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• Center for Common Disease Genomics (CCDG) Neuropsychiatric: The Autism Simplex Collection (TASC)

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs001741

• NIAID Centralized Sequencing Program

  Investigators at the National Institute of Allergy and Infectious Diseases (NIAID) use next-generation sequencing technologies to help determine genetic contributions to immune diseases. These efforts have increased rates of molecular diagnosis for a subset of NIAID participants as well as uncovered fundamental insights into the cellular and signaling pathways in host defense and immune regulation. Despite these successes, analysis and interpretation of genomic data remain a substantial challenge. Simply, researchers do not understand the functional and clinical consequences of most human genetic variation. Making progress in this area requires a coordinated, systematic, and transparent approach to clinical genomics research. This protocol is specific to genetic testing and explicitly aims to both strengthen clinical care and enhance research. Probands provide biological specimens for genetic testing and primary clinical and research evaluations are completed via a research protocol at NIAID. This protocol serves as a vehicle for a programmatic effort that includes standardized phenotyping, test ordering through the Clinical Research Information System (CRIS) at the National Institutes of Health Clinical Center, sample collection and isolation, nucleic acid analysis, bioinformatics, clinical interpretation, reporting in CRIS, genetic counseling, and supporting effective use of genomics as a research tool throughout the institute. Overall, increased process standardization will support data integrity and efficiency while still accommodating the need for investigator flexibility. This study aims to generate and analyze evidence regarding the genetic contribution to diverse immune diseases studied by the NIAID intramural research program.

  Study phs001899

• Medulloblastoma exome sequence analysis

  Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma. "Reprinted from 'MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATION', with permission from Nature"

  Study phs000504

• Utility of Capillary Blood in Gene Expression Studies

  The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using capillary blood collected by fingerstick, with the goal of developing practical fingerstick blood collections to expand blood collection capabilities and allow large-scale or field-based collections. We compared the RNA sequencing results obtained from two different capillary blood collection and RNA extraction methods with the results obtained from a standard venous blood collection and RNA extraction protocol. We also compared capillary blood processing methods, as well as fingerstick locations, within one capillary collection/extraction method. Within each method we sought to distinguish male from female participants to assess the capacity of each collection/extraction method for gene expression profiling. The study population included 40 participants aged 18-60 who were free from any acute illness or any illness that would preclude blood collection. We determined that capillary blood possesses large-scale significant differences from venous blood and that the two capillary methods produced similar gene expression profiles. We further determined that all methods were useful for detecting gene expression differences between assessed groups (male and female participants in this case). We conclude that capillary blood is suitable for gene expression profiling in quantities as low as 100 μL whole blood, but recommend that researchers should rely on a single blood collection method if they desire to compare results between individual studies. Raw sequencing files (.fastq) from this study are available in dbGaP.

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• METABRIC miRNA landscape

  MicroRNAs (miRNAs) are key players in cancer pathogenesis1. They display differential expression across breast cancer subtypes, and play oncogenic and tumor-suppressive roles2-6. A systematic study of the global miRNA landscape in breast cancer and the factors shaping it has not been undertaken. Here we report the results of profiling miRNA expression in 1,302 breast tumors with detailed clinical annotation and long-term follow-up, and for which matching genomic and mRNA expression data were available7. This provides a comprehensive view of the quantity, distribution and variation of the miRNA population and dissects how much genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture. The key clinical parameters and cellular pathways related to the miRNA landscape are identified, exemplified by context-dependent interaction with cell adhesion and Wnt signaling. Strikingly, in breast cancer miRNAs appear to act as modulators of mRNA-mRNA interactions rather than molecular switches. We demonstrate an important modulatory role for miRNAs in the biology of breast tumors devoid of somatic copy number aberrations, a common subtype where immune response is prominent. Remarkably, prognostic miRNA signatures derived in this subtype are consistently prognostic across several other subtypes and validate in external cohorts. These findings represent a new framework to study the biology of miRNA in human cancer.

  Study EGAS00000000122

• Risk Factors for Asymptomatic Diverticulosis

  Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

  Study phs003556

• The Dynamic Immune Behavior of Primary and Metastatic Ovarian Carcinoma

  Patients with high-grade serous ovarian carcinoma are usually diagnosed at an advanced stage and often develop resistance to conventional therapy. Epithelial ovarian tumors have been shown to be rich in CD8+ lymphocytes, which infiltrate both primary and omental sites. In recent years, several prominent studies have highlighted a positive association between the presence of these immune cells and a good prognosis; however, clinical trials of immune checkpoint inhibitors have so far shown unsatisfactory results in ovarian cancer. In this study, we used an innovative combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in primary and metastatic HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, while several immune cell subtypes were present in all samples, their relative abundance differed between primary and omental tumors. Finally, we found that primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation, while omental tumors were mostly populated by naïve immune cells; this, in turn, was correlated with expression changes in the interferon α and γ pathways in epithelial cells, showing that cross-communication between the epithelial and immune compartments is important for immune suppression in ovarian cancer. These findings can impact the timing and choice of immune-modulating drugs and should be considered when planning treatment for patients with high-grade serous ovarian carcinoma.

  Study EGAS50000000038

• The Genomic and Transcriptomic Landscape of a HeLa Cell Line

  HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology. Copyright Landry et al., "The Genomic and Transcriptomic Landscape of a HeLa Cell Line," G3: Genes | Genomes | Genetics (2013).

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• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• Delineating pediatric brain tumor progression using single-nuclei sequencing

  Pediatric brain cancers are the most common solid tumors in children with varying survival rates depending on molecular features of cancer cells and associated microenvironment. Several studies have used single-cell RNA sequencing to define transcriptional programs active in cancer cells and highlighted supportive roles of non-cancerous cells embedded in these tumors. Although application of single-cell RNA sequencing technology has expanded our understanding of intratumoral heterogeneity and underlying transcriptional mechanisms in brain tumors at diagnosis, mechanisms of disease remains elusive. Therefore, the purpose of this proposal is to characterize cellular and transcriptional states of malignant and non-malignant compartments at primary diagnosis and at relapse. In this study, we performed single-nuclei sequencing of 42 patient samples taken at various disease stages (initial diagnosis, progressive disease, and relapsed disease) from 20 patients with low-grade glioma or Atypical Teratoid Rhabdoid Tumor (ATRT). Bulk whole genome and RNA-seq data for these samples are available from the Children’s Brain Tumor Network and the Gabriella Miller Kids First Data Resource Center. Findings from our study will help define the mechanistic shifts of tumor and non-cancerous cells over course of disease progression. Collectively with the single-cell Pediatric Cancer Atlas funded, this project lays the foundation of an important data set focused on lethal relapsed cancers that can continue to be expanded to identify cancer-intrinsic and extrinsic microenvironmental factors supporting recurrence of pediatric brain tumors.

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