4014 results for "*geneti*"

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• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006641

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• Combinatorial CRISPR screen identifies fitness effects of paralogues FAM50A and FAM50B

  Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1,191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. This dataset includes CRISPR screening of cancer cell lines, RNA sequencing studies of cancer cell lines and also data from the sequencing of tumour xenografts collected from mice.

  Dataset EGAD00001006648

• Resequencing candidate genes for male spermatogenic impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1/2 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes plus a selection of phylogenetically informative Y-chromosomal markers have been amplified by standard PCR, amplicon lengths range from 178 to 486 bp. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 480 submitted samples, approx. 1 microgram of amplified DNA pool was provided in a total volume of 120 microlitres. The samples were indexed and libraries prepared for PE250bp Illumina MiSeq runs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006784

• November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001007529

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  We performed genetic analysis of HLA and immune escape genes in samples from 44 patients sequenced by whole exome sequencing (34 tumor samples, 32 normal samples) and whole genome sequencing (10 tumor samples, 12 normal samples). We also performed HLA targeted sequencing in 26/44 patients (26 tumor samples, 26 normal samples).

  Dataset EGAD00001007565

• Evolutionary trajectories and clonal migration underlying tumor progression and lymph node metastasis in resectable lung cancer

  In this prospective study, targeted deep sequencing was performed on a total of 160 primary tumors (474 regions) and 112 lymph nodes from 125 patients with stage I-III lung cancer (LuCaTH). Progressive evolution at clonal divergence scale was observed while specific driver events were positively selected for clonal sweeps during tumor development. Between-region genetic divergence (BRGD) of tumors were assessed and positively correlated with tumor differentiation. A machine learning algorithm was employed to evaluate clinicopathological and molecular parameters of primary tumors underlying lymph node metastasis. By analyzing clonal lineages and metastatic trajectories across multiple nodal stations, we unraveled a common sequential LNM seeding pattern but with divergent modes of clonal spread.

  Dataset EGAD00001007587

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - WGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007714

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - TGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007715

• Novel de novo pathogenic variant in the GNAI1 as a cause of severe disorders of intellectual development with autistic features

  Our probands A and B are boys-monozygotic twins with the clinical diagnosis of severe intellectual impairment, developmental stagnation, and dysphasia. They were diagnosed at the Department of Medical Genetics and Genomics (University Hospital Brno). Parents provided written informed consent, which was approved by the Research Ethics Committee of Masaryk University and Ethics Committee of University Hospital Brno. Peripheral blood samples were collected in sterile heparinized tubes for cytogenetic analysis. Genomic DNA samples were obtained from 1 ml peripheral blood in EDTA, according to the standard DNA isolation process using the MagNaPure system (Roche Diagnostics, Basel, Switzerland). Quality and quantity were checked using a DeNovix DS-11 Spectrophotometer (DeNovix Inc., Wilmington, DE, USA) and Qubit® 2.0 (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

  Dataset EGAD00001007736

• GNAI1 CGH Array

  The cytogenetic analysis of probands was performed with a result of normal male karyotypes (46,XY). The microarray analysis on oligonucleotide 180K CGH+SNP microarray platform was then indicated resulting in a detection of a 8q24.23q24.3 duplication (694 kb) in both probands. The family-based real-time PCR confirmed this CNV in both probands and their unaffected mother. Based on the information obtained from databases mentioned above it was classified as likely benign.

  Dataset EGAD00001007742

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Dataset EGAD00001007792

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793