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• Single-Gene vs. Panel Sequencing in Advanced HR+/HER2− Breast Cancer

  Background: Hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer is the most common subtype of breast cancer, with biomarker-driven therapies improving outcomes. Liquid biopsies, which analyze circulating tumor DNA (ctDNA), are increasingly essential in clinical management, offering a minimally invasive approach to assess somatic alterations and guide therapy decisions. However, the choice of assay directly affects clinical utility and global access to validated testing platforms remains inconsistent. To address these challenges, this study aimed to compare the performance of single-gene and panel-based sequencing for detecting PIK3CA mutations in HR+/HER2− breast cancer and evaluate the added value of broader genomic profiling in guiding treatment decisions. Patients and methods: We conducted a prospective, multicenter study comparing our previously established SiMSen-Seq (SSS) assay, a single-gene method targeting PIK3CA hotspot mutations, with the AVENIO ctDNA Expanded assay, enriching for 77 clinically relevant cancer genes. Additionally, tumor fractions were estimated with mFAST-SeqS by assessing chromosomal aneuploidy. We analyzed 161 plasma samples collected from 146 patients with HR+/HER2− advanced breast cancer before starting a new line of palliative therapy. Results: High concordance (92.6%) was observed between SSS and AVENIO for PIK3CA mutation detection, with accurate variant allele frequency (VAF) quantification confirmed by Bland-Altman analysis and linear mixed-effects modeling. AVENIO identified additional PIK3CA mutations in 19% of samples as well as other actionable alterations, including ESR1 mutations (17.5%) and PI3K pathway alterations (40.6%). Panel sequencing improved the interpretation of negative liquid biopsy results by integrating tumor fraction and VAF metrics. Conclusions: Panel sequencing assays such as AVENIO provide broader genomic coverage, enhance the detection of actionable mutations and refine the interpretation of negative liquid biopsy findings. These findings support the integration of comprehensive ctDNA profiling into routine clinical practice for HR+/HER2− advanced breast cancer while highlighting the need for improved assay accessibility and expanded genomic targets.

  Study EGAS00001008200

• Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

  The four main medulloblastoma subgroups are characterized by distinct biology, clinicopathological features and clinical outcomes. While the WNT and SHH subgroups are characterized by clearly defined aberrant signaling of developmental pathways, the underlying biology of Group 3 and 4 remains poorly understood. Here, we delineate distinct post-translational regulation orchestrating active oncogenic signaling networks in Groups 3 and 4. Specifically, aberrant ERBB4-SRC signaling constitutes a novel hallmark feature of Group 4, with great promise as a novel oncogenic mechanism and potential vulnerability for therapeutic intervention in the most common subgroup. Altogether, this novel integrative proteogenomic landscape demonstrates the added value of proteomics and phosphoproteomics analysis to discover and exploit unexpected oncogenic mechanisms in medulloblastoma and beyond.

  Study EGAS00001002757

• 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

• Functional Analysis of Genetic Variants in African Americans with Breast Cancer

  The goal of this study is to identify and characterize novel genetic variants associated with a predisposition to breast cancer (BCa) in African Americans (AAs) using a family case-family control study design. Variants of unknown clinical significance (VUS) were characterized using bioinformatics tools. Future studies will further characterize select VUSs using in vitro genomic editing methods and functional assays to determine the functional consequences. The targeted sequencing data is made available for 85 actionable cancer genes. These genes have been previously classified with deleterious mutation(s) and whose phenotype results in a specific, defined medical recommendation(s).

  Study phs002977

• Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms

  This study is focused on multiple sclerosis (MS). MS is likely caused by a combination of genetic and environmental factors; however, the mechanisms contributing to these factors remain poorly understood. Epstein-Barr virus (EBV) in particular is a well-established environmental risk factor for MS. We have created a computational algorithm that systematically searches for common molecular mechanisms that might be impacted at multiple MS-associated loci. Using this algorithm, we have discovered that over 40% of MS-associated loci contain MS genetic variants that fall within regions of the human genome occupied by the EBV-encoded EBNA2 protein. The same MS-associated variants also impact gene expression levels of MS-associated genes in EBV-infected B cell lines. Our hypothesis is that allele-dependent binding of EBNA2 and its co-factors explains the allele-dependent risk at many MS genetic loci. Importantly, this hypothesis links the genetic associations of MS to the known molecular roles played by EBV and Notch signaling in disease processes.Subjects with and without MS were recruited into an Institutional Review Board (IRB)-approved protocol through the Cincinnati Autoimmune Registry and Repository. From each subject, DNA from peripheral blood was isolated for whole genome sequencing (WGS). These data will be used to identify genotype-dependent transcriptional regulation in cells assessed from patients and controls. This WGS data was deposited before the full integration of sequence data with other functional genomic data types.From each subject, 90 mL of blood is drawn for isolation of peripheral blood mononuclear cells from which primary B and T cells will be isolated. For each B cell isolation, an EBV-transformed B cell line will be derived.

  Study phs003240

• Single-cell/single-nucleus RNA-seq of Embryonal Tumor with Multilayered Rosettes (ETMR)

  Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. We analyzed eleven ETMR patient samples using single-cell transcriptomics. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment. Systematic analysis of receptor-ligand interactions between malignant cell types reveals FGFR and NOTCH signaling as oncogenic pathways. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.

  Study EGAS50000000937

• Targeted_sequencing_of_blood_DNA_from_Human_twins_

  The goals of this study is to investigate the prevalence and heritability of age-related clonal haemopoeisis (ARCH) in healthy elderly individuals.We will use a bespoke bait set to pull down DNA regions of interest in whole blood samples combined with HiSeq at a deep level . By correlating findings from each individual to their respective twin we hope to elucidate whether heritable traits influence the development of ARCH. a. 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/

  Study EGAS00001002210

• Investigation of the Causal Etiology in a Patient with T-B+NK+ Immunodeficiency

  We describe a male proband with normal B lymphocyte and natural killer (NK) cell numbers, but who had T lymphopenia beginning at 1 week of age. His peripheral blood contained very few T cell receptor excision circles (TREC), suggesting impaired thymic T cell development. He received an allogeneic hematopoietic stem cell marrow transplant, but despite engraftment, it did not fully correct the T lymphopenia. Sequencing excluded known immunodeficiency genes; however, whole exome sequencing revealed X-linked inheritance by the male proband of a missense mutation in MED14 (MED14V763A), a component of the mediator complex. Functional screening of the MED14V763A variant in zebrafish suggested that MED14 is essential for normal development, since morpholino (MO)-mediated loss of MED14 function attenuated T cell development, but it was rescued by ectopic expression of the wild type human MED14 but not by the MED14V763A variant. This defect in T cell repopulation is consistent with the incomplete T cell reconstitution observed upon transplantation of the proband with bone marrow from his healthy male sibling, who was found to have the same MED14V763A variant. However, the brother was normal, indicating that the altered MED14 could not by itself explain the disease. WES also revealed a mutation in the L1 cell adhesion molecule (L1CAMQ498H); however, introducing that mutation in vivo in mice did not disrupt T cell development. Consequently, the immunodeficiency in the patient is not fully elucidated. It is possible that MED14 contributes, but it is also possible that another gene is fully responsible for the disease.

  Study phs002990

• Establishment and characterization of an Epstein-Barr virus-positive cell line from a non-keratinizing differentiated primary nasopharyngeal carcinoma

  Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing (WGS) revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing (WGBS) and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively.

  Study EGAS00001007172

• The British Autozygosity Populations BioResource (2022-04-26)

  This data set contains whole exome sequences of individuals from 8086 (mostly British Pakistani/British Bangladeshi, mostly self-reported parentally related) individuals from the following studies: 1. 5236 British Pakistani/British Bangladeshi adults from East London Genes & Health, now known as Genes & Health 2. 2624 British South Asian mothers from Born in Bradford (mostly Pakistani) 3. 1061 British South Asian adults from Birmingham (mostly Pakistani) This dataset contains all the exome sequence data available for this study on 2022-04-26

  Dataset EGAD00001008736

• cfDNA methylation profiling on longitudinally collected blood plasma of patients with esophageal adenocarcinoma

  Esophageal adenocarcinoma (EAC) is an aggressive cancer characterized by a high risk of relapse post-surgery. Analyzing cell-free DNA (cfDNA) from blood plasma emerges as a promising avenue for therapy response monitoring. This study aims to evaluate the cost-effective and genome-wide cell-free reduced representation bisulfite sequencing (cfRRBS) method combined with computational deconvolution for effective disease monitoring in EAC patients.

  Study EGAS50000000514

• Biological insights from the whole genome sequences of human embryonic stem cell lines

  Human embryonic stem cells (hESCs) are a powerful tool for the study of human development and can form the basis of cellular disease models or therapies. However, the genetic make-up and stability of hESCs has not been systematically studied at a genome-wide level with single nucleotide resolution. We therefore sequenced the whole genome and whole exomes of widely available hESC. This online resource will enable investigators to access raw sequencing data in order to interrogate cell lines for different disease- and trait-associated genetic variants.

  Study EGAS00001002400

• CNV detection in targeted NGS panel data

  The aim of this study was to compare copy-number-variation (CNV) detection methods for targeted NGS panel data in a clinical diagnostic setting. We present targeted NGS panel data from 170 samples that were processed using the TruSight(TM) Cancer (TSC) panel (Illumina, San Diego, CA, USA), which targets 94 genes and 284 SNPs associated with a predisposition towards cancer. The samples are enriched for CNVs in the genes of interest. All CNVs have previously been assessed with MLPA and can therefore be considered as confirmed.

  Study EGAS00001002481

• ILyAD (Indolent Lymphoma And vitamin D)

  Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In our double-blind, placebo-controlled, randomized trial we evaluated if vitamin D supplementation with 2000IU oral cholecalciferol daily for three years improved the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization included histology and Follicular Lymphoma International Prognostic Index (FL-IPI) prognostic score. The primary endpoint of the trial was progression-free survival over three years; secondary endpoints included response at 13 weeks, and overall survival. Eligible participants were adults with biopsy proven follicular lymphoma (grades 1-3a), small lymphocytic lymphoma, marginal zone lymphoma and mucosal-associated lymphoid tissue with no prior anti-lymphoma systemic therapy. Participants had Ann Arbor stage II or greater, measurable disease defined by Lugano criteria. Participants with osteoporosis requiring prescription treatment, symptomatic primary hyperthyroidism, hypercalcemia, creatinine greater than 1.5 times the upper limit of normal or a history of calcium-related kidney stones were excluded. Germline DNA was isolated from saliva samples obtained from participants at baseline. Whole exome sequencing was performed and SNPs were analyzed using the Agilent SureSelectXT Human All Exon V6 +UTR array. SNP data from 185 participants are available through dbGaP.

  Study phs003503

• SCANDARE ovarian WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 91 frozen samples (n = 53 at baseline, n = 31 Post-NAC, n= 7 Recurrence, and n = 62 germline DNA) from 64 ovarian cancer patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001658

• SCANDARE TNBC transcriptomics data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 124 frozen samples (n=84 at baseline and n=40 paired at post-NAC surgery) from 91 TNBC patients using total RNAseq technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001416

• An integrated single-cell reference atlas of the human endometrium

  This dataset includes both the anchor scRNA-seq and snRNA-seq datasets used to build the Human Endometrial Cell Atlas (HECA). HECA provides a comprehensive definition of endometrial cell types and states throughout the menstrual cycle in donor with and without endometriosis. It identifies consensus cell types across datasets generated by teams worldwide, as well as previously unreported cell types, all of which are validated and mapped in situ using spatial transcriptomics. Processed data is available from ArrayExpress with accession number E-MTAB-14039. See Marečková, M., Garcia-Alonso, L., Moullet, M. et al. An integrated single-cell reference atlas of the human endometrium. Nat Genet 56, 1925–1937 (2024) https://doi.org/10.1038/s41588-024-01873-w for more information.

  Dataset EGAD00001015446

• Sperm sequencing reveals extensive positive selection in the human germline -WGS

  Mutations that occur during human ageing in the cell lineages of sperm or eggs have the potential to be transmitted to offspring. In males, positive selection of driver mutations during spermatogenesis is known to increase the birth prevalence of certain developmental disorders and cancer predisposition syndromes. However, direct observation of the scope of this selection in sperm has been limited by the error rates of sequencing technologies. Using the duplex sequencing method known as NanoSeq, we sequenced bulk sperm samples from individuals aged 24 to 75 years. Our findings revealed a linear accumulation mutations per year and mutational signatures consistent with pedigree studies. Deep targeted and deep exome NanoSeq of sperm samples identified genes subject to significant positive selection in the male germline, which are linked to diverse cellular pathways including RAS/MAPK and BMP signaling. Strikingly, nearly all positively selected genes are associated with developmental or cancer predisposition disorders in children. We find that this effect drives an elevated risk of known likely disease-causing mutations in sperm across a wide age range. This implies that the disorders attributed to these genes likely exhibit elevated birth prevalence in human populations, particularly among older fathers. These findings shed light on the dynamics of germline mutations and highlight an increased disease risk for children born to fathers of advanced age.

  Dataset EGAD00001015592

• Sperm sequencing reveals extensive positive selection in the human germline -NanoSeq

  Mutations that occur during human ageing in the cell lineages of sperm or eggs have the potential to be transmitted to offspring. In males, positive selection of driver mutations during spermatogenesis is known to increase the birth prevalence of certain developmental disorders and cancer predisposition syndromes. However, direct observation of the scope of this selection in sperm has been limited by the error rates of sequencing technologies. Using the duplex sequencing method known as NanoSeq, we sequenced bulk sperm samples from individuals aged 24 to 75 years. Our findings revealed a linear accumulation mutations per year and mutational signatures consistent with pedigree studies. Deep targeted and deep exome NanoSeq of sperm samples identified genes subject to significant positive selection in the male germline, which are linked to diverse cellular pathways including RAS/MAPK and BMP signaling. Strikingly, nearly all positively selected genes are associated with developmental or cancer predisposition disorders in children. We find that this effect drives an elevated risk of known likely disease-causing mutations in sperm across a wide age range. This implies that the disorders attributed to these genes likely exhibit elevated birth prevalence in human populations, particularly among older fathers. These findings shed light on the dynamics of germline mutations and highlight an increased disease risk for children born to fathers of advanced age.

  Dataset EGAD00001015590

• Sperm sequencing reveals extensive positive selection in the human germline -TargetedNanoSeq

  Mutations that occur during human ageing in the cell lineages of sperm or eggs have the potential to be transmitted to offspring. In males, positive selection of driver mutations during spermatogenesis is known to increase the birth prevalence of certain developmental disorders and cancer predisposition syndromes. However, direct observation of the scope of this selection in sperm has been limited by the error rates of sequencing technologies. Using the duplex sequencing method known as NanoSeq, we sequenced bulk sperm samples from individuals aged 24 to 75 years. Our findings revealed a linear accumulation mutations per year and mutational signatures consistent with pedigree studies. Deep targeted and deep exome NanoSeq of sperm samples identified genes subject to significant positive selection in the male germline, which are linked to diverse cellular pathways including RAS/MAPK and BMP signaling. Strikingly, nearly all positively selected genes are associated with developmental or cancer predisposition disorders in children. We find that this effect drives an elevated risk of known likely disease-causing mutations in sperm across a wide age range. This implies that the disorders attributed to these genes likely exhibit elevated birth prevalence in human populations, particularly among older fathers. These findings shed light on the dynamics of germline mutations and highlight an increased disease risk for children born to fathers of advanced age.

  Dataset EGAD00001015591

• MutWP4: CRUK Grand Challenge Mutographs of Cancer: Pancreatic Organoids (2021-02-02)

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2021-02-02.

  Dataset EGAD00001006933

• MutWP4: CRUK Grand Challenge Mutographs of Cancer: Gastric Organoids (2019-08-07)

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2019-08-07.

  Dataset EGAD00001005234

• Small variants in mtDNA Canary Islands - WES Illumina (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005678

• Small variants in mtDNA Canary Islands - WGS Illumina (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005679

• Small variants in mtDNA Canary Islands - WGS Oxford Nanopore Technologies (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005677