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• Ancient tree-topologies and gene-flow processes among human lineages in Africa

  The deep history of human evolution in Africa remain intensely debated. We produced 73 novel high-quality whole genomes from 14 Central and Southern African populations with diverse cultural practices. With extensive simulations and machine-learning Approximate Bayesian Computation inferences, we reconstruct jointly their complex history of divergences and migrations. We find vast genome-wide diversity within and among populations, often uncorrelated with geography and cultural practices. This demonstrates the necessity to explicitly consider local genomic patterns, without merging samples indiscriminately into larger a priori categories, to reconstruct human evolutionary histories. We find that tree-like evolutions with long periods of drift between short periods of unidirectional gene-flow best explain the data, and that the lineage ancestral to Khoe-San populations diverged around 300,000 years ago from a lineage ancestral to rainforest hunter-gatherers and neighboring agriculturalists. We also find that short periods of ancient and recent gene-flow coincide with epochs of major ecological and cultural changes in Sub-Saharan Africa.

  Study EGAS50000001072

• Efficacy and safety of entrectinib in patients with ROS1-positive advanced/metastatic non-small cell lung cancer (NSCLC) from the Blood First Assay Screening Trial (BFAST)

  BFAST is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations, identified by blood-based molecular testing. We present data from Cohort D (ROS1-positive). Patients ≥18 years old with stage IIIB/IV, ROS1-positive NSCLC detected by blood-based testing, received entrectinib 600 mg daily. At data cut-off (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint; the confirmed objective response rate (ORR) by investigator was 81.5% which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR: 73.4%, data cut-off May 2019, ≥12 months follow-up). The safety profile of entrectinib was consistent with prior reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing and support the clinical value of blood-based testing to inform clinical decision-making.

  Study EGAS50000000105

• Human lymphoid-neutrophil/monocyte restriction co-ordinately activates increased proliferation despite parallel heterogeneity in transcriptional changes

  Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and their use to identify biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of the changes observed revealed the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal properties. Parallel, single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. These results uncover a connected regulation of lineage-shared proliferation control with persistent heterogeneity in the biological and transcriptional changes in the same cells undergoing B and NM lineage restriction.

  Study EGAS50000000278

• Genomic Data of Pediatric MDS

  The dataset consists of - 126 whole exome sequencings (SAMD9/9Lmut: 64; GATA2mut 24, MDS wildtype 38/471) performed using SureSelect Human All Exon V6 enrichment (Agilent, cat# 5190-8863). The generated libraries were sequenced on the Illumina Hiseq 2500 with 150bp paired-end reads. FASTQ files were processed using SeqNext platform (JSI medical system, Germany), with gene-based alignment to a virtual panel of 300 genes (including 28 MDS-associated genes, SAMD9, and SAMD9L), consisting of genes relevant to bone marrow failure, MDS predisposition, and hematological cancers as per the Pan-Cancer studies with cohorts of >10,000 cancers. The respective BAM files are provided. - Custom panel targeting SAMD9, SAMD9L, and 22 single nucleotide polymorphisms (SNP) on chromosome 7q (allele frequency >35% in all ethnic sub-populations in gnomAD) (Ampliseq #IAD104171) were performed in 666/669 cases. And Custom panel targeting 28 MDS-associated genes (GATA2, RUNX1, HOXA9, CEBPA, GATA1, KRAS, NRAS, CBL, PTPN11, ASXL1, EZH2, SETBP1, FLT3, KIT, JAK2, JAK3, CSF3R, MPL, SH2, BCOR, BCORL1; RAD21, STAG2, CTCF, TP53, PTEN, CALR, VPS45) was performed in 544 cases (Ampliseq #IAD51150). Both custom panel libraries were prepared using NEBNext Ultra II DNA library prep kit (New England BioLabs, cat#E7645S/L) per manufacturer’s instruction and samples were sequenced on an Illumina Miseq 2000 with 2 x 150 bp reads. The respective BAM files are provided - 4 SAMD9/9L patients were subjected to MissionBio custom single-cell panel (CO-112) targeting 250 heterozygous gnomAD population polymorphisms on 7q arm and 69 amplicons in SAMD9/9L and other cancer genes. All libraries were sequenced on an Illumina NovaSeq6000 with 150 base-paired ending multiplexed runs. Fastq files were processed using the Tapestri Pipeline V2 and python-based Mosaic package (multi-omics analysis, data visualization). The derived BAM and loom files are provided.

  Dataset EGAD00001007856

• Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas

  Pheochromocytomas (PCC) and paragangliomas (PGL) are neural crest-derived tumors. We performed the integrated genomic analysis of a collection of PCC/PGL from the French COMETE network using SNP arrays, whole-exome sequencing, DNA methylation arrays, mRNA expression arrays and miRNA sequencing. We found that PCC/PGL are characterized by a low mutation rate, with few recurrent somatic mutations and focal copy number alterations (CNAs). In contrast, we detected recurrent broad CNAs strongly associated with known molecular groups, often leading to the biallelic inactivation of the known susceptibility genes of PCC/PGL. We also identified DNA methylation changes and miRNA expression clusters strongly associated with molecular groups. Of note, overexpression of the miRNA cluster 182/96/183 is specific of SDHB-mutated tumors and induces invasive traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster due to a loss of heterozygosity of the 14q32.2 locus is a potential driver in a subset of sporadic tumors. This comprehensive analysis illustrates the functional interdependence between genomic and epigenomic dysregulations underlying PCC/PGL.

  Study EGAS00001000933

• Integrated single cell analysis in transformed follicular lymphoma

  Histological transformation of follicular lymphoma to aggressive form occurs 2-3% per year with poor outcome. Divergent evolution and an altered tumour-microenvironment (TME) have been implicated during transformation. However, phenotypic consequences of this evolution and its implication in TME remain unknown. To address this, we performed single cell whole genome and whole transcriptome sequencing of paired pre/post transformation patient samples. We further performed scWTS of additional samples from patients without transformation. Our analysis revealed evolutionary dynamics of transformation at unprecedented resolution. Integration of scWGS and scWTS identified pathways upregulated during evolution. scWTS analysis revealed a shifting TME landscape, with an exhausted signature emerging during transformation. Using multi-color immunofluorescence we transferred these findings to a TME-based transformation biomarker, subsequently validated in independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation, and shifting cross-talk between malignant cells and TME.

  Study EGAS00001007023

• MicroRNA Biomarkers for Prediction of Preeclampsia

  Maternal serum was collected between 17-28 weeks gestation. Samples were obtained from the high-risk Placental Study at the University of California, San Diego (n=48) and from the average-risk Proteomic Assessment of Preterm Risk (PAPR) Study at Sera Prognostics (n=164). RNA was extracted from 500 microliter of maternal serum using the miRNeasy Micro kit (Qiagen). NEBNext Small RNAseq Library Preparation Kit was used for library construction.

  Study phs002016

• We evaluate the PGD/PGS including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities.

  A total of 395 couples were subjected to IVF-PGD treatment, including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities. The NGS test was performed using low coverage whole genome sequencing with HiSeq 2000 platform. And the SNP array test was using Affymetrix Gene Chip Mapping Nsp I 262K.

  Study EGAS00001000981

• PPGL WES dataset

  Dataset includes fastq files for WES experiments for tumor samples of PPGL patients. Paired end reads fastq files are available for 87 different samples

  Dataset EGAD00001008579

• Paired RNA-Seq of fCAB treated and bisulfite treated VDH01, partly depleted for NSUN3

  Paired RNA-seq of bisulfite treated VDH01 samples control or depleted for NSUN3 (4 replicates each). The samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated vdh01 samples control or depleted for NSUN3(4 replicates each). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of bisulfite treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq.

  Dataset EGAD00001008742