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• Gene Expression Study of Individuals with Sex Chromosome Aneuploidies

  Males and females show dramatic differences in their vulnerability to the same diseases. For example, compared to men, lupus is six times more prevalent, thyroid cancer is three times more prevalent, and unipolar depression is twice as prevalent in women. Diseases with a strong male bias include autism (5:1), dilated cardiomyopathy (3:1), and ankylosing spondylitis (5:1). Historically, such differences have been attributed solely to extrinsic factors such as circulating sex hormones or environmental influences. We hypothesized that intrinsic factors - genetic differences between XX and XY cells - have unappreciated biological consequences throughout the body and contribute to sex differences in disease incidence and severity. This hypothesis stems from our long-term effort to sequence the sex chromosomes of diverse mammalian species, which has identified a set of homologous genes on the X and Y chromosomes that are dosage-sensitive, expressed throughout the body, and encode regulators of chromatin modification, transcription, translation, and protein stability. These X- and Y-encoded genes differ in sequence and expression pattern, which likely manifests in genome-wide differences in gene regulation between XX and XY cells and influences all aspects of human biology, including sex differences in disease susceptibility. These hard-wired molecular sex differences have been largely overlooked and understudied, representing a significant gap in our knowledge of human biology.The gene expression study of individuals with sex chromosome aneuploidies takes advantage of natural human variation in sex chromosome number, i.e. sex chromosome aneuploidy, to investigate alterations in genome-wide gene expression that correlate with changes in X- and Y-chromosome dosage. We analyzed samples from 114 individuals with a variety of sex chromosome aneuploidies, including 45,X; 47,XXY; 47,XYY; 47,XXX; 48,XXYY; and 49,XXXXY. We generated lymphoblastoid cell lines (LCLs) from blood samples and, in some cases, fibroblast cultures from skin biopsies. We supplemented our collection with previously-derived cell lines. To evaluate gene expression, we performed deep profiling of the transcriptome (RNA-seq) from these LCLs and fibroblasts. We performed parallel analyses on samples collected from 62 control 46,XX and 46,XY individuals, 6 individuals with trisomy 21, and 14 individuals with structural variations of the X and Y chromosomes. In addition, we performed CRISPRi knockdowns on 3 of the 46,XX and 3 of the 46,XY fibroblast samples for the homologous transcription factors ZFX and ZFY, encoded on the X and Y chromosomes, respectively.In the April 2024 update, we added RNA-seq datasets derived from isolated CD4+ T cells and monocytes from 76 and 72 adults, respectively, with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXX; 47,XXY; 47,XYY. These individuals are largely a subset of the same cohort described above. In addition, we performed RNA-seq on in-vitro stimulated CD4+ T cells with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXY.In the August 2024 update, we added RNA-seq datasets generated from the following: 1) LCLs derived from individuals with AZFa deletions of the Y chromosome, 2) DDX3X and DDX3Y knockdown (via CRISPRi) in XY fibroblasts, and 3) 5-ethyl uridine (5-EU) treatment in XY and XYYYY LCLs.

  Study phs002481

• Pharmacological improvement of CFTR function rescues airway epithelial homeostasis and host defense in cystic fibrosis children

  Rationale: Recent clinical trials have shown that elexacaftor/tezacaftor/ivacaftor (ETI) provides significant benefit to patients with cystic fibrosis (CF) by improving CFTR function. Despite these promising clinical findings, the specific effects on the airway inflammatory status leading to structural damage and impaired lung function, remain elusive. Objectives: We investigated the transcriptional changes at the single cell level of airway epithelial and immune cells that underlie the clinical improvement by ETI therapy in children with CF. Methods: Nasal swabs from thirteen children with CF and at least one F508del allele aged 6 to 12 years were collected at baseline and three months after initiation of ETI and subjected to scRNA-seq. In addition, we collected nasal swabs from 12 age- and sex-matched controls. Sweat chloride concentrations, spirometry and multiple breath washout were used for clinical evaluation of CF children. Measurements and main results: ETI significantly reduced sweat chloride concentrations (-52.2 ± 14.3 mmol/L, P < 0.001) and improved the lung clearance index (-1.3 ± 1.8, P < 0.05). Single cell transcriptomics revealed an impaired interferon signalling in epithelial cells of CF children at baseline, which was partially restored by ETI in conjunction with an ETI-induced increase in expression of MHC I and II encoding genes similar to control levels. Additionally, ETI markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Improvement of CFTR function by ETI restores epithelial homeostasis and reduces immune cell inflammatory responses in the upper airways of children with CF, highlighting the potential of early initiation of ETI therapy.

  Study EGAS50000000128

• Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Through this collaborative effort, we submitted and obtained usable genotyping data on 2184 patients and 1155 controls from the Center for Inherited Disease Research (CIDR).

  Study phs000182

• Molecular Evolution of Cancer

  Recently developed methods that utilize partitioning of long genomic DNA fragments, and barcoding of shorter fragments derived from them, have succeeded in retaining long-range information in short sequencing reads. These so-called read cloud approaches represent a powerful, accurate, and cost-effective alternative to single-molecule long-read sequencing. We developed software, GROC-SVs, that takes advantage of read clouds for structural variant detection and assembly. We apply the method to two 10x Genomics data sets, one chromothriptic sarcoma with several spatially separated samples, and one breast cancer cell line, all Illumina-sequenced to high coverage. Comparison to short-fragment data from the same samples, and validation by mate-pair data from a subset of the sarcoma samples, demonstrate substantial improvement in specificity of breakpoint detection compared to short-fragment sequencing, at comparable sensitivity, and vice versa. The embedded long-range information also facilitates sequence assembly of a large fraction of the breakpoints; importantly, consecutive breakpoints that are closer than the average length of the input DNA molecules can be assembled together and their order and arrangement reconstructed, with some events exhibiting remarkable complexity. These features facilitated an analysis of the structural evolution of the sarcoma. In the chromothripsis, rearrangements occurred before copy number amplifications, and using the phylogenetic tree built from point mutation data, we show that single nucleotide variants and structural variants are not correlated. We predict significant future advances in structural variant science using 10x data analyzed with GROC-SVs and other read cloud-specific methods.

  Study phs001255

• Genetics of Prostate Cancer in Africa

  African Americans (AA) suffer from the highest rates of Prostate Cancer (CaP) in the world, but while men of African descent around the world suffer disproportionately from CaP compared to men of other races or ethnicities, our understanding of the reasons for these disparities remains incomplete. To date, few exposure, lifestyle, or environmental influences have been identified in CaP etiology. In contrast, CaP is among the most heritable of common cancers, and over 290 susceptibility loci have been identified. However, many of these loci have not been replicated in AA, in part because of limited African descent sample sizes, incomplete capture of African alleles, and a limited understanding of African genomic architecture. To better understand the etiology of CaP in African descent men, we established a large, multicenter consortium known as &#8220;Men of African Descent and Carcinoma of the Prostate&#8221; (MADCaP). Using resources of this consortium, we have undertaken a multicenter study of CaP in Sub-Saharan Africa, enrolling CaP cases from 7 institutions in 4 countries in Africa (Nigeria, Senegal, Ghana, and South Africa) and age matched controls from the same institutions. We designed a novel genotyping array, in partnership with Thermo Fisher Scientific, leveraging its Applied BiosystemTM AxiomTM Genotyping solution, to provide good coverage of African genomic variation, as well as incorporating cancer loci, with the goal of being able to fine-map existing prostate cancer loci, as well as mapping novel loci. The data available encompasses genotyping our Africa cohort on this array.

  Study phs002718

• Breast Cancer Family Registry

  The Breast Cancer Family Registry (BCFR) is a multi-center prospective cohort, comprised of over 30,000 women and men from nearly 12,000 families from the United States, Canada, and Australia. Our BCFR resource has been used, and continues to be used, by breast cancer researchers around the world in order to find new ways to prevent, diagnose, and treat cancer. The BCFR provides an extensive and diverse range of resources, expertise, and specialized skills, and has several unique strengths: 1) the collection of a large number of individuals and families across a wide spectrum of breast cancer risk, including both affected and unaffected individuals; 2) the large collection of families with early-onset breast cancer; 3) the large collection of racial/ethnic minority families not replicated elsewhere; 4) the extensive molecular characterization performed to date; and 5) active follow-up of both probands and family members. Thus, the BCFR comprises a unique cohort of probands and family members at familial/genetic risk of breast cancer that will continue to facilitate a wide range of research studies, such as gene discovery, examination of cancer-related outcomes and risk factors in high-risk subjects, investigation of novel behavioral interventions, and cancer prevention trials among at-risk family members. Consequently, the BCFR Cohort, as one of the few cohorts available worldwide with biospecimens and extensive molecular and genetic characterization, combined with epidemiologic data and long-term follow up, will be an invaluable resource for translational research in the genetic epidemiology of breast cancer.

  Study phs002835

• DNA Methylomic Profiling of Preeclampsia Across Pregnancy

  Preeclampsia (PE) is a hypertensive, multi-system disorder of pregnancy that significantly impacts maternal and infant morbidity/mortality across the globe, as it increases risk of cardiovascular disease and remains a leading killer of women and babies. Despite PE&#39;s significant impact on morbidity/mortality, there are no clinically reliable biomarkers that predict PE. DNA methylation, a dynamic regulator of gene expression, represents a mechanism that is known to be impacted by the environment. Because PE stems from a dysfunctional placenta that releases debris into the maternal circulation, we hypothesized that the in-vivo environment created by the dysfunctional placenta will impact DNA methylation in the maternal circulation, and that these blood-based methylation profiles would serve as a systemic biomarker of the maternal response to placental dysfunction. Our overall objective of this pilot study was to longitudinally characterize DNA methylation profiles across the three trimesters of pregnancy in the maternal blood at time points before and after clinically overt PE using a targeted (endoglin and endoglin-related genes) and a discovery-based approach. For this pilot study, 28 normotensive control participants and 28 PE case participants enrolled in the NICHD funded pregnancy study entitled Prenatal Exposures and Preeclampsia Prevention: Mechanisms of Preeclampsia and the Impact of Obesity (PEPP3; P01HD30367) were 1:1 frequency matched on self-reported race, pre-pregnancy BMI, smoking history, and gestational age at sample collection. Methylation data were collected with the Infinium&#174; MethylationEPIC Beadchip. Methylation assay data collection were carried out at Johns Hopkins University Genetic Resources Core Facility, The SNP Center, Baltimore, MD, USA.

  Study phs001937

• Clonally selected lines after CRISPR/Cas editing are not isogenic

  The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (i) editing cultured cells and (ii) selection of clones, which are presumed to be isogenic, with and without the intended edit. The application of the CRISPR-Cas9 system may result in off-target edits, while cloning would reveal culture-acquired mutations. We analyzed the extent of the former and of the latter by whole genome sequencing (WGS) involving separate genomic loci in three experiments conducted by three independent laboratories. In all experiments we hardly found any off-target edits, while we detected hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations that were several kb to several mb in size, representing the largest source of genomic divergence among clones. This study in dbGaP includes data from experiments carried out by investigators at the Oklahoma Medical Research Foundation and Baylor College of Medicine (OMRF/BCM) involving an iPSC line derived from fibroblasts of a female patient (line c7) carrying a constitutional heterozygous variant (chr1:1,464,679 C&gt;T; GRCh37) in exon 15 of the ATPase family, AAA domain containing 3A (ATAD3A) gene. The parental line was edited by introducing a double stranded break at the variant allele to correct the variant by homology directed repair. Two unedited control clones (clone7 and clone8) and one edited clone (SC20) were selected for WGS.

  Study phs003110

• High-Resolution Clonal Mapping of Multi-Organ Metastasis, and Resistance to Neoadjuvant Chemotherapy, in Triple Negative Breast Cancer

  Clonal dynamics during metastasis were studied in two patient-derived xenograft (PDX) models established from treatment-naive primary breast tumors from TNBC patients diagnosed with concurrent metastatic disease. Genomic sequencing and barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and metastases. Polyclonal seeding and maintenance of low-abundance subclones was observed in each metastatic lesion examined. Lung, liver, and brain metastases were enriched for an identical population of subclones. Clones dominating multi-organ metastases shared a genomic lineage. Thus, properties of rare mammary tumor subclones enabled the seeding and colonization of metastases in multiple secondary organ sites. In this study, patient-derived xenograft (PDX) models of treatment-naive TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after chemotherapy maintained the subclonal architecture of untreated tumors yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to chemotherapy-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Taken together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as a chemotherapy resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes as well as maintenance of stable subclonal architecture, demonstrating that PDXs capture molecular features characteristic of human TNBC chemoresistance.

  Study phs001742

• Norepinephrine Transporter Blockade as a Pathophysiological Biomarker in Neurogenic Orthostatic Hypotension

  The clinical picture of autonomic failure is dominated by disabling orthostatic hypotension. Recent developments in the understanding of the underlying pathophysiology of the discrete clinical forms of autonomic failure have revealed that participants with multiple system atrophy (MSA) are characterized by impairment of central autonomic pathways crucial for autonomic cardiovascular control, but have intact peripheral postganglionic noradrenergic fibers. Participants with MSA have peripheral residual sympathetic tone that is no longer modulated by central autonomic centers and is not under baroreflex control and, therefore, cannot be harnessed to improve their orthostatic hypotension. On the other hand, participants with pure autonomic failure (PAF) and with Parkinson&#39; s disease (PD) are characterized by neurodegeneration and loss of peripheral noradrenergic fibers, as evidenced by low levels of plasma norepinephrine and absent cardiac uptake of labeled catechols. Pharmacological inhibition of the norepinephrine transporter (NET) is an example of an approach that can take advantage of the participants&#39; own residual sympathetic tone. NET inhibition will increase synaptic norepinephrine that is tonically released in MSA participants by preventing its reuptake. This should result in an increase in blood pressure. This is a longitudinal study of 50 participants, age 18-80 years with neurogenic orthostatic hypotension associated with impaired reflexes. The purpose of this study is to determine if the magnitude of the pressor response to atomoxetine at study entry, will be useful as a biomarker to differentiate those participants that will ultimately be shown to have pre-ganglionic (central) lesions (MSA) with those shown to have post ganglionic (peripheral) lesions (PAF and PD).

  Study phs001595