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1.
Cytogenet Genome Res ; 158(3): 115-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266029

RESUMO

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.


Assuntos
Cromossomos Humanos Par 7/genética , Cromossomos Humanos Y/genética , Transtornos do Desenvolvimento Sexual/genética , Genes sry/genética , Doenças Testiculares/genética , Translocação Genética/genética , Adulto , Pontos de Quebra do Cromossomo , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariótipo , Masculino , Adulto Jovem
2.
BMC Genomics ; 20(1): 382, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31096907

RESUMO

BACKGROUND: Several lines of evidence suggest that recombination plays a central role in replication and evolution of herpes simplex virus-1 (HSV-1). G-quadruplex (G4)-motifs have been linked to recombination events in human and microbial genomes, but their role in recombination has not been studied in DNA viruses. RESULTS: The availability of near full-length sequences from 40 HSV-1 recombinant strains with exact position of the recombination breakpoints provided us with a unique opportunity to investigate the role of G4-motifs in recombination among herpes viruses. We mapped the G4-motifs in the parental and all the 40 recombinant strains. Interestingly, the genome-wide distribution of breakpoints closely mirrors the G4 densities in the HSV-1 genome; regions of the genome with higher G4 densities had higher number of recombination breakpoints. Biophysical characterization of oligonucleotides from a subset of predicted G4-motifs confirmed the formation of G-quadruplex structures. Our analysis also reveals that G4-motifs are enriched in regions flanking the recombination breakpoints. Interestingly, about 11% of breakpoints lie within a G4-motif, making these DNA secondary structures hotspots for recombination in the HSV-1 genome. Breakpoints within G4-motifs predominantly lie within G4-clusters rather than individual G4-motifs. Of note, we identified the terminal guanosine of G4-clusters at the boundaries of the UL (unique long) region on either side of the OriL (origin of replication within UL) represented the commonest breakpoint among the HSV-1 recombinants. CONCLUSION: Our findings suggest a correlation between the HSV-1 recombination landscape and the distribution of G4-motifs and G4-clusters, with possible implications for the evolution of DNA viruses.


Assuntos
Pontos de Quebra do Cromossomo , DNA Viral/genética , Quadruplex G , Genoma Viral , Herpesvirus Humano 1/genética , Recombinação Genética , Replicação do DNA , Humanos
3.
BMC Cancer ; 19(1): 434, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077166

RESUMO

BACKGROUND: Chromosomal rearrangements are the typical phenomena in cancer genomes causing gene disruptions and fusions, corruption of regulatory elements, damage to chromosome integrity. Among the factors contributing to genomic instability are non-B DNA structures with stem-loops and quadruplexes being the most prevalent. We aimed at investigating the impact of specifically these two classes of non-B DNA structures on cancer breakpoint hotspots using machine learning approach. METHODS: We developed procedure for machine learning model building and evaluation as the considered data are extremely imbalanced and it was required to get a reliable estimate of the prediction power. We built logistic regression models predicting cancer breakpoint hotspots based on the densities of stem-loops and quadruplexes, jointly and separately. We also tested Random Forest models varying different resampling schemes (leave-one-out cross validation, train-test split, 3-fold cross-validation) and class balancing techniques (oversampling, stratification, synthetic minority oversampling). RESULTS: We performed analysis of 487,425 breakpoints from 2234 samples covering 10 cancer types available from the International Cancer Genome Consortium. We showed that distribution of breakpoint hotspots in different types of cancer are not correlated, confirming the heterogeneous nature of cancer. It appeared that stem-loop-based model best explains the blood, brain, liver, and prostate cancer breakpoint hotspot profiles while quadruplex-based model has higher performance for the bone, breast, ovary, pancreatic, and skin cancer. For the overall cancer profile and uterus cancer the joint model shows the highest performance. For particular datasets the constructed models reach high predictive power using just one predictor, and in the majority of the cases, the model built on both predictors does not increase the model performance. CONCLUSION: Despite the heterogeneity in breakpoint hotspots' distribution across different cancer types, our results demonstrate an association between cancer breakpoint hotspots and stem-loops and quadruplexes. Approximately for half of the cancer types stem-loops are the most influential factors while for the others these are quadruplexes. This fact reflects the differences in regulatory potential of stem-loops and quadruplexes at the tissue-specific level, which yet to be discovered at the genome-wide scale. The performed analysis demonstrates that influence of stem-loops and quadruplexes on breakpoint hotspots formation is tissue-specific.


Assuntos
Pontos de Quebra do Cromossomo , DNA/química , Neoplasias/genética , DNA/genética , Feminino , Heterogeneidade Genética , Instabilidade Genômica , Humanos , Modelos Logísticos , Aprendizado de Máquina , Masculino , Conformação de Ácido Nucleico , Especificidade de Órgãos
4.
Nat Commun ; 10(1): 1459, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926794

RESUMO

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.


Assuntos
Linfoma de Burkitt/genética , Genoma Humano , Transcriptoma/genética , Adolescente , Processamento Alternativo/genética , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Estudos de Coortes , Metilação de DNA/genética , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Sequenciamento Completo do Genoma
5.
Genome Res ; 29(4): 576-589, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760546

RESUMO

The role of chromosome rearrangements in driving evolution has been a long-standing question of evolutionary biology. Here we focused on ruminants as a model to assess how rearrangements may have contributed to the evolution of gene regulation. Using reconstructed ancestral karyotypes of Cetartiodactyls, Ruminants, Pecorans, and Bovids, we traced patterns of gross chromosome changes. We found that the lineage leading to the ruminant ancestor after the split from other cetartiodactyls was characterized by mostly intrachromosomal changes, whereas the lineage leading to the pecoran ancestor (including all livestock ruminants) included multiple interchromosomal changes. We observed that the liver cell putative enhancers in the ruminant evolutionary breakpoint regions are highly enriched for DNA sequences under selective constraint acting on lineage-specific transposable elements (TEs) and a set of 25 specific transcription factor (TF) binding motifs associated with recently active TEs. Coupled with gene expression data, we found that genes near ruminant breakpoint regions exhibit more divergent expression profiles among species, particularly in cattle, which is consistent with the phylogenetic origin of these breakpoint regions. This divergence was significantly greater in genes with enhancers that contain at least one of the 25 specific TF binding motifs and located near bovidae-to-cattle lineage breakpoint regions. Taken together, by combining ancestral karyotype reconstructions with analysis of cis regulatory element and gene expression evolution, our work demonstrated that lineage-specific regulatory elements colocalized with gross chromosome rearrangements may have provided valuable functional modifications that helped to shape ruminant evolution.


Assuntos
Pontos de Quebra do Cromossomo , Evolução Molecular , Ruminantes/genética , Sintenia , Animais , Elementos de DNA Transponíveis , Elementos Facilitadores Genéticos , Cariótipo , Ligação Proteica , Seleção Genética , Fatores de Transcrição/metabolismo
6.
Cancer Genet ; 231-232: 14-21, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803552

RESUMO

AIMS: Distinct types of PML-RARα hybrid transcripts viz bcr-1, bcr-2 and bcr-3 result from translocation between chromosomes 15 and 17 t(15;17) in Acute Promyelocytic Leukemia patients. We aimed to determine the frequencies of the PML-RARα transcripts and FLT3-ITD mutations in APL patients to evaluate their prognostic implications and also to analyze their impact on disease outcome. MAIN METHOD: RT-PCR and Rq-PCR were adopted for transcript typing and quantitation of PML-RARα transcripts while FLT3-ITD was detected by PCR in APL patients. KEY FINDINGS: PML-RARα bcr-1, bcr-2 and bcr-3 transcripts were found in 26, 3 and 16 cases respectively. 64.4% patients achieved complete remission, 22.2% expired early wherein majority of the cases expressed bcr-3 transcript (p = 0.03). 50% relapse rate was observed in patients with bcr-3 transcripts. Multivariate analysis showed expression of bcr-3 transcript associated with early death (p = 0.027) and increased relapse risk (P = 0.046). Patients expressing bcr-3 hybrid transcript showed lowest OS of 28.0 months (±â€¯5.26) (p = 0.027). FLT3-ITD mutation was detected in 5 (11.1%) patients and presence of these mutations was not associated either with PML-RARα transcripts or with disease outcome. SIGNIFICANCE: bcr-3 transcript has a more lethal outcome and is also associated with frequent relapse risk in APL patients of our region.


Assuntos
Trióxido de Arsênio/uso terapêutico , Pontos de Quebra do Cromossomo , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Intervalo Livre de Doença , Feminino , Humanos , Índia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Adulto Jovem
7.
Genes Chromosomes Cancer ; 58(3): 139-148, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30614587

RESUMO

Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next-generation sequencing with an AML/MDS gene panel. Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age-matched controls. Additional neo-telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere-based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.


Assuntos
Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Encurtamento do Telômero , Translocação Genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pontos de Quebra do Cromossomo , Feminino , Humanos , Lactente , Cariótipo , Masculino , Pessoa de Meia-Idade , Mutação
8.
J Hum Genet ; 64(3): 253-255, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30542208

RESUMO

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.


Assuntos
Transtorno Autístico/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtorno Autístico/patologia , Estudos de Coortes , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Humanos , Deficiência Intelectual/patologia , Fenótipo
9.
Genet Sel Evol ; 50(1): 36, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29980171

RESUMO

BACKGROUND: It has been known for almost a century that the belted phenotype in cattle follows a pattern of dominant inheritance. In 2009, the approximate position of the belt locus in Brown Swiss cattle was mapped to a 922-kb interval on bovine chromosome 3 and, subsequently, assigned to a 336-kb haplotype block based on an animal set that included, Brown Swiss, Dutch Belted (Lakenvelder) and Belted Galloway individuals. A possible candidate gene in this region i.e. HES6 was investigated but the causal mutation remains unknown. Thus, to elucidate the causal mutation of this prominent coat color phenotype, we decided to remap the belted phenotype in an independent animal set of several European bovine breeds, i.e. Gurtenvieh (belted Brown Swiss), Dutch Belted and Belted Galloway and to systematically scan the candidate region. We also checked the presence of the detected causal mutation in the genome of belted individuals from a Siberian cattle breed. RESULTS: A combined linkage disequilibrium and linkage analysis based on 110 belted and non-belted animals identified a candidate interval of 2.5 Mb. Manual inspection of the haplotypes in this region identified four candidate haplotypes that consisted of five to eight consecutive SNPs. One of these haplotypes overlapped with the initial 922-kb interval, whereas two were positioned proximal and one was positioned distal to this region. Next-generation sequencing of one heterozygous and two homozygous belted animals identified only one private belted candidate allele, i.e. a multiplication event that is located between 118,608,000 and 118,614,000 bp. Targeted locus amplification and quantitative real-time PCR confirmed an increase in copy number of this region in the genomes of both European (Belted Galloway, Dutch Belted and Gurtenvieh) and Siberian (Yakutian cattle) breeds. Finally, using nanopore sequencing, the exact breakpoints were determined at 118,608,362 and 118,614,132 bp. The closest gene to the candidate causal mutation (16 kb distal) is TWIST2. CONCLUSIONS: Based on our findings and those of a previously published study that identified the same multiplication event, a quadruplication on bovine chromosome 3 between positions 118,608,362 and 118,614,132 bp is the most likely candidate causal mutation for the belted phenotype in cattle.


Assuntos
Mapeamento Cromossômico/veterinária , Dosagem de Genes , Mutação , Locos de Características Quantitativas , Proteína 2 Relacionada a Twist/genética , Animais , Bovinos , Pontos de Quebra do Cromossomo , Cromossomos de Mamíferos/genética , Cor , Feminino , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , Desequilíbrio de Ligação , Fenótipo , Análise de Sequência de DNA/veterinária
10.
Med Sci Monit ; 24: 4162-4168, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29911662

RESUMO

BACKGROUND The literature indicates that chromosome 6 is involved in balanced translocation and is involved in reproductive failure. This aim of this study was to explore the clinical features of chromosome 6 translocation in male carriers. MATERIAL AND METHODS We identified 10 patients who were carriers of chromosome 6 translocations and excluded the patients with varicocele, ejaculatory duct obstruction, and the other cause of infertility. The karyotype was analyzed using G-banding. A search for translocations on chromosome 6 involved in male infertility was performed using PubMed. We included cases of balanced chromosome 6 translocations involving adult men of fertile age and excluded those cases of live-born children, or those without breakpoints involving chromosome 6, or those with complex chromosomal translocations or chimeras. RESULTS All 10 patients underwent genetic counseling for infertility. Semen analysis showed that 1 case had azoospermia, while 9 cases exhibited normal semen criteria. The respective partners of the 9 cases with normal semen parameters had a tendency to miscarry: 3 experienced spontaneous and induced abortion because of abnormal embryos; 3 experienced 3 incidents of spontaneous abortion, 2 experienced double spontaneous abortion, and 1 experienced biochemical pregnancy on 3 occasions. Most of the chromosome 6 breakpoints in translocation carriers obtained by the PubMed search were associated with spontaneous abortion. CONCLUSIONS Chromosome translocations involving chromosome 6 influence fertility status and lead to increased risk of miscarriage. Cytogenetic screening before opting for assisted reproductive technology and the breakpoints of chromosome 6 translocation should be considered for infertile male carriers.


Assuntos
Cromossomos Humanos Par 6/genética , Infertilidade Masculina/genética , Adulto , Pontos de Quebra do Cromossomo , Citogenética/métodos , Aconselhamento Genético , Heterozigoto , Humanos , Cariotipagem , Masculino , Análise do Sêmen , Translocação Genética/genética
11.
Genes Chromosomes Cancer ; 57(9): 459-470, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29726617

RESUMO

Copy number variation (CNV) is a common form of structural variation detected in human genomes, occurring as both constitutional and somatic events. Cytogenetic techniques like chromosomal microarray (CMA) are widely used in analyzing CNVs. However, CMA techniques cannot resolve the full nature of these structural variations (i.e. the orientation and location of associated breakpoint junctions) and must be combined with other cytogenetic techniques, such as karyotyping or FISH, to do so. This makes the development of a next-generation sequencing (NGS) approach capable of resolving both CNVs and breakpoint junctions desirable. Mate-pair sequencing (MPseq) is a NGS technology designed to find large structural rearrangements across the entire genome. Here we present an algorithm capable of performing copy number analysis from mate-pair sequencing data. The algorithm uses a step-wise procedure involving normalization, segmentation, and classification of the sequencing data. The segmentation technique combines both read depth and discordant mate-pair reads to increase the sensitivity and resolution of CNV calls. The method is particularly suited to MPseq, which is designed to detect breakpoint junctions at high resolution. This allows for the classification step to accurately calculate copy number levels at the relatively low read depth of MPseq. Here we compare results for a series of hematological cancer samples that were tested with CMA and MPseq. We demonstrate comparable sensitivity to the state-of-the-art CMA technology, with the benefit of improved breakpoint resolution. The algorithm provides a powerful analytical tool for the analysis of MPseq results in cancer.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala , Algoritmos , Pontos de Quebra do Cromossomo , Rearranjo Gênico , Humanos , Análise Serial de Tecidos/métodos
12.
Medicine (Baltimore) ; 97(15): e0452, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29642220

RESUMO

RATIONALE: Infertile male carrying balanced translocations can be broadly divided into two types: pregestational and gestational infertility. Chromosome and breakpoints involved translocation should be considered in genetic counselling for these patients. To date, > 100 cases have been described with carrying balanced translocations involving chromosome 10 in fertile male. PATIENT CONCERNS: We report 11 cases translocation carriers involving chromosome 10, and review 99 carriers of chromosome 10 translocation from reported literature. DIAGNOSES: Eleven cases of chromosomal translocation were diagnosed by cytogenetic analysis. Three of these men had azoospermia or oligozoospermia, while eight had normal semen. Of these latter cases, their partners were able to conceive, but had a tendency to miscarry or have a stillbirth. INTERVENTIONS: Chromosome breakpoints should be considered in genetic counseling. Preimplantation genetic diagnosis should be performed to decrease the high risk of miscarriage and to minimize the genetic risks to offspring for patients with gestational infertility. OUTCOMES: The most common translocations and breakpoints were at t(4;10) and 10q24, observed in 12 and 10 patients respectively. Breakpoints at 10p15.1, 10p12, 10q10, 10q22.1, 10q24.2, and 10q26.3 were linked to pregestational infertility; breakpoints at 10p12.1, 10q11, 10q21.2, and 10q23.3 were associated with gestational infertility; the other breakpoints were connected with both forms of infertility. LESSONS: Breakpoints at 10p12 and 10q26.3 were associated with pregestational infertility. Other breakpoints at chromosome 10 were correlated with gestational infertility. These breakpoints should be considered when counseling men with chromosome 10 translocations should be informed of their options.


Assuntos
Cromossomos Humanos Par 10/genética , Triagem de Portadores Genéticos , Infertilidade Masculina/genética , Translocação Genética/genética , Adulto , Azoospermia/diagnóstico , Azoospermia/genética , Pontos de Quebra do Cromossomo , Feminino , Aconselhamento Genético , Humanos , Cariotipagem , Masculino , Oligospermia/diagnóstico , Oligospermia/genética , Gravidez , Diagnóstico Pré-Implantação
13.
BMC Nephrol ; 19(1): 26, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29394883

RESUMO

BACKGROUND: It has been reported that mutations in arginine vasopressin type 2 receptor (AVPR2) cause congenital X-linked nephrogenic diabetes insipidus (NDI). However, only a few cases of AVPR2 deletion have been documented in China. METHODS: An NDI pedigree was included in this study, including the proband and his mother. All NDI patients had polyuria, polydipsia, and growth retardation. PCR mapping, long range PCR and sanger sequencing were used to identify genetic causes of NDI. RESULTS: A novel 22,110 bp deletion comprising AVPR2 and ARH4GAP4 genes was identified by PCR mapping, long range PCR and sanger sequencing. The deletion happened perhaps due to the 4-bp homologous sequence (TTTT) at the junctions of both 5' and 3' breakpoints. The gross deletion co-segregates with NDI. After analyzing available data of putative clinical signs of AVPR2 and ARH4GAP4 deletion, we reconsider the potential role of AVPR2 deletion in short stature. CONCLUSIONS: We identified a novel 22.1-kb deletion leading to X-linked NDI in a Chinese pedigree, which would increase the current knowledge in AVPR2 mutation.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Insípido Nefrogênico/genética , Proteínas Ativadoras de GTPase/genética , Deleção de Genes , Receptores de Vasopressinas/genética , Adolescente , Pontos de Quebra do Cromossomo , Diabetes Insípido Nefrogênico/diagnóstico , Feminino , Humanos , Masculino , Mutação/genética , Linhagem , Deleção de Sequência/genética
14.
Nature ; 555(7694): 112-116, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29466339

RESUMO

Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 and MYC. Remarkably, both oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.


Assuntos
Replicação do DNA , Fase G1/genética , Instabilidade Genômica/genética , Neoplasias/genética , Oncogenes/genética , Origem de Replicação/genética , Fase S/genética , Linhagem Celular Tumoral , Pontos de Quebra do Cromossomo , Estudos de Coortes , Ciclina E/genética , Ciclina E/metabolismo , DNA/biossíntese , DNA/genética , Quebras de DNA de Cadeia Dupla , Replicação do DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes myc/genética , Humanos , Proteínas Oncogênicas/genética , Transcrição Genética/genética , Translocação Genética/genética
15.
Genome ; 61(3): 177-185, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29470932

RESUMO

The wheat - Thinopyrum intermedium derived line Z4 has displayed novel and effective stripe rust resistance for over 40 years. This study aimed to precisely identify the chromosome constitution of line Z4 and determine the stripe rust resistance contribution using multicolor fluorescent in situ hybridization (FISH) and molecular marker analysis. The results indicated that the Z4 line (2n = 44) contained two pairs of non-Robertsonian translocations without the 3A chromosomes of wheat. FISH karyotypes of F3 progenies derived from crosses between Z4 and MY11 indicated that the transmission of the translocated chromosomes appeared normal and the number of wheat chromosomes 3A and 3D frequently varied. The FISH signal distribution of a new repetitive probe, named Oligo-3A1, confirmed the physical breakage points on chromosome 3AL incorporated into translocated chromosomes. PLUG markers revealed the breakage points on chromosomes 3A, 7JS, and 3D invloved in the translocated chromosomes, and they were designated as T3DS-3AS.3AL-7JSS and T3AL-7JSS.7JSL. Stripe rust resistances surveys indicated that the proximal region of 7JSS or 7JSL may confer the resistance at the adult plant stage. The precise characterization of the chromosome complements of wheat - Th. intermedium Z4 and derived progenies has demonstrated the importance of combining cytogenetic and molecular approaches in the genomics era for further wheat genetic manipulation and breeding purposes.


Assuntos
Pontos de Quebra do Cromossomo , Resistência à Doença/genética , Translocação Genética , Triticum/genética , Basidiomycota/patogenicidade , Cromossomos de Plantas/genética , Triticum/imunologia , Triticum/microbiologia
16.
Gene ; 645: 113-118, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29273555

RESUMO

Genomic rearrangements, such as intragenic deletions and duplications, are the most prevalent types of mutation in the DMD gene, and DMD mutations underlie Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Using multiplex ligation dependent probe amplification (MLPA) and DMD gene-targeted sequencing, we performed a molecular characterization of two cases of complex noncontiguous duplication rearrangements that involved inverted duplications. The breakpoint sequences were analyzed to investigate the mechanisms of the rearrangement. The two cases shared the same duplication events (Dup-nml-Dup/inv), and both involved microhomology and small insertions at the breakpoints. Additionally, in case 1, SNP sequencing results indicated that the de novo duplication mutation arose in the allele that originated from the grandfather. This study has identified a novel type of DMD complex rearrangement and provides insight into the molecular basis of this genomic rearrangement.


Assuntos
Duplicação Cromossômica , Deficiências do Desenvolvimento/genética , Distrofina/genética , Distrofia Muscular de Duchenne/genética , Criança , Pontos de Quebra do Cromossomo , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência de DNA , Inversão de Sequência
17.
J Hum Genet ; 63(3): 349-356, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29279609

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.


Assuntos
Síndrome de Lange/diagnóstico , Síndrome de Lange/genética , Estudos de Associação Genética , Histona Desacetilases/genética , Fenótipo , Proteínas Repressoras/genética , Deleção de Sequência , Sequência de Bases , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Éxons , Facies , Feminino , Duplicação Gênica , Humanos , Análise de Sequência de DNA , Inativação do Cromossomo X
18.
Gene ; 642: 110-115, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29129813

RESUMO

BACKGROUND: Brachydactyly type A2 (BDA2) is an autosomal dominant disease characterized by the deformation of the middle phalanx of the second fingers and toes. It has been reported to be associated with three genes regulating the osteogenesis, including BMPR1B, GDF5 and BMP2. MATERIALS AND METHODS: 10 BDA2 patients and 7 unaffected individuals in a Chinese family were identified through clinical signs and radiographs. The mutation analyses of BMPR1B, GDF5 and BMP2 gene was performed in all the available family members and 100 control subjects. The duplication analysis for the downstream of BMP2 was also performed in all the samples. RESULTS: A novel 4671bp duplication downstream the BMP2 gene was identified in all the patients undergoing molecular analysis but not in the unaffected individuals and healthy controls, with a 28bp microhomology flanking it. There was no mutation in all the exons of BMPR1B, GDF5 and BMP2 in all the tested family members. CONCLUSION: The novel duplication has different breakpoints compared with the previous ones but highly overlapped with them. The duplication narrows the range of the potential cis-regulatory sequence, and further supports the association between BDA2 and the duplication downstream BMP2.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteína Morfogenética Óssea 2/genética , Braquidactilia/genética , Mutação , Sequência de Bases , Pontos de Quebra do Cromossomo , Duplicação Cromossômica , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Sequências de Repetição em Tandem
19.
Biochim Biophys Acta Gen Subj ; 1862(3): 649-659, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29246583

RESUMO

Maintaining genome integrity is crucial for normal cellular functions. DNA double-strand breaks (DSBs), when unrepaired, can potentiate chromosomal translocations. t(14;18) translocation involving BCL2 gene on chromosome 18 and IgH loci at chromosome 14, could lead to follicular lymphoma. Molecular basis for fragility of translocation breakpoint regions is an active area of investigation. Previously, formation of non-B DNA structures like G-quadruplex, triplex, B/A transition were investigated at peak I of BCL2 major breakpoint region (MBR); however, it is less understood at peak III. In vitro gel shift assays show faster mobility for MBR peak III sequences, unlike controls. CD studies of peak III sequences reveal a spectral pattern different from B-DNA. Although complementary C-rich stretches exhibit single-strandedness, corresponding guanine-rich sequences do not show DMS protection, ruling out G-quadruplex and triplex DNA. Extrachromosomal assay indicates that peak III halts transcription, unlike its mutated version. Taken together, multiple lines of evidence suggest formation of potential cruciform DNA structure at MBR peak III, which was also supported by in silico studies. Thus, our study reveals formation of non-B DNA structure which could be a basis for fragility at BCL2 breakpoint regions, eventually leading to chromosomal translocations.


Assuntos
Pontos de Quebra do Cromossomo , Sítios Frágeis do Cromossomo/genética , Cromossomos Humanos Par 14/ultraestrutura , Cromossomos Humanos Par 18/ultraestrutura , DNA Cruciforme/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Translocação Genética , Sequência de Bases , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Dicroísmo Circular , DNA Cruciforme/análise , Eletroforese em Gel de Poliacrilamida , Predisposição Genética para Doença , Humanos , Leucemia de Células B/patologia , Modelos Genéticos , Transcrição Genética/genética
20.
Mol Genet Genomic Med ; 6(1): 56-68, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29168350

RESUMO

BACKGROUND: The risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a "Systematic Survey of Balanced Chromosomal Rearrangements in Finns." In the first family, carriers (n = 6) manifest with learning problems in childhood, and later with unexplained neurological symptoms (chronic headache, balance problems, tremor, fatigue) and cerebral infarctions in their 50s. In the second family, two carriers suffer from tetralogy of Fallot, one from transient ischemic attack and one from migraine. The translocation cosegregates with these vascular phenotypes and neurological symptoms. METHODS AND RESULTS: We narrowed down the breakpoint regions using mate pair sequencing. We observed conserved haplotypes around the breakpoints, pointing out that this translocation has arisen only once. The chromosome 1 breakpoint truncates a CHRM3 processed transcript, and is flanked by the 5' end of CHRM3 and the 3' end of RYR2. TRHDE, KCNC2, and ATXN7L3B flank the chromosome 12 breakpoint. CONCLUSIONS: This study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3, RYR2, TRHDE, KCNC2, and/or ATXN7L3B.


Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 1/genética , Adulto , Idoso , Sequência de Bases , Aberrações Cromossômicas , Pontos de Quebra do Cromossomo , Feminino , Finlândia , Haplótipos/genética , Heterozigoto , Humanos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Receptor Muscarínico M3/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canais de Potássio Shaw/genética , Fatores de Transcrição/genética , Translocação Genética/genética
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