4002 results for "*geneti*"

in 19.96 milliseconds.

• Immune cell atlas of environmental and ancestral diversity in Indonesia [WGS]

  Island Southeast Asia (ISEA) remains consistently underrepresented in large-scale human genomic resources despite its rich ancestral and lifestyle diversity. The region's complex population history and environmental/pathogen pressures could have shaped its populations' unique immune responses. Here, we generated single-cell PBMC profiles from 199 Indonesians sampled across four populations in the islands of Bali and New Guinea. The dataset consists of low-pass whole genome sequencing and pooled single-cell PBMC transcriptome sequencing, including T-cell receptor (TCR). These groups capture diversity in regional genetic ancestries (West ISEA-like and Papuan-like) and lifestyle contrasts (urban versus rural communities in Bali; highland versus lowland communities in New Guinea), providing a window into how ancestry and environment jointly shape immune variation across ISEA. Together, this study provides the first large-scale single-cell immune atlas of ISEA, highlighting how ancestral and environmental diversity jointly shape human immunity in this globally important yet understudied region.

  Study EGAS50000001655

• Human four week embryo head as reference for generating an enhancer compendium for neuronal and neural crest development using neural tube organoids.

  This study has the aim of generating an enhancer code compendium of early human neuronal and neural crest development. For this purpose, we generated human neural tube organoids from single cells from two induced pluripotent stem cell lines. The organoids were subject to combined single cell multiomics at four time points of differentiation. To evaluate the biological relevance of the cell types and states obtained from the organoids, we compared with data obtained from 10XGenomics single cell multiomics on the head of a single four weeks post conception human embryo.

  Study EGAS50000001031

• Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

  Study EGAS00001003627

• The landscape of somatic mutations in epigenetic regulators across 1000 pediatric cancer genomes

  To define the frequency and pattern of somatic mutations in epigenetic regulators in pediatric cancer, we sequenced 633 genes, encoding the majority of proteins involved in patterning the epigenome, in 1000 pediatric tumors spanning 21 different cancer subtypes. This analysis establishes an epigenetic landscape of pediatric cancer, which expands the knowledge for potential therapeutic targets and for developing personalized therapy.

  Study EGAS00001000449

• BLUEPRINT Hematopoietic Stem/Progenitor Cell Methylomes

  An optimized whole genome bisulfite sequencing protocol (µWGBS, Farlik et al. 2015 Cell Reports) was used to establish DNA methylation profiles of FACS-purified stem and progenitor cells types of the human blood lineage. Most cell types were sorted from the peripheral blood of three donors with eight pools of ten cells, two pools of 50 cells, and one pool of 1000 cells. HSCs and MPPs were also sorted from fetal liver (HSCs only), cord blood, and bone marrow. Single-cell methylomes using the scWGBS protocol (Farlik et al. 2015 Cell Reports) were established for six cell types (HSC, MPP, CMP, GMP, CLP, MLP0). Gene expression profiling using the Smart-seq2 protocol (Picelli et al. 2013 Nature Methods) was done for nine stem/progenitor cell types (HSC, MPP, CMP, GMP, CLP, MLP0, MLP1, MLP2, MLP3).

  Study EGAS00001002070

• ATAC-seq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001438

• Clonal evolution of metastatic colorectal cancer under anticancer therapies

  To investigate the clonal evolution of metastatic CRC at the single-cell level, we performed WGS in 58 clonal organoids and 18 fresh-frozen (FT) bulk-tissue samples from surgically resected primary and metastatic tumors before and after anticancer therapies in 6 patients. This approach enabled detailed phylogenetic reconstruction of individual clones. We discovered the timing and burden of treatment-related mutations as well as the heterogeneous evolution in driver mutations and genomic rearrangements in late-stage clonal evolution under anticancer therapies in metastatic CRC.

  Study EGAS50000001023

• Whole Genome Methylation in CLL

  We have extensively characterized the DNA methylome of chronic lymphocytic leukemia (CLL) with mutated and unmutated IGHV as well as several mature B cell subpopulations using whole-genome bisulfite sequencing and high-density microarrays.

  Study EGAS00001000272

• Sequencing and analysis of a South Asian-Indian personal genome

  India with over 1.3 billion people is estimated to carry three times more genetic diversity compared to Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While multiple genomes from people of European and a few of Asian descent have been sequenced, only recently a single male genome from the Indian subcontinent at sufficient depth and coverage was published. We have in this study sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it is closely related to the U1a3 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In assessing SNPs that modulate drug response we found a variation that predicts a favorable response to metformin used for treating diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition to these, we report the presence of several other SNPs of medical relevance.

  Study EGAS00001000328

• Genetic landscape of pediatric Retinoblastoma

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study EGAS00001000346