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• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A73044B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 2057 samples; filetype=bam

  Dataset EGAD00001004720

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A73046B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1970 samples; filetype=bam

  Dataset EGAD00001004721

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A73047D

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 2091 samples; filetype=bam

  Dataset EGAD00001004722

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A73056B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1267 samples; filetype=bam

  Dataset EGAD00001004723

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A75616A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 230 samples; filetype=bam

  Dataset EGAD00001004724

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A75616B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 232 samples; filetype=bam

  Dataset EGAD00001004725

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A75616C

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 239 samples; filetype=bam

  Dataset EGAD00001004726

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A75617A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 692 samples; filetype=bam

  Dataset EGAD00001004727

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A90553A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 612 samples; filetype=bam

  Dataset EGAD00001004728

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A90553C

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1700 samples; filetype=bam

  Dataset EGAD00001004729

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95664B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 606 samples; filetype=bam

  Dataset EGAD00001004752

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95670A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 615 samples; filetype=bam

  Dataset EGAD00001004753

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95670B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 636 samples; filetype=bam

  Dataset EGAD00001004754

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95722A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 968 samples; filetype=bam

  Dataset EGAD00001004755

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95724A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 480 samples; filetype=bam

  Dataset EGAD00001004756

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95724B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 561 samples; filetype=bam

  Dataset EGAD00001004757

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95732A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 928 samples; filetype=bam

  Dataset EGAD00001004759

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95732B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 635 samples

  Dataset EGAD00001004760

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A95736A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1072 samples

  Dataset EGAD00001004761

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96139A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1436 samples; filetype=bam

  Dataset EGAD00001004762

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96145A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 589 samples; filetype=bam

  Dataset EGAD00001004763

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96150A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 656 samples; filetype=bam

  Dataset EGAD00001004764

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96156A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 648 samples; filetype=bam

  Dataset EGAD00001004765

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96156B

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 375 samples; filetype=bam

  Dataset EGAD00001004766

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96165A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 755 samples; filetype=bam

  Dataset EGAD00001004767

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96171A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 492 samples; filetype=bam

  Dataset EGAD00001004768

• Whole genome sequencing of single cells identifies stochastic aneuploidies, genome replication, states, and clonal repertoires for library A96187A

  Transposase-based amplification-free single-cell genome direct library preparation in nanowell chips; 1222 samples; filetype=bam

  Dataset EGAD00001004770

• Tobacco exposure and somatic mutations in normal human bronchial epithelium

  That tobacco smoking causes lung cancer is well-established, but we lack quantitative understanding of its effects on genomes of normal bronchial epithelium. We sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking is the major influence on mutation burden, adding 1000-10,000+ mutations/cell, massively increasing both between-subject and within-subject variance, and generating several distinct signatures of substitutions and indels. A population of cells in subjects with smoking history had mutation burdens equivalent to that expected for never-smokers: these cells lacked tobacco-specific mutational signatures, were four-fold more frequent in ex-smokers than current smokers, and had significantly longer telomeres than their more mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged never-smokers. In current smokers, ≥25% of cells carried driver mutations and 0-6% cells had 2 or even 3 drivers. Thus, tobacco smoking increases mutation burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

  Dataset EGAD00001005193

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma -- CA209-010

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Dataset EGAD00001006026

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma -- CA209-009

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Dataset EGAD00001006027

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma -- CA209-025

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Dataset EGAD00001006029

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006641

• Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor infiltrating T cells.

  Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying functional and dysfunctional states of human tumor infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify tissue-specific and general gene-regulatory landscapes in the wide breadth of CD8+ TIL functional states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor entity-matching samples and prioritize key elements by super enhancer analysis. Our analysis reveals a human core chromatin trajectory to TIL dysfunction and identifies key enhancers, transcriptional regulators, and deregulated target genes involved in this process. Finally, we validate enhancer regulation at loci encoding PD1, TCF1, and TIM3 by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study advances the understanding of molecular regulation of TIL (dys-)function and provides a framework for modulating immunotherapeutic relevant TIL genes via their enhancers.

  Dataset EGAD00001008662

• Dataset for gynecologic_cancer-RNA

  Rare cancer sequencing data of 48 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008856

• Dataset for melanoma-RNA

  Rare cancer sequencing data of 49 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008858

• Dataset for hematopoietic_malignancy-RNA

  Rare cancer sequencing data of 47 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008860

• Dataset for soft_tissue_tumor-WHOLE_GENOME

  Rare cancer sequencing data of 142 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008900

• Dataset for leiomyosarcoma-RNA

  Rare cancer sequencing data of 87 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008849

• Single-cell RNA-sequencing of CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) from a Phase I clinical study in paediatric ALL: CARPALL

  Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.

  Dataset EGAD00001010018

• Whole exome sequencing of tumors from the Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

  Sequencing libraries were constructed according to standard procedures from 600 ng of tumor and paired constitutional DNA. WES was captured using Agilent SureSelect V5 (50 Mb), Clinical Research Exome (54 Mb) kit, SureSelect XT human All exon CRE version 1 or 2, or Twist Human Core Exome Enrichment System. Sequencing of subsequent libraries was performed using Illumina sequencers (Next-Seq 500 or Hiseq 2000/2500/4000) in 75 bp paired-end mode, aiming for a mean depth of coverage of 100x.

  Dataset EGAD00001010928

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - wgs

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011181

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - 0.25mm punches targeted

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011182

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - nanoseq

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011183

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - 2mm targeted

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011184

• Exome sequencing of UK Birth Cohorts - Born in Bradford

  Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights from population genetics to rare disease associations. Avon Longitudinal Study of Parents and Children (ALSPAC)recruited 14,775 babies of predominantly White ethnicity in the Avon county of south-west England between 1991 and 1992. Born in Bradford (BiB) is similarly focused on a particular local area, the city of Bradford in the north of England, and recruited 13,858 babies between 2007 and 2011, of whom ~41% self-report as white British and ~59% as other ethnicities, predominantly Pakistani. Millennium Cohort Study (MCS) is a national cohort that recruited 18,827 children born between 2000 and 2002, intentionally over-sampling areas with high child poverty, large ethnic minority populations, and smaller UK nations (Wales, Scotland and Northern Ireland) Available here is a subset of exome-sequenced parents and children from these studies (CRAMS and post-QC VCFs) as detailed in https://doi.org/10.12688/wellcomeopenres.22697 [doi.org]. Phenotypic data is also available by submitting an application to the corresponding cohort: https://borninbradford.nhs.uk/ [borninbradford.nhs.uk]

  Dataset EGAD00001015370

• 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

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• Gabriella Miller Kids First Pediatric Research Project in Microtia in Hispanic Populations

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Microtia is a rare congenital deformity of the external ear, the pinna. The severity of microtia is variable and ranges from subtle deformities in the pinna to absence of the external ear. Microtia is often associated with closure of the external auditory ear canal causing significant hearing loss. Microtia can be an isolated, unilateral or bilateral malformation, or occur solely with ear canal deformities, or with additional craniofacial or syndromic manifestations. Earlier studies of identical twins with microtia demonstrated a significant genetic contribution. The molecular pathogenesis for most microtia remains unknown. We propose to leverage our clinical acumen in diagnosis and treatment of microtia (R.E.), our relationship to the microtia community (M.T.) and our collected DNA samples from microtia patients to identify genetic variant(s) that contribute to this congenital malformation. Microtia prevalence is much higher among Native Americans and some Latin Americans (17 per 10000 Ecuadorian births) than among individuals of European-descent (0.6 -1.6 per 10,000 births). To capitalize on this epidemiologic data, we have recruited microtia cohorts from Latin America and the U.S, including clinical data and DNA samples.

  Study phs002172