3906 results for "*geneti*"

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• Philippine Ayta possess the highest level of Denisovan ancestry in the world

  Multiple lines of evidence show that modern humans interbred with archaic Denisovans. Here, we report an account of shared demographic history between Australasians and Denisovans distinctively in Island Southeast Asia. Our analyses are based on ~2.3 million genotypes from 118 ethnic groups of the Philippines including 25 diverse self-identified Negrito populations, along with high-coverage genomes of AustraloPapuans and Ayta Magbukon Negritos. We show that Ayta Magbukon possess the highest level of Denisovan ancestry in the world – ~30-40% greater than that of Australians and Papuans – consistent with an independent admixture event into Negritos from Denisovans. Together with the recently described Homo luzonensis, we suggest that there were multiple archaic species that inhabited the Philippines prior to the arrival of modern humans, and that these archaic groups may have been genetically related. Altogether, our findings unveil a complex intertwined history of modern and archaic humans in the Asia-Pacific region, where distinct Islander Denisovan populations differentially admixed with incoming Australasians across multiple locations and at various points in time.

  Study EGAS00001005407

• Targeted sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003840

• H3Africa - Collaborative African Genomics Network

  Genomic studies have become one of the potential tools that could aid in the understanding of disease. HIV disease progression and active TB infection have been studied using these genomic methods to interrogate host factors associated with these diseases and their progression. Prior work has focused on adult populations and limited African cohorts. The Collaborative African Genomics Network aims to fill this gap by conducting HIV and TB disease mapping studies in African children to understand how genetic variation impacts disease progression through the use of genomic technologies.

  Study EGAS00001002656

• Genome Asia 100K Project

  The underrepresentation of non-European individuals in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

  Study EGAS00001002921

• Spatial concordance of DNA methylation classification in diffuse glioma

  Background: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. Methods: We used neuronavigation to acquire 133 image-guided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast enhanced T1 weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a three-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. Results: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. Conclusion: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

  Study EGAS00001005434

• Adult-type Granulosa Cell Tumour of the Ovary

  A recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult-type granulosa cell tumours (AGCTs). In contrast, various loss-of-function mutations in FOXL2 lead to the development of blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). BPES is characterized by an eyelid malformation often accompanied with primary ovarian insufficiency but not granulosa cell tumours. Two recent studies suggest that FOXL2 C402G is a gain or change-of-function mutation with altered DNA-binding specificity. Another study proposes that FOXL2 C402G is selectively targeted for degradation inducing somatic haploinsufficiency suggesting its role as a tumour suppressor. The latter study relies on data indicative of an FOXL2 allelic imbalance in AGCTs. Here we present RNA-seq data as genetic evidence that no real allelic imbalance is observed at the transcriptomic level in AGCTs. Additionally, there is no loss of protein expression in tumours harboring the mutated allele. These data and other features of this mutation as compared to other oncogenes and tumour suppressor genes argue strongly against FOXL2 being a tumour suppressor in this context. Given the likelihood that FOXL2 C402G is oncogenic, targeting the variant protein or its downstream consequences is the most viable path forward to identifying an effective treatment for this cancer.

  Study EGAS00001005414

• Whole exome sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003839

• Clonal fitness inferred from timeseries modeling of single cell cancer genomes

  Progress in defining genomic fitness landscapes in cancer by copy number alterations (CNA) has been impeded by lack of single cell and timeseries sampling. We generated 42,000 single cell whole genomes (scWGS) from breast epithelium and primary triple negative breast cancer (TNBC) patient-derived xenografts (PDX) collected during multi-year time series. Using a Wright-Fisher population genetics model, we inferred reproducible CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy, with accurate forecasting of experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDX resulted in cisplatin resistant clones that had shown low fitness in the untreated setting. By contrast high fitness clones from treatment naive controls were eradicated reflecting an inversion of the fitness landscape. Upon drug release selective pressure dynamics were reversed indicating a fitness cost of treatment resistance. Taken together, our findings reveal clonal fitness dynamics linked to CNA and therapeutic resistance in polyclonal tumours.

  Study EGAS00001004448

• Khoe-San genomes reveal unique variation and confirm deepest population divergence in Homo sapiens

  The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene-regions with extreme values in genome-wide distributions, potentially caused by natural selection early in the modern human lineage and more recent in time. These gene-regions included immunity-, sperm-, brain-, diet- and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

  Study EGAS00001004459

• Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

  SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

  Study EGAS00001004460