals Epigenetic conflict on a degenerating Y chromosome increases mutational burden in Drosophila males

2020 ◽  
Author(s):  
Kevin H.-C. Wei ◽  
Lauren Gibilisco ◽  
Doris Bachtrog
Keyword(s):  
Y Chromosome ◽  
Early Development ◽  
Defense Mechanisms ◽  
De Novo ◽  
Genome Integrity ◽  
Selfish Dna ◽  
Mutational Burden ◽  
Y Chromosomes ◽  
Genome Wide ◽  
Eukaryotic Genomes

AbstractLarge portions of eukaryotic genomes consist of transposable elements (TEs), and the establishment of transcription-repressing heterochromatin during early development safeguards genome integrity in Drosophila. Repeat-rich Y chromosomes can act as reservoirs for TEs (‘toxic’ Y effect), and incomplete epigenomic defenses during early development can lead to deleterious TE mobilization. Here, we contrast the dynamics of early TE activation in two Drosophila species with vastly different Y chromosomes of different age. Zygotic TE expression is elevated in male embryos relative to females in both species, mostly due to expression of Y-linked TEs. Interestingly, male-biased TE misexpression diminishes across development in D. pseudoobscura, but remains elevated in D. miranda, the species with the younger and larger Y chromosome. The repeat-rich Y of D. miranda still contains many actively transcribed genes, which compromise the formation of silencing heterochromatin. Elevated TE expression results in more de novo insertions of repeats in males compared to females. This lends support to the idea that the ‘toxic’ Y chromosome can create a mutational burden in males when genome-wide defense mechanisms are compromised, and suggests a previously unappreciated epigenetic conflict on evolving Y chromosomes between transcription of essential genes and silencing of selfish DNA.

scholarly journals Unique structure and positive selection promote the rapid divergence of Drosophila Y chromosomes

2021 ◽  
Author(s):  
Ching-Ho Chang ◽  
Lauren E. Gregory ◽  
Kathleen E. Gordon ◽  
Colin D. Meiklejohn ◽  
Amanda M. Larracuente
Keyword(s):  
Positive Selection ◽  
Y Chromosome ◽  
Related Species ◽  
De Novo ◽  
Gene Families ◽  
Chromosome Organization ◽  
End Joining ◽  
Sexual Antagonism ◽  
Closely Related Species ◽  
Y Chromosomes

AbstractY chromosomes across diverse species convergently evolve a gene-poor, heterochromatic organization enriched for duplicated genes, LTR retrotransposable elements, and satellite DNA. Sexual antagonism and a loss of recombination play major roles in the degeneration of young Y chromosomes. However, the processes shaping the evolution of mature, already degenerated Y chromosomes are less well-understood. Because Y chromosomes evolve rapidly, comparisons between closely related species are particularly useful. We generated de novo long read assemblies complemented with cytological validation to reveal Y chromosome organization in three closely related species of the Drosophila simulans complex, which diverged only 250,000 years ago and share >98% sequence identity. We find these Y chromosomes are divergent in their organization and repetitive DNA composition and discover new Y-linked gene families whose evolution is driven by both positive selection and gene conversion. These Y chromosomes are also enriched for large deletions, suggesting that the repair of double-strand breaks on Y chromosomes may be biased toward microhomology-mediated end joining over canonical non-homologous end-joining. We propose that this repair mechanism generally contributes to the convergent evolution of Y chromosome organization.

scholarly journals Genome-wide prediction of topoisomerase IIβ binding by architectural factors and chromatin accessibility

2020 ◽  
Author(s):  
Pedro Manuel Martínez-García ◽  
Miguel García-Torres ◽  
Federico Divina ◽  
José Terrón-Bautista ◽  
Irene Delgado-Sainz ◽  
...  
Keyword(s):  
Machine Learning ◽  
Developmental Disorders ◽  
Topoisomerase Ii ◽  
Catalytic Mechanism ◽  
De Novo ◽  
Deep Understanding ◽  
Genome Integrity ◽  
Sequencing Data ◽  
Genome Wide ◽  
Genome Dynamics

AbstractDNA topoisomerase II-β (TOP2B) is fundamental to remove topological problems linked to DNA metabolism and 3D chromatin architecture, but its cut-and-reseal catalytic mechanism can accidentally cause DNA double-strand breaks (DSBs) that can seriously compromise genome integrity. Understanding the factors that determine the genome-wide distribution of TOP2B is therefore not only essential for a complete knowledge of genome dynamics and organization, but also for the implications of TOP2-induced DSBs in the origin of oncogenic translocations and other types of chromosomal rearrangements. Here, we conduct a machine-learning approach for the prediction of TOP2B binding sites using publicly available sequencing data. We achieve highly accurate predictions, with accessible chromatin and architectural factors being the most informative features. Strikingly, TOP2B is sufficiently explained by only three features: DNase I hypersensitivity, CTCF and cohesin binding, for which genome-wide data are widely available. Based on this, we develop a predictive model for TOP2B genome-wide binding that can be used across cell lines and species, and generate virtual probability tracks that accurately mirror experimental ChIP-seq data. Our results deepen our knowledge on how the accessibility and 3D organization of chromatin determine TOP2B function, and constitute a proof of principle regarding the in silico prediction of sequence-independent chromatin-binding factors.Author summaryType II DNA topoisomerases (TOP2) are a double-edged sword. They solve topological problems in the form of supercoiling, knots and tangles that inevitably accompany genome metabolism, but they do so at the cost of transiently cleaving DNA, with the risk that this entails for genome integrity, and the serious consequences for human health, such as neurodegeneration, developmental disorders or predisposition to cancer. A comprehensive analysis of TOP2 distribution throughout the genome is therefore essential for a deep understanding of its function and regulation, and how this can affect genome dynamics and stability. Here, we use machine learning to thoroughly explore genome-wide binding of TOP2B, a vertebrate TOP2 paralog that has been linked to genome organization and cancer-associated translocations. Our analysis shows that TOP2B-DNA binding can be accurately predicted exclusively using information on DNA accessibility and binding of genome-architecture factors. We show that such information is enough to generate virtual maps of TOP2B binding along the genome, which we validate with de novo experimental data. Our results highlight the importance of TOP2B for accessibility and 3D organization of chromatin, and show that computationally predicted TOP2 maps can be accurately obtained using minimal publicly available datasets, opening the door for their use in different organisms, cell types and conditions with experimental and/or clinical relevance.

scholarly journals Unique structure and positive selection promote the rapid divergence of Drosophila Y chromosomes

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Ching-Ho Chang ◽  
Lauren E Gregory ◽  
Kathleen E Gordon ◽  
Colin D Meiklejohn ◽  
Amanda M Larracuente
Keyword(s):  
Positive Selection ◽  
Y Chromosome ◽  
Related Species ◽  
De Novo ◽  
Gene Families ◽  
Chromosome Organization ◽  
End Joining ◽  
Sexual Antagonism ◽  
Closely Related Species ◽  
Y Chromosomes

Y chromosomes across diverse species convergently evolve a gene-poor, heterochromatic organization enriched for duplicated genes, LTR retrotransposons, and satellite DNA. Sexual antagonism and a loss of recombination play major roles in the degeneration of young Y chromosomes. However, the processes shaping the evolution of mature, already degenerated Y chromosomes are less well-understood. Because Y chromosomes evolve rapidly, comparisons between closely related species are particularly useful. We generated de novo long read assemblies complemented with cytological validation to reveal Y chromosome organization in three closely related species of the Drosophila simulans complex, which diverged only 250,000 years ago and share >98% sequence identity. We find these Y chromosomes are divergent in their organization and repetitive DNA composition and discover new Y-linked gene families whose evolution is driven by both positive selection and gene conversion. These Y chromosomes are also enriched for large deletions, suggesting that the repair of double-strand breaks on Y chromosomes may be biased toward microhomology-mediated end joining over canonical non-homologous end-joining. We propose that this repair mechanism contributes to the convergent evolution of Y chromosome organization across organisms.

scholarly journals Heterochromatin-enriched assemblies reveal the sequence and organization of the Drosophila melanogaster Y chromosome

2018 ◽  
Author(s):  
Ching-Ho Chang ◽  
Amanda M. Larracuente
Keyword(s):  
Drosophila Melanogaster ◽  
Gene Family ◽  
Gene Conversion ◽  
Y Chromosome ◽  
Single Molecule ◽  
De Novo ◽  
High Rate ◽  
Genome Wide ◽  
Conversion Rates ◽  
Multiple Copies

ABSTRACTHeterochromatic regions of the genome are repeat-rich and gene poor, and are therefore underrepresented in even in the best genome assemblies. One of the most difficult regions of the genome to assemble are sex-limited chromosomes. The Drosophila melanogaster Y chromosome is entirely heterochromatic, yet has wide-ranging effects on male fertility, fitness, and genome-wide gene expression. The genetic basis of this phenotypic variation is difficult to study, in part because we do not know the detailed organization of the Y chromosome. To study Y chromosome organization in D. melanogaster, we develop an assembly strategy involving the in silico enrichment of heterochromatic long single-molecule reads and use these reads to create targeted de novo assemblies of heterochromatic sequences. We assigned contigs to the Y chromosome using Illumina reads to identify male-specific sequences. Our pipeline extends the D. melanogaster reference genome by 11.9-Mb, closes 43.8% of the gaps, and improves overall contiguity. The addition of 10.6 MB of Y-linked sequence permitted us to study the organization of repeats and genes along the Y chromosome. We detected a high rate of duplication to the pericentric regions of the Y chromosome from other regions in the genome. Most of these duplicated genes exist in multiple copies. We detail the evolutionary history of one sex-linked gene family—crystal-Stellate. While the Y chromosome does not undergo crossing over, we observed high gene conversion rates within and between members of the crystal-Stellate gene family, Su(Ste), and PCKR, compared to genome-wide estimates. Our results suggest that gene conversion and gene duplication play an important role in the evolution of Y-linked genes.

scholarly journals The Drosophila Y chromosome affects heterochromatin integrity genome-wide

2017 ◽  
Author(s):  
Emily J. Brown ◽  
Alison H. Nguyen ◽  
Doris Bachtrog
Keyword(s):  
Y Chromosome ◽  
Sex Chromosome ◽  
Gene Activation ◽  
Chromatin Modifications ◽  
Active Chromatin ◽  
Genomic Distribution ◽  
Sexual Dimorphisms ◽  
Y Chromosomes ◽  
Genome Wide ◽  
Males And Females

AbstractThe Drosophila Y-chromosome is gene poor and mainly consists of silenced, repetitive DNA. Nonetheless, the Y influences expression of hundreds of genes genome-wide, possibly by sequestering key components of the heterochromatin machinery away from other positions in the genome. To test the influence of the Y chromosome on the genome-wide chromatin landscape, we assayed the genomic distribution of histone modifications associated with gene activation (H3K4me3), or heterochromatin (H3K9me2 and H3K9me3) in fruit flies with varying sex chromosome complements (X0, XY and XYY males; XX and XXY females). Consistent with the general deficiency of active chromatin modifications on the Y, we find that Y gene dose has little influence on the genomic distribution of H3K4me3. In contrast, both the presence and the number of Y-chromosomes strongly influence genome-wide enrichment patterns of repressive chromatin modifications. Highly repetitive regions such as the pericentromeres, the dot, and the Y chromosome (if present) are enriched for heterochromatic modifications in wildtype males and females, and even more strongly in X0 flies. In contrast, the additional Y chromosome in XYY males and XXY females diminishes the heterochromatic signal in these normally silenced, repeat-rich regions, which is accompanied by an increase in expression of Y-linked repeats. We find hundreds of genes that are expressed differentially between individuals with aberrant sex chromosome karyotypes, many of which also show sex-biased expression in wildtype Drosophila. Thus, Y-chromosomes influence heterochromatin integrity genome-wide, and differences in the chromatin landscape of males and females may also contribute to sex-biased gene expression and sexual dimorphisms.

scholarly journals Broad noncoding transcription suggests genome surveillance by RNA polymerase V

2020 ◽  
Vol 117 (48) ◽  
pp. 30799-30804
Author(s):  
Masayuki Tsuzuki ◽  
Shriya Sethuraman ◽  
Adriana N. Coke ◽  
M. Hafiz Rothi ◽  
Alan P. Boyle ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
De Novo ◽  
Genome Integrity ◽  
Biological Functions ◽  
Pol V ◽  
Low Levels ◽  
Interfering Rna ◽  
Eukaryotic Genomes ◽  
Transcribed Sequences ◽  
Pervasive Transcription

Eukaryotic genomes are pervasively transcribed, yet most transcribed sequences lack conservation or known biological functions. InArabidopsis thaliana, RNA polymerase V (Pol V) produces noncoding transcripts, which base pair with small interfering RNA (siRNA) and allow specific establishment of RNA-directed DNA methylation (RdDM) on transposable elements. Here, we show that Pol V transcribes much more broadly than previously expected, including subsets of both heterochromatic and euchromatic regions. At already established RdDM targets, Pol V and siRNA work together to maintain silencing. In contrast, some euchromatic sequences do not give rise to siRNA but are covered by low levels of Pol V transcription, which is needed to establish RdDM de novo if a transposon is reactivated. We propose a model where Pol V surveils the genome to make it competent to silence newly activated or integrated transposons. This indicates that pervasive transcription of nonconserved sequences may serve an essential role in maintenance of genome integrity.

scholarly journals siRNA-mediated de novo silencing of Ac/Ds transposons is initiated by alternative transposition in maize

2020 ◽  
Author(s):  
Dafang Wang ◽  
Jianbo Zhang ◽  
Tao Zuo ◽  
Damon Lisch ◽  
Meixia Zhao ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Defense Mechanisms ◽  
De Novo ◽  
Inverted Repeats ◽  
Small Interfering Rnas ◽  
Major Fraction ◽  
First Case ◽  
Transposon Silencing ◽  
Alternative Transposition ◽  
Eukaryotic Genomes

AbstractAlthough Transposable Elements (TEs) comprise a major fraction of many higher eukaryotic genomes, most TEs are silenced by host defense mechanisms. The means by which otherwise active TEs are recognized and silenced remains poorly understood. Here we analyzed two independent cases of spontaneous silencing of the active maize Ac/Ds transposon system. This silencing was initiated by Alternative Transposition (AT), a type of aberrant transposition event that engages the termini of two nearby separate TEs. AT during DNA replication can generate Composite Insertions (CIs) that contain inverted duplications of the transposon sequences. We show that the inverted duplications of two CIs are transcribed to produce dsRNAs that trigger the production of two distinct classes of siRNAs: a 24-nt class complementary to the TE terminal inverted repeats (TIRs) and non-coding sub-terminal regions, and a 21-22 nt class corresponding to the TE transcribed regions. Plants containing these siRNA-generating CIs exhibit decreased levels of Ac transcript and heritable repression of Ac/Ds transposition. This study documents the first case of TE silencing attributable to transposon self-initiated AT and may represent a general initiating mechanism for silencing of DNA transposons.Article summaryTransposable Elements (TEs) are often silenced by their hosts, but how TEs are initially recognized for silencing remains unclear. Here we describe two independent loci that induce de novo heritable silencing of maize Ac/Ds transposons. Plants containing these loci produce dsRNA and Ac-homologous small interfering RNAs, and exhibit decreased levels of Ac transcript and heritable repression of Ac/Ds transposition. We show that these loci comprise inverted duplications of TE sequences generated by Alternative Transposition coupled with DNA re-replication. This study documents the first case of transposon silencing induced by AT and may represent a general initiating mechanism for TE silencing.

scholarly journals The Drosophila Y Chromosome Affects Heterochromatin Integrity Genome-Wide

2020 ◽  
Vol 37 (10) ◽  
pp. 2808-2824 ◽  
Author(s):  
Emily J Brown ◽  
Alison H Nguyen ◽  
Doris Bachtrog
Keyword(s):  
Y Chromosome ◽  
Sex Chromosome ◽  
Gene Activation ◽  
Chromatin Modifications ◽  
Active Chromatin ◽  
Genomic Distribution ◽  
Sexual Dimorphisms ◽  
Y Chromosomes ◽  
Genome Wide ◽  
Males And Females

Abstract The Drosophila Y chromosome is gene poor and mainly consists of silenced, repetitive DNA. Nonetheless, the Y influences expression of hundreds of genes genome-wide, possibly by sequestering key components of the heterochromatin machinery away from other positions in the genome. To test the influence of the Y chromosome on the genome-wide chromatin landscape, we assayed the genomic distribution of histone modifications associated with gene activation (H3K4me3) or heterochromatin (H3K9me2 and H3K9me3) in fruit flies with varying sex chromosome complements (X0, XY, and XYY males; XX and XXY females). Consistent with the general deficiency of active chromatin modifications on the Y, we find that Y gene dose has little influence on the genomic distribution of H3K4me3. In contrast, both the presence and the number of Y chromosomes strongly influence genome-wide enrichment patterns of repressive chromatin modifications. Highly repetitive regions such as the pericentromeres, the dot, and the Y chromosome (if present) are enriched for heterochromatic modifications in wildtype males and females, and even more strongly in X0 flies. In contrast, the additional Y chromosome in XYY males and XXY females diminishes the heterochromatic signal in these normally silenced, repeat-rich regions, which is accompanied by an increase in expression of Y-linked repeats. We find hundreds of genes that are expressed differentially between individuals with aberrant sex chromosome karyotypes, many of which also show sex-biased expression in wildtype Drosophila. Thus, Y chromosomes influence heterochromatin integrity genome-wide, and differences in the chromatin landscape of males and females may also contribute to sex-biased gene expression and sexual dimorphisms.

scholarly journals Small RNA-Mediated De Novo Silencing of Ac/Ds Transposons Is Initiated by Alternative Transposition in Maize

Genetics ◽  
2020 ◽  
Vol 215 (2) ◽  
pp. 393-406 ◽  
Author(s):  
Dafang Wang ◽  
Jianbo Zhang ◽  
Tao Zuo ◽  
Meixia Zhao ◽  
Damon Lisch ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
De Novo ◽  
Inverted Repeats ◽  
Small Interfering Rnas ◽  
Major Fraction ◽  
First Case ◽  
Transposon Silencing ◽  
Alternative Transposition ◽  
Interfering Rna ◽  
Eukaryotic Genomes

Although transposable elements (TEs) comprise a major fraction of many higher eukaryotic genomes, most TEs are silenced by host defense mechanisms. The means by which otherwise active TEs are recognized and silenced remains poorly understood. Here we analyzed two independent cases of spontaneous silencing of the active maize Ac/Ds transposon system. This silencing is initiated by alternative transposition, a type of aberrant transposition event that engages the termini of two nearby separate TEs. Alternative transposition during DNA replication can generate Composite Insertions that contain inverted duplications of the transposon sequences. We show that the inverted duplications of two Composite Insertions are transcribed to produce double-stranded RNAs that trigger the production of two distinct classes of small interfering RNAs: a 24-nt class complementary to the TE terminal inverted repeats and noncoding subterminal regions, and a 21- to 22-nt class corresponding to the TE transcribed regions. Plants containing these small interfering RNA-generating Composite Insertions exhibit decreased levels of Ac transcript and heritable repression of Ac/Ds transposition. Further, we demonstrate that Composite Insertions can heritably silence otherwise active elements in trans. This study documents the first case of transposon silencing induced by alternative transposition and may represent a general initiating mechanism for silencing of DNA transposons.

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