4076 results for "*geneti*"

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• CYP2C19 long-read sequencing

  Inter-individual differences in drug response based on genetic variations can lead to drug toxicity and treatment inefficacy. A large part of this variability is caused by genetic variants in pharmacogenes. Unfortunately, the Single Nucleotide Variant (SNV) panels currently used in clinical pharmacogenomic (PGx) testing are unable to detect all genetic variability in these genes. Long-read sequencing, on the other hand, has been shown to be able to resolve complex (pharmaco)genes. In this study we have assessed the added value of long-read sequencing for PGx focusing on the clinically important and highly polymorphic CYP2C19 gene. With a capture-based long-read sequencing panel we were able to characterize the entire region and assign variants to their allele of origin (phasing), resulting in the identification of 813 unique variants in 37 samples. To assess the clinical utility of this data we have compared the performance of three different *-allele tools (Aldy, PharmCat and PharmaKU) which are specifically designed to assign clinical haplotypes to pharmacogenes based on all input variants. We conclude that long-read sequencing can improve our ability to characterize the CYP2C19 locus, help to identify novel haplotypes and that *-allele tools are an useful asset in phenotype prediction. Ultimately, this approach could help to better predict an individual’s drug response and improve therapy outcomes.

  Study EGAS00001006929

• Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

  Critically ill infants and children with suspected monogenic conditions underwent ultra-rapid whole exome genetic testing. A molecular diagnosis was established in 51% of the patients. This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients.

  Study EGAS00001005430

• The multifaceted genomic history of Ashaninka from Amazonian Peru

  Genome-wide profiles of Ashaninkas from Peruvian Amazonia reveal two genetic subgroups. Ashaninka ancestors derived from a south-north migration from southeastern South America. The Ashaninka1 subgroup testifies to an Arawakan-Caribbean genetic link in the Early Ceramic Age. The Ashaninka2 subgroup had recent interactions with Andean and Pacific Indigenous populations.

  Study EGAS00001006958

• HLA-DR is absent in primitive macrophages through epigenetic silencing of master regulator CIITA

  The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. This process is poorly understood in humans and in the mouse is thought to be spatially restricted to the yolk sac. Human fetal placental macrophages, Hofbauer cells (HBC), arise during the primitive haematopoietic wave at ~18 days post conception. Here we identify a population of placental erythro-myeloid progenitors (PEMPs) in the early human placenta that give rise to HBC. PEMP are fetal CD34+CD43+ progenitors found exclusively at early gestational timepoints. Transcriptomic analyses reveal that PEMP have conserved features of primitive yolk sac EMPs, including the lack of HLF expression. Using in vitro single-cell culture experiments we show that PEMP generate HBC-like cells that completely lack HLA-DR expression  and demonstrate that this is a conserved feature of all macrophages generated by primitive haematopoiesis in humans. Finally, we demonstrate that the class II transactivator, CTIIA, the master regulator HLA-DR expression, is epigenetically silenced during primitive haematopoiesis, leading to HLA-DRneg macrophages. These findings demonstrate that HBC are derived locally from PEMP and establish the human placenta as an additional site of primitive haematopoiesis.

  Study EGAS00001006981

• Genome wide variation in the Angolan Namib desert reveals unique Pre-Bantu ancestry

  The populations of the Angolan Namib Desert have been largely neglected in previous surveys of the genomic landscape of southern Africa. Although at present, the Namib is culturally dominated by Southwest Bantu-speaking cattle-herders, the region exhibits an extraordinary ethnographic diversity which includes an array of semi-nomadic peoples whose subsistence strategies fall outside the traditional division between foraging and food production and can thus be referred to as “peripatetic”. Among these small-scale populations are the last speakers of the Kwadi branch of the Khoe-Kwadi language family associated with the introduction of pastoralism into southern Africa (Kwepe), as well as a range of groups whose origins remain enigmatic (Kwisi, Twa and Tjimba). Using genome-wide data from 208 individuals belonging to nine ethnically diverse groups from the Angolan Namib and adjacent areas (Kwepe, Kwisi, Twa, Tjimba, !Xun, Kuvale, Himba, Nyaneka, Ovimbundu) in combination with published data from other regions of Africa, we reconstruct in detail the histories of contact emerging from pre-historic migrations to southern Africa and show that peripatetic groups from southwestern Angola stand out for exhibiting elevated levels of an unique, regionally-specific and highly divergent Pre-Bantu ancestry. These findings highlight the importance of the Namib for understanding the deep genetic structure of Africa.

  Study EGAS00001007011

• Genetic origins of the Kiritimati population from central-eastern Micronesia

  The migration of Austronesian-speaking populations through Oceania has intrigued researchers for decades. The Kiribati islands, situated along the boundaries of Micronesia and Polynesia, provide a crucial link in this migration. We analyzed the genome-wide data of the Kiritimati population of Kiribati to uncover their genetic origins and connections with other Oceanian groups. Our study reveals that the Kiritimati population primarily exhibits Remote Oceanian-related ancestry associated with ancient Lapita and present-day Polynesian populations. In addition, our identity-by-descent analysis identifies populations from Philippines as their closest relatives in Island Southeast Asia. The genetic links between Kiritimati, ancient Lapita, and modern Polynesians underscore the shared ancestry and continuous gene flow across these regions. This genetic continuity and ongoing links are supported by linguistic and cultural evidence, illustrating a complex history of migration and admixture in Oceania.

  Study EGAS00001008060

• Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

  Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data. Our approach can be used to quantify the personal information contained within gut metagenome data.

  Study EGAS00001007027

• Germline genome sequencing samples from the Hereditary Cancer Syndromes (ICCon) Cancer Flagship

  A prospective study of individuals with suspicion of a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or was not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing and a comprehensive cancer virtual gene panel analysis were undertaken.

  Study EGAS00001007045

• Whole genome and whole exome sequencing of serial biopsies of relapsed/refractory diffuse large B-cell lymphoma.

  Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Patients and methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

  Study EGAS00001007053

• cis-eQTL mapping of TB-T2D comorbidity in a five-way admixed SA cohort

  The aim of the study was to identify ancestry-specific genetic variants associated with differentially expressed genes in TB-T2D comorbid patients compared to T2D patients, as well as between TB patients and healthy controls. Both global and local ancestry was incorporated in regression models to account for the genetic heterogeneity in our complex multi-way admixed population.

  Study EGAS00001007059