• MeSH
• Cytogenetics MeSH
• Terminology as Topic MeSH

• Conspectus
• Obecná genetika. Obecná cytogenetika. Evoluce
• NML Fields
• cytologie, klinická cytologie
• genetika, lékařská genetika
• NML Publication type
• kolektivní monografie

The genomes of many plants, animals, and fungi frequently comprise dispensable B chromosomes that rely upon various chromosomal drive mechanisms to counteract the tendency of non-essential genetic elements to be purged over time. The B chromosome of rye - a model system for nearly a century - undergoes targeted nondisjunction during first pollen mitosis, favouring segregation into the generative nucleus, thus increasing their numbers over generations. However, the genetic mechanisms underlying this process are poorly understood. Here, using a newly-assembled, ~430 Mb-long rye B chromosome pseudomolecule, we identify five candidate genes whose role as trans-acting moderators of the chromosomal drive is supported by karyotyping, chromosome drive analysis and comparative RNA-seq. Among them, we identify DCR28, coding a microtubule-associated protein related to cell division, and detect this gene also in the B chromosome of Aegilops speltoides. The DCR28 gene family is neo-functionalised and serially-duplicated with 15 B chromosome-located copies that are uniquely highly expressed in the first pollen mitosis of rye.

• MeSH
• Aegilops genetics   metabolism   MeSH
• Chromosomes, Plant * genetics   MeSH
• Karyotyping MeSH
• Mitosis * genetics   MeSH
• Nondisjunction, Genetic MeSH
• Pollen genetics   MeSH
• Gene Expression Regulation, Plant MeSH
• Genes, Plant MeSH
• Plant Proteins genetics   metabolism   MeSH
• Secale * genetics   MeSH
• Publication type
• Journal Article MeSH

Glioblastoma is the commonest primary malignant brain tumor, with a very poor prognosis and short overall survival. It is characterized by its high intra- and intertumoral heterogeneity, in terms of both the level of single-nucleotide variants, copy number alterations, and aneuploidy. Therefore, routine diagnosis can be challenging in some cases. We present a complicated case of glioblastoma, which was characterized with five cytogenomic methods: interphase fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, comparative genomic hybridization array and single-nucleotide polymorphism, targeted gene panel, and whole-genome sequencing. These cytogenomic methods revealed classical findings associated with glioblastoma, such as a lack of IDH and TERT mutations, gain of chromosome 7, and loss of chromosome 10. At least three pathological clones were identified, including one with whole-genome duplication, and one with loss of 1p and suspected loss of 19q. Deletion and mutation of the TP53 gene were detected with numerous breakends on 17p and 20q. Based on these findings, we recommend a combined approach to the diagnosis of glioblastoma involving the detection of copy number alterations, mutations, and aneuploidy. The choice of the best combination of methods is based on cost, time required, staff expertise, and laboratory equipment. This integrated strategy could contribute directly to tangible improvements in the diagnosis, prognosis, and prediction of the therapeutic responses of patients with brain tumors.

• MeSH
• Glioblastoma * genetics   pathology   diagnosis   MeSH
• In Situ Hybridization, Fluorescence methods   MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   MeSH
• Brain Neoplasms * genetics   pathology   diagnosis   MeSH
• Prognosis MeSH
• Comparative Genomic Hybridization methods   MeSH
• DNA Copy Number Variations MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

CONTEXT: Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. OBJECTIVE: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. METHODS: Children with FTS (the life-maximum height in both the child and his/her taller parent > 2 SD for age and sex) referred to the Endocrinology center of Motol University Hospital were enrolled into the study. Their DNA was examined cytogenetically and via a next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation. RESULTS: In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47,XXX and 47,XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic signs and 24 had dysmorphic features. CONCLUSION: Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.

• MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Adolescent MeSH
• Growth Disorders genetics   diagnosis   MeSH
• Child, Preschool MeSH
• Body Height * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51-67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.

• MeSH
• Child MeSH
• DNA-Binding Proteins * genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma * genetics   MeSH
• Child, Preschool MeSH
• Transcription Factors * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   pathology   MeSH
• Fusion Proteins, bcr-abl * genetics   MeSH
• Chromosome Breakpoints * MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * genetics   pathology   MeSH
• Child MeSH
• Adult MeSH
• Humans MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Letter MeSH

Polyploidy, the result of whole-genome duplication (WGD), is a major driver of eukaryote evolution. Yet WGDs are hugely disruptive mutations, and we still lack a clear understanding of their fitness consequences. Here, we study whether WGDs result in greater diversity of genomic structural variants (SVs) and how they influence evolutionary dynamics in a plant genus, Cochlearia (Brassicaceae). By using long-read sequencing and a graph-based pangenome, we find both negative and positive interactions between WGDs and SVs. Masking of recessive mutations due to WGDs leads to a progressive accumulation of deleterious SVs across four ploidal levels (from diploids to octoploids), likely reducing the adaptive potential of polyploid populations. However, we also discover putative benefits arising from SV accumulation, as more ploidy-specific SVs harbor signals of local adaptation in polyploids than in diploids. Together, our results suggest that SVs play diverse and contrasting roles in the evolutionary trajectories of young polyploids.

• MeSH
• Gene Duplication * MeSH
• Genome, Plant * genetics   MeSH
• Evolution, Molecular * MeSH
• Mutation MeSH
• Polyploidy * MeSH
• Genomic Structural Variation genetics   MeSH
• Publication type
• Journal Article MeSH

Transition fibres and distal appendages surround the distal end of mature basal bodies and are essential for ciliogenesis, but only a few of the proteins involved have been identified and functionally characterised. Here, through genome-wide analysis, we have identified 30 transition fibre proteins (TFPs) and mapped their arrangement in the flagellated eukaryote Trypanosoma brucei. We discovered that TFPs are recruited to the mature basal body before and after basal body duplication, with differential expression of five TFPs observed at the assembling new flagellum compared to the existing fixed-length old flagellum. RNAi-mediated depletion of 17 TFPs revealed six TFPs that are necessary for ciliogenesis and a further three TFPs that are necessary for normal flagellum length. We identified nine TFPs that had a detectable orthologue in at least one basal body-forming eukaryotic organism outside of the kinetoplastid parasites. Our work has tripled the number of known transition fibre components, demonstrating that transition fibres are complex and dynamic in their composition throughout the cell cycle, which relates to their essential roles in ciliogenesis and flagellum length regulation.

• MeSH
• Basal Bodies metabolism   MeSH
• Time Factors MeSH
• Cilia genetics   metabolism   MeSH
• Flagella genetics   metabolism   MeSH
• Conserved Sequence MeSH
• Protozoan Proteins * genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• Protein Transport MeSH
• Trypanosoma brucei brucei * genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH

Východiska: Mnohočetný myelom (MM) je heterogenní hematoonkologické onemocnění charakterizované klonální expanzí maligních plazmatických buněk v kostní dřeni. Onemocnění je doprovázeno různými klinickými projevy, jedná se o kostní léze, anemii, hyperkalcemii a renální insuficienci. Navzdory značnému pokroku v léčbě v posledních dvou dekádách však zůstává onemocněním těžko léčitelným a většina pacientů relabuje. Ačkoliv dosud nebyla objasněna jeho patogeneze, je zřejmé, že genomová nestabilita hraje klíčovou roli v jeho rozvoji či v rezistenci na léčbu. V některých případech je příčinou této nestability chromotripse, tedy druh komplexní genomové přestavby, která zahrnuje rozsáhlou fragmentaci a opětovné náhodné spojení chromozomů během jediné katastrofické události. Výsledné přestavby zahrnují různé strukturální změny vč. delecí, duplikací, inverzí a translokací, což vede k narušení genomu, konkrétně např. k alteraci nebo inaktivaci tumor supresorových genů (TP53 a CDKN2C), aktivaci onkogenů (MAF, FGFR3 a CCND1) nebo genů zapojených do klíčových buněčných procesů. Odhalení mechanizmů, které vedou k chromotripsi, nabízí možnosti identifikace kritických genů a drah, které se podílejí na patogenezi MM. Tyto poznatky mohou být podkladem pro zlepšení diagnostických přístupů. Cíl: Cílem přehledového článku je shrnout časté primární a sekundární chromozomové aberace u MM a kromě toho představit komplexní chromozomové aberace s důrazem na chromotripsi u MM.

Background: Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by clonal expansion of malignant plasma cells in the bone marrow. The disease is accompanied by various clinical manifestations, such as bone lesions, anemia, hypercalcemia, and renal insufficiency. However, despite significant advances in treatment over the last two decades, the disease remains challenging to treat, and most patients relapse. Although its pathogenesis has not yet been elucidated, it is clear that genomic instability plays a key role in its development or resistance to treatment. In some instances, the cause of this instability is chromothripsis, a form of complex genomic rearrangement that involves shattering and subsequent haphazard reassembly of chromosomes within a single catastrophic event. The resulting rearrangements involve a variety of structural changes, including deletions, duplications, inversions, and translocations, that lead to genome disruption. Specifically, these changes may result in alteration or inactivation of tumor suppressor genes (TP53 and CDKN2C), activation of oncogenes (MAF, FGFR3, and CCND1) or genes involved in key cellular processes. Unraveling the mechanisms that result in chromothripsis provides opportunities to identify critical genes and pathways involved in MM pathogenesis. These findings may serve as a basis for improved diagnostic approaches. Purpose: The goal of this review is to summarize the common primary and secondary chromosomal aberrations in MM with a particular focus on introducing complex chromosomal aberrations, especially chromothripsis in MM.

• MeSH
• Chromothripsis MeSH
• Chromosome Aberrations classification   MeSH
• Humans MeSH
• Multiple Myeloma * diagnosis   genetics   pathology   MeSH
• Molecular Medicine methods   MeSH
• Pathology, Molecular * methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Accurate and complete replication of genetic information is a fundamental process of every cell division. The replication licensing is the first essential step that lays the foundation for error-free genome duplication. During licensing, minichromosome maintenance protein complexes, the molecular motors of DNA replication, are loaded to genomic sites called replication origins. The correct quantity and functioning of licensed origins are necessary to prevent genome instability associated with severe diseases, including cancer. Here, we delve into recent discoveries that shed light on the novel functions of licensed origins, the pathways necessary for their proper maintenance, and their implications for cancer therapies.

• MeSH
• Humans MeSH
• Minichromosome Maintenance Proteins genetics   metabolism   MeSH
• Neoplasms * genetics   MeSH
• DNA Replication * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH