RESUMEN
Replication origins, fragile sites, and rDNA have been implicated as sources of chromosomal instability. However, the defining genomic features of replication origins and fragile sites are among the least understood elements of eukaryote genomes. Here, we map sites of replication initiation and breakage in primary cells at high resolution. We find that replication initiates between transcribed genes within nucleosome-depleted structures established by long asymmetrical poly(dA:dT) tracts flanking the initiation site. Paradoxically, long (>20 bp) (dA:dT) tracts are also preferential sites of polar replication fork stalling and collapse within early-replicating fragile sites (ERFSs) and late-replicating common fragile sites (CFSs) and at the rDNA replication fork barrier. Poly(dA:dT) sequences are fragile because long single-strand poly(dA) stretches at the replication fork are unprotected by the replication protein A (RPA). We propose that the evolutionary expansion of poly(dA:dT) tracts in eukaryotic genomes promotes replication initiation, but at the cost of chromosome fragility.
Asunto(s)
Replicación del ADN , ADN Ribosómico/química , Nucleosomas/metabolismo , Poli dA-dT/química , Origen de Réplica , Secuencias de Aminoácidos , Animales , Línea Celular , Inmunoprecipitación de Cromatina , Inestabilidad Cromosómica , Sitios Frágiles del Cromosoma , Fragilidad Cromosómica , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Saccharomyces cerevisiae , Schizosaccharomyces , Sitio de Iniciación de la Transcripción , Transcripción GenéticaRESUMEN
Germ cells are the only cell type that is capable of transmitting genetic information to the next generation, which has enabled the continuation of multicellular life for the last 1.5 billion years. Surprisingly little is known about the mechanisms supporting the germline's remarkable ability to continue in this eternal cycle, termed germline immortality. Even unicellular organisms age at a cellular level, demonstrating that cellular aging is inevitable. Extensive studies in yeast have established the framework of how asymmetric cell division and gametogenesis may contribute to the resetting of cellular age. This review examines the mechanisms of germline immortality-how germline cells reset the aging of cells-drawing a parallel between yeast and multicellular organisms.
Asunto(s)
División Celular Asimétrica , Saccharomyces cerevisiae , División Celular Asimétrica/genética , Saccharomyces cerevisiae/genética , Células Germinativas , Células MadreRESUMEN
It is unknown how ribosomal gene (rDNA) arrays from multiple chromosomal nucleolar organizers (NORs) partition within human nucleoli. Exploration of this paradigm for chromosomal organization is complicated by the shared DNA sequence composition of five NOR-bearing acrocentric chromosome p-arms. Here, we devise a methodology for genetic manipulation of individual NORs. Efficient "scarless" genome editing of rDNA repeats is achieved on "poised" human NORs held within monochromosomal cell hybrids. Subsequent transfer to human cells introduces "active" NORs yielding readily discernible functional customized ribosomes. We reveal that ribosome biogenesis occurs entirely within constrained territories, tethered to individual NORs inside a larger nucleolus.
Asunto(s)
Nucléolo Celular/metabolismo , Región Organizadora del Nucléolo/genética , Región Organizadora del Nucléolo/metabolismo , Ribosomas/metabolismo , Secuencia de Bases , Línea Celular , Nucléolo Celular/genética , Cromosomas/metabolismo , Edición Génica , Humanos , Ribosomas/genéticaRESUMEN
The recent discovery of an association between ribosomal DNA (rDNA) copy number and body mass index (BMI) by Law et al. sheds light on a possible role of 45S rDNA in body-weight regulation. This finding opens new avenues for further investigations into the effect of rDNA on various human phenotypes.
RESUMEN
The ribosomal DNA (rDNA) represents a particularly unstable locus undergoing frequent breakage. DNA double-strand breaks (DSBs) within rDNA induce both rDNA transcriptional repression and nucleolar segregation, but the link between the two events remains unclear. Here we found that DSBs induced on rDNA trigger transcriptional repression in a cohesin- and HUSH (human silencing hub) complex-dependent manner throughout the cell cycle. In S/G2 cells, transcriptional repression is further followed by extended resection within the interior of the nucleolus, DSB mobilization at the nucleolar periphery within nucleolar caps, and repair by homologous recombination. We showed that nuclear envelope invaginations frequently connect the nucleolus and that rDNA DSB mobilization, but not transcriptional repression, involves the nuclear envelope-associated LINC complex and the actin pathway. Altogether, our data indicate that rDNA break localization at the nucleolar periphery is not a direct consequence of transcriptional repression but rather is an active process that shares features with the mobilization of persistent DSB in active genes and heterochromatin.
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Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN/genética , ADN Ribosómico/genética , Regulación de la Expresión Génica/genética , ARN Largo no Codificante/metabolismo , Nucléolo Celular/metabolismo , Histonas/metabolismo , Recombinación Homóloga/genética , Membrana Nuclear/metabolismo , CohesinasRESUMEN
Although the nucleolus was first described in the early 19th century from both animal and plant cells, human nucleoli and particularly the five human nucleolus organizers have not been well characterized. In this issue of Genes & Development, van Sluis and colleagues (pp. 1688-1701) present a detailed molecular analysis of these organizers, which occur on the short arms of five human chromosomes. The near identity of these arms suggests extensive interchromosomal exchange during evolutionary history.
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Nucléolo Celular , Región Organizadora del Nucléolo , Animales , ADN Ribosómico , HumanosRESUMEN
Human nucleolar organizer regions (NORs), containing ribosomal gene (rDNA) arrays, are located on the p-arms of acrocentric chromosomes (HSA13-15, 21, and 22). Absence of these p-arms from genome references has hampered research on nucleolar formation. Previously, we assembled a distal junction (DJ) DNA sequence contig that abuts rDNA arrays on their telomeric side, revealing that it is shared among the acrocentrics and impacts nucleolar organization. To facilitate inclusion into genome references, we describe sequencing the DJ from all acrocentrics, including three versions of HSA21, â¼3 Mb of novel sequence. This was achieved by exploiting monochromosomal somatic cell hybrids containing single human acrocentric chromosomes with NORs that retain functional potential. Analyses revealed remarkable DJ sequence and functional conservation among human acrocentrics. Exploring chimpanzee acrocentrics, we show that "DJ-like" sequences and abutting rDNA arrays are inverted as a unit in comparison to humans. Thus, rDNA arrays and linked DJs represent a conserved functional locus. We provide direct evidence for exchanges between heterologous human acrocentric p-arms, and uncover extensive structural variation between chromosomes and among individuals. These findings lead us to revaluate the molecular definition of NORs, identify novel genomic structural variation, and provide a rationale for the distinctive chromosomal organization of NORs.
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Cromosomas/química , Cromosomas/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Región Organizadora del Nucléolo/química , Región Organizadora del Nucléolo/genética , Animales , Secuencia de Bases , Línea Celular , Secuencia Conservada/genética , Estructuras Genéticas/genética , Variación Genética , Humanos , Células Híbridas , Ratones , Pan troglodytes/genéticaRESUMEN
The rRNA genes [ribosomal DNA (rDNA)] are organized in a prominent nuclear compartment, the nucleolus. It is now well established that the nucleolus functions beyond ribosome biosynthesis, regulating several physiological cellular responses. The nucleoli constitute dynamic genomic/nuclear hubs and demonstrate unique inherent characteristics, rendering them ideal to sense, signal, and respond to various intrinsic and environmental insults. Here, we discuss emerging findings supporting direct links between rDNA/nucleolar instability and cellular senescence/organismal aging from yeast to mammals. Moreover, we highlight evidence that nucleolar functionality and rDNA architecture impact on meiotic/transgenerational rejuvenation, thus revealing causality underlying connections between rDNA/nucleolar instability and aging.
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Envejecimiento , Nucléolo Celular , Envejecimiento/genética , Animales , Nucléolo Celular/genética , Senescencia Celular , ADN Ribosómico/genética , Mamíferos , ARN Ribosómico/genética , Saccharomyces cerevisiae/genéticaRESUMEN
Ribosomal DNA (rDNA) loci contain hundreds of tandemly repeated copies of ribosomal RNA genes needed to support cellular viability. This repetitiveness makes it highly susceptible to copy number (CN) loss due to intrachromatid recombination between rDNA copies, threatening multigenerational maintenance of rDNA. How this threat is counteracted to avoid extinction of the lineage has remained unclear. Here, we show that the rDNA-specific retrotransposon R2 is essential for restorative rDNA CN expansion to maintain rDNA loci in the Drosophila male germline. The depletion of R2 led to defective rDNA CN maintenance, causing a decline in fecundity over generations and eventual extinction. We find that double-stranded DNA breaks created by the R2 endonuclease, a feature of R2's rDNA-specific retrotransposition, initiate the process of rDNA CN recovery, which relies on homology-dependent repair of the DNA break at rDNA copies. This study reveals that an active retrotransposon provides an essential function for its host, contrary to transposable elements' reputation as entirely selfish. These findings suggest that benefiting host fitness can be an effective selective advantage for transposable elements to offset their threat to the host, which may contribute to retrotransposons' widespread success throughout taxa.
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Drosophila , Retroelementos , Animales , Retroelementos/genética , ADN Ribosómico/genética , Drosophila/genética , Elementos Transponibles de ADNRESUMEN
Ribosomal DNA (rDNA) encodes ribosomal RNA and exists as tandem repeats of hundreds of copies in the eukaryotic genome to meet the high demand of ribosome biogenesis. Tandemly repeated DNA elements are inherently unstable; thus, mechanisms must exist to maintain rDNA copy number (CN), in particular in the germline that continues through generations. A phenomenon called rDNA magnification was discovered over 50 y ago in Drosophila as a process that recovers the rDNA CN on chromosomes that harbor minimal CN. Our recent studies indicated that rDNA magnification is the mechanism to maintain rDNA CN under physiological conditions to counteract spontaneous CN loss that occurs during aging. Our previous studies that explored the mechanism of rDNA magnification implied that asymmetric division of germline stem cells (GSCs) may be particularly suited to achieve rDNA magnification. However, it remains elusive whether GSCs are the unique cell type that undergoes rDNA magnification or differentiating germ cells are also capable of magnification. In this study, we provide empirical evidence that suggests that rDNA magnification operates uniquely in GSCs, but not in differentiating germ cells. We further provide computer simulation that suggests that rDNA magnification is only achievable through asymmetric GSC divisions. We propose that despite known plasticity and transcriptomic similarity between GSCs and differentiating germ cells, GSCs' unique ability to divide asymmetrically serves a critical role of maintaining rDNA CN through generations, supporting germline immortality.
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Proteínas de Drosophila , Drosophila , Animales , ADN Ribosómico/genética , ADN Ribosómico/metabolismo , Simulación por Computador , Drosophila/genética , Drosophila/metabolismo , Células Germinativas/metabolismo , Células Madre/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismoRESUMEN
The ribosomal DNA (rDNA) in Drosophila is found as two additive clusters of individual 35 S cistrons. The multiplicity of rDNA is essential to assure proper translational demands, but the nature of the tandem arrays expose them to copy number variation within and between populations. Here, we discuss means by which a cell responds to insufficient rDNA copy number, including a historical view of rDNA magnification whose mechanism was inferred some 35 years ago. Recent work has revealed that multiple conditions may also result in rDNA loss, in response to which rDNA magnification may have evolved. We discuss potential models for the mechanism of magnification, and evaluate possible consequences of rDNA copy number variation.
Asunto(s)
Variaciones en el Número de Copia de ADN , Drosophila melanogaster , Animales , ADN Ribosómico/genética , Variaciones en el Número de Copia de ADN/genética , Drosophila melanogaster/genética , Drosophila/genética , RibosomasRESUMEN
Although both are salient features of genomes, at first glance ribosomal DNAs and transposable elements are genetic elements with not much in common: whereas ribosomal DNAs are mainly viewed as housekeeping genes that uphold all prime genome functions, transposable elements are generally portrayed as selfish and disruptive. These opposing characteristics are also mirrored in other attributes: organization in tandem (ribosomal DNAs) versus organization in a dispersed manner (transposable elements); evolution in a concerted manner (ribosomal DNAs) versus evolution by diversification (transposable elements); and activity that prolongs genomic stability (ribosomal DNAs) versus activity that shortens it (transposable elements). Re-visiting relevant instances in which ribosomal DNA-transposable element interactions have been reported, we note that both repeat types share at least four structural and functional hallmarks: (1) they are repetitive DNAs that shape genomes in evolutionary timescales, (2) they exchange structural motifs and can enter co-evolution processes, (3) they are tightly controlled genomic stress sensors playing key roles in senescence/aging, and (4) they share common epigenetic marks such as DNA methylation and histone modification. Here, we give an overview of the structural, functional, and evolutionary characteristics of both ribosomal DNAs and transposable elements, discuss their roles and interactions, and highlight trends and future directions as we move forward in understanding ribosomal DNA-transposable element associations.
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Elementos Transponibles de ADN , Genómica , ADN Ribosómico , Metilación de ADN , Análisis Citogenético , Evolución MolecularRESUMEN
With the advent of long-read sequencing, previously unresolvable genomic elements are being revisited in an effort to generate fully complete reference genomes. One such element is ribosomal DNA (rDNA), the highly conserved genomic region that encodes rRNAs. Genomic structure and content of the rDNA are variable in both prokarya and eukarya, posing interesting questions about the biology of rDNA. Here, we consider the types of variation observed in rDNA - including locus structure and number, copy number, and sequence variation - and their known phenotypic consequences. With recent advances in long-read sequencing technology, incorporating the full rDNA sequence into reference genomes is within reach. This knowledge will have important implications for understanding rDNA biology within the context of cell physiology and whole-organism phenotypes.
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Genómica , ARN Ribosómico , ADN Ribosómico/genética , Eucariontes/genética , ARN Ribosómico/genéticaRESUMEN
The complex processes and interactions that regulate aging and determine lifespan are not fully defined for any organism. Here, taking advantage of recent technological advances in studying aging in budding yeast, we discovered a previously unappreciated relationship between the number of copies of the ribosomal RNA gene present in its chromosomal array and replicative lifespan (RLS). Specifically, the chromosomal ribosomal DNA (rDNA) copy number (rDNA CN) positively correlated with RLS and this interaction explained over 70% of variability in RLS among a series of wild-type strains. In strains with low rDNA CN, SIR2 expression was attenuated and extrachromosomal rDNA circle (ERC) accumulation was increased, leading to shorter lifespan. Suppressing ERC formation by deletion of FOB1 eliminated the relationship between rDNA CN and RLS. These data suggest that previously identified rDNA CN regulatory mechanisms limit lifespan. Importantly, the RLSs of reported lifespan-enhancing mutations were significantly impacted by rDNA CN, suggesting that changes in rDNA CN might explain the magnitude of some of those reported effects. We propose that because rDNA CN is modulated by environmental, genetic, and stochastic factors, considering rDNA CN is a prerequisite for accurate interpretation of lifespan data.
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Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Replicación del ADN/genética , ADN Ribosómico/genética , Longevidad , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomycetales/genéticaRESUMEN
Nucleolar dominance (ND) is a widespread epigenetic phenomenon in hybridizations where nucleolus transcription fails at the nucleolus organizer region (NOR). However, the dynamics of NORs during the formation of Triticum zhukovskyi (GGAu Au Am Am ), another evolutionary branch of allohexaploid wheat, remains poorly understood. Here, we elucidated genetic and epigenetic changes occurring at the NOR loci within the Am , G, and D subgenomes during allopolyploidization by synthesizing hexaploid wheat GGAu Au Am Am and GGAu Au DD. In T. zhukovskyi, Au genome NORs from T. timopheevii (GGAu Au ) were lost, while the second incoming NORs from T. monococcum (Am Am ) were retained. Analysis of the synthesized T. zhukovskyi revealed that rRNA genes from the Am genome were silenced in F1 hybrids (GAu Am ) and remained inactive after genome doubling and subsequent self-pollinations. We observed increased DNA methylation accompanying the inactivation of NORs in the Am genome and found that silencing of NORs in the S1 generation could be reversed by a cytidine methylase inhibitor. Our findings provide insights into the ND process during the evolutionary period of T. zhukovskyi and highlight that inactive rDNA units may serve as a 'first reserve' in the form of R-loops, contributing to the successful evolution of T. zhukovskyi.
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Nucléolo Celular , Triticum , Triticum/genética , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Región Organizadora del Nucléolo , ADN Ribosómico/metabolismo , Metilación de ADN/genéticaRESUMEN
BACKGROUND: Despite the many cheap and fast ways to generate genomic data, good and exact genome assembly is still a problem, with especially the repeats being vastly underrepresented and often misassembled. As short reads in low coverage are already sufficient to represent the repeat landscape of any given genome, many read cluster algorithms were brought forward that provide repeat identification and classification. But how can trustworthy, reliable and representative repeat consensuses be derived from unassembled genomes? RESULTS: Here, we combine methods from repeat identification and genome assembly to derive these robust consensuses. We test several use cases, such as (1) consensus building from clustered short reads of non-model genomes, (2) from genome-wide amplification setups, and (3) specific repeat-centred questions, such as the linked vs. unlinked arrangement of ribosomal genes. In all our use cases, the derived consensuses are robust and representative. To evaluate overall performance, we compare our high-fidelity repeat consensuses to RepeatExplorer2-derived contigs and check, if they represent real transposable elements as found in long reads. Our results demonstrate that it is possible to generate useful, reliable and trustworthy consensuses from short reads by a combination from read cluster and genome assembly methods in an automatable way. CONCLUSION: We anticipate that our workflow opens the way towards more efficient and less manual repeat characterization and annotation, benefitting all genome studies, but especially those of non-model organisms.
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Algoritmos , Elementos Transponibles de ADN , Secuencia de Consenso , Análisis por Conglomerados , GenómicaRESUMEN
During the first cell cycles of early development, the chromatin of the embryo is highly reprogrammed while the embryonic genome starts its own transcription. The spatial organization of the genome is an important process that contributes to regulating gene transcription in time and space. It has, however, been poorly studied in the context of early embryos. To study the cause-and-effect link between transcription and spatial organization in embryos, we focused on ribosomal genes, which are silent initially but start to be transcribed in 2-cell mouse embryos. We demonstrated that ribosomal sequences and early unprocessed rRNAs are spatially organized in a very particular manner between 2-cell and 16-cell stage. By using drugs that interfere with ribosomal DNA transcription, we showed that this organization - which is totally different in somatic cells - depends on an active transcription of ribosomal genes and induces a unique chromatin environment that favors transcription of major satellite sequences once the 4-cell stage has been reached.
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Cromatina , ARN Ribosómico , Animales , Cromatina/genética , Cromatina/metabolismo , ADN Ribosómico/genética , Embrión de Mamíferos/metabolismo , Ratones , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Ribosomas/metabolismo , Transcripción GenéticaRESUMEN
Ribosomal deoxyribonucleic acid (DNA) (rDNA) repeats are tandemly located on five acrocentric chromosomes with up to hundreds of copies in the human genome. DNA methylation, the most well-studied epigenetic mechanism, has been characterized for most genomic regions across various biological contexts. However, rDNA methylation patterns remain largely unexplored due to the repetitive structure. In this study, we designed a specific mapping strategy to investigate rDNA methylation patterns at each CpG site across various physiological and pathological processes. We found that CpG sites on rDNA could be categorized into two types. One is within or adjacent to transcribed regions; the other is distal to transcribed regions. The former shows highly variable methylation levels across samples, while the latter shows stable high methylation levels in normal tissues but severe hypomethylation in tumors. We further showed that rDNA methylation profiles in plasma cell-free DNA could be used as a biomarker for cancer detection. It shows good performances on public datasets, including colorectal cancer [area under the curve (AUC) = 0.85], lung cancer (AUC = 0.84), hepatocellular carcinoma (AUC = 0.91) and in-house generated hepatocellular carcinoma dataset (AUC = 0.96) even at low genome coverage (<1×). Taken together, these findings broaden our understanding of rDNA regulation and suggest the potential utility of rDNA methylation features as disease biomarkers.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Ácidos Nucleicos Libres de Células/genética , Islas de CpG , Metilación de ADN , ADN Ribosómico/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Regiones Promotoras GenéticasRESUMEN
Chamaecrista is a Pantropical legume genus of the tribe Cassieae, which includes six other genera. In contrast to most of the other Cassieae genera, Chamaecrista shows significant variability in chromosome number (from 2n = 14 to 2n = 56), with small and morphologically similar chromosomes. Here, we performed a new cytomolecular analysis on chromosome number, genome size, and rDNA site distribution in a molecular phylogenetic perspective to interpret the karyotype trends of Chamaecrista and other two genera of Cassieae, seeking to understand their systematics and evolution. Our phylogenetic analysis revealed that Chamaecrista is monophyletic and can be divided into four major clades corresponding to the four sections of the genus. Chromosome numbers ranged from 2n = 14, 16 (section Chamaecrista) to 2n = 28 (sections Absus, Apoucouita, and Baseophyllum). The number of 5S and 35S rDNA sites varied between one and three pairs per karyotype, distributed on different chromosomes or in synteny, with no obvious phylogenetic significance. Our data allowed us to propose x = 7 as the basic chromosome number of Cassieae, which was changed by polyploidy generating x = 14 (sections Absus, Apoucouita, and Baseophyllum) and by ascending dysploidy to x = 8 (section Chamaecrista). The DNA content values supported this hypothesis, with the genomes of the putative tetraploids being larger than those of the putative diploids. We hypothesized that ascending dysploidy, polyploidy, and rDNA amplification/deamplification are the major events in the karyotypic diversification of Chamaecrista. The chromosomal marks characterized here may have cytotaxonomic potential in future studies.
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Chamaecrista , Fabaceae , Filogenia , Chamaecrista/genética , Fabaceae/genética , Cromosomas de las Plantas/genética , Genoma de Planta , Cariotipo , Poliploidía , ADN Ribosómico/genéticaRESUMEN
BACKGROUND AND AIMS: Dogroses (Rosa sect. Caninae) are mostly pentaploid, bearing 2nâ =â 5xâ =â 35 chromosomes in somatic cells. They evolved a unique form of asymmetrical meiosis characterized by two types of chromosomes: (1) chromosomes forming bivalents and distributed in the normal sexual way; and (2) chromosomes occurring as univalents and transferred by a female gamete only. In the mature pollen of pentaploid species, seven bivalent-derived chromosomes are transmitted to offspring, and 21 unpaired univalent chromosomes are eliminated during microsporogenesis. To discriminate between bivalent- and univalent-forming chromosomes, we studied histone H3 phosphorylation patterns regulating meiotic chromosome condensation and segregation. METHODS: We analysed histone modification patterns during male canina meiosis in two representative dogrose species, 5x Rosa canina and 5x Rosa rubiginosa, by immunohistochemical and molecular cytogenetics approaches. Immunostaining of meiotic cells included α-tubulin, histone H3 phosphorylation (H3S10p, H3S28p and H3T3p) and methylation (H3K4me3 and H3K27me3) marks. In addition, fluorescent in situ hybridization was carried out with an 18S rDNA probe. KEY RESULTS: In the first meiotic division, univalent chromosomes underwent equational division into chromatids, while homologues in bivalents were segregated as regular dyads. In diakinesis, bivalent chromosomes displayed strong H3 phosphorylation signals in proximal regions, spreading to the rest of the chromosome. In contrast, in univalents, the H3 phosphorylation signals were weaker, occurring mostly outside proximal regions largely overlapping with the H3K4me3 signals. Reduced phosphorylation was associated with relative under-condensation of the univalent chromosomes, particularly at early diakinesis. CONCLUSIONS: We hypothesize that the absence of pairing and/or recombination in univalent chromosomes negatively affects the histone H3 phosphorylation of their chromatin and perhaps the loading of meiotic-specific cohesins. This apparently destabilizes cohesion of sister chromatids, leading to their premature split in the first meiotic division.