Genomics Commons^™

A Bayesian Deep Segmentation Framework For Glioblastoma Tumor Segmentation Using Follow-Up Mris, Tanjida Kabir, Kang-Lin Hsieh, Luis Nunez, Yu-Chun Hsu, Juan C Rodriguez Quintero, Octavio Arevalo, Kangyi Zhao, Jay-Jiguang Zhu, Roy F Riascos, Mahboubeh Madadi, Xiaoqian Jiang, Shayan Shams

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) is the most common malignant brain tumor with an abysmal prognosis. Since complete tumor cell removal is impossible due to the infiltrative nature of GBM, accurate measurement is paramount for GBM assessment. Preoperative magnetic resonance images (MRIs) are crucial for initial diagnosis and surgical planning, while follow-up MRIs are vital for evaluating treatment response. The structural changes in the brain caused by surgical and therapeutic measures create significant differences between preoperative and follow-up MRIs. In clinical research, advanced deep learning models trained on preoperative MRIs are often applied to assess follow-up scans, but their effectiveness in this …

Dynamic Dysregulation Of Retrotransposons In Neurodegenerative Diseases At The Single-Cell Level\, Wankun Deng, Citu Citu, Andi Liu, Zhongming Zhao

Faculty, Staff and Student Publications

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea

Faculty, Staff and Student Publications

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion …

Crispr-Cas9 And Cas12a Target Site Richness Reflects Genomic Diversity In Natural Populations Of Anopheles Gambiae And Aedes Aegypti Mosquitoes, Travis C Collier, Yoosook Lee, Derrick K Mathias, Víctor López Del Amo

Faculty, Staff and Student Publications

Due to limitations in conventional disease vector control strategies including the rise of insecticide resistance in natural populations of mosquitoes, genetic control strategies using CRISPR gene drive systems have been under serious consideration. The identification of CRISPR target sites in mosquito populations is a key aspect for developing efficient genetic vector control strategies. While genome-wide Cas9 target sites have been explored in mosquitoes, a precise evaluation of target sites focused on coding sequence (CDS) is lacking. Additionally, target site polymorphisms have not been characterized for other nucleases such as Cas12a, which require a different DNA recognition site (PAM) and would …

Discovery Of Runs-Of-Homozygosity Diplotype Clusters And Their Associations With Diseases In Uk Biobank, Ardalan Naseri, Degui Zhi, Shaojie Zhang

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Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number …

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

Effects Of Protein-Enriched Nutritional Support On Skeletal Muscle Mass And Rehabilitative Outcomes In Brain Tumor Patients: A Randomized Controlled Trial, Kye Hee Cho, Eun Young Han, Min Kyu Jung, Chang Moo Kang, Ji Cheol Shin, Sang Hee Im

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Patients with brain tumors require extensive and prolonged rehabilitation efforts as they suffer from lesion-induced motor weakness as well as treatment-related side effects, often leading to a significant decline in function. Protein supplements have shown positive effects on promoting muscle strength and physical performance in various tumor etiologies. However, reports on their effects specifically in brain tumor patients remain scarce. This study aims to investigate the feasibility and efficacy of protein supplements in enhancing rehabilitative outcomes via muscle strengthening and functional gain in brain tumor patients with neurological demise. Sixty brain tumor patients were randomly assigned to either a protein …

Tissue-Specific Atlas Of Trans-Models For Gene Regulation Elucidates Complex Regulation Patterns, Robert Dagostino, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms.

RESULTS: We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the …

Nodal Variants Are Associated With A Continuum Of Laterality Defects From Simple D-Transposition Of The Great Arteries To Heterotaxy, Zain Dardas, Jawid M Fatih, Angad Jolly, Moez Dawood, Haowei Du, Christopher M Grochowski, Edward G Jones, Shalini N Jhangiani, Xander H T Wehrens, Pengfei Liu, Weimin Bi, Eric Boerwinkle, Jennifer E Posey, Donna M Muzny, Richard A Gibbs, James R Lupski, Zeynep Coban-Akdemir, Shaine A Morris

Faculty, Staff and Student Publications

BACKGROUND: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.

METHODS: We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with …

Genome-Wide Crispr Screen Reveals The Synthetic Lethality Between Bcl2l1 Inhibition And Radiotherapy, Ling Yin, Xiaoding Hu, Guangsheng Pei, Mengfan Tang, You Zhou, Huimin Zhang, Min Huang, Siting Li, Jie Zhang, Citu Citu, Zhongming Zhao, Bisrat G Debeb, Xu Feng, Junjie Chen

Faculty, Staff and Student Publications

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

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Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Sox On Tumors, A Comfort Or A Constraint?, Junqing Jiang, Yufei Wang, Mengyu Sun, Xiangyuan Luo, Zerui Zhang, Yijun Wang, Siwen Li, Dian Hu, Jiaqian Zhang, Zhangfan Wu, Xiaoping Chen, Bixiang Zhang, Xiao Xu, Shuai Wang, Shengjun Xu, Wenjie Huang, Limin Xia

Faculty, Staff and Student Publications

The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes …

The Hsp90-Myc-Cdk9 Network Drives Therapeutic Resistance In Mantle Cell Lymphoma, Fangfang Yan, Vivian Jiang, Alexa Jordan, Yuxuan Che, Yang Liu, Qingsong Cai, Yu Xue, Yijing Li, Joseph Mcintosh, Zhihong Chen, Jovanny Vargas, Lei Nie, Yixin Yao, Heng-Huan Lee, Wei Wang, Johnnelson R Bigcal, Maria Badillo, Jitendra Meena, Christopher Flowers, Jia Zhou, Zhongming Zhao, Lukas M Simon, Michael Wang

Faculty, Staff and Student Publications

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma. However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics™ analysis. Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Genetic Determinants Underlying The Progressive Phenotype Of Β-Lactam/Β-Lactamase Inhibitor Resistance In Escherichia Coli, William C Shropshire, Hatim Amiji, Jordan Bremer, Selvalakshmi Selvaraj Anand, Benjamin Strope, Pranoti Sahasrabhojane, Marc Gohel, Samuel Aitken, Sarah Spitznogle, Xiaowei Zhan, Jiwoong Kim, David E Greenberg, Samuel A Shelburne

Faculty, Staff and Student Publications

Currently, whole-genome sequencing (WGS) data have not shown strong concordance with Escherichia coli susceptibility profiles to the commonly used β-lactam/β-lactamase inhibitor (BL/BLI) combinations: ampicillin-sulbactam (SAM), amoxicillin-clavulanate (AMC), and piperacillin-tazobactam (TZP). Progressive resistance to these BL/BLIs in the absence of cephalosporin resistance, also known as extended-spectrum resistance to BL/BLI (ESRI), has been suggested to primarily result from increased copy numbers of bla TEM variants, which is not routinely assessed in WGS data. We sought to determine whether addition of gene amplification could improve genotype-phenotype associations through WGS analysis of 147 E. coli bacteremia isolates with increasing categories of BL/BLI non-susceptibility ranging …

An Overview Of The Immune Modulatory Properties Of Long Non-Coding Rnas And Their Potential Use As Therapeutic Targets In Cancer, Moises Martinez-Castillo, Abdelrahman M Elsayed, Gabriel López-Berestein, Paola Amero, Cristian Rodríguez-Aguayo

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Long non-coding RNAs (lncRNAs) play pivotal roles in regulating immune responses, immune cell differentiation, activation, and inflammatory processes. In cancer, they are gaining prominence as potential therapeutic targets due to their ability to regulate immune checkpoint molecules and immune-related factors, suggesting avenues for bolstering anti-tumor immune responses. Here, we explore the mechanistic insights into lncRNA-mediated immune modulation, highlighting their impact on immunity. Additionally, we discuss their potential to enhance cancer immunotherapy, augmenting the effectiveness of immune checkpoint inhibitors and adoptive T cell therapies. LncRNAs as therapeutic targets hold the promise of revolutionizing cancer treatments, inspiring further research in this field …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Faculty, Staff and Student Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

Multi-Ancestry Genome-Wide Study Identifies Effector Genes And Druggable Pathways For Coronary Artery Calcification, Maryam Kavousi, Maxime M Bos, Hanna J Barnes, Christian L Lino Cardenas, Doris Wong, Haojie Lu, Chani J Hodonsky, Lennart P L Landsmeer, Adam W Turner, Minjung Kho, Natalie R Hasbani, Paul S De Vries, Donald W Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M Lutz, Leo-Pekka Lyytikäinen, Lotte Slenders, Albert V Smith, Maggie A Stanislawski, Jessica Van Setten, Quenna Wong, Lisa R Yanek, Diane M Becker, Marian Beekman, Matthew J Budoff, Mary F Feitosa, Chris Finan, Austin T Hilliard, Sharon L R Kardia, Jason C Kovacic, Brian G Kral, Carl D Langefeld, Lenore J Launer, Shaista Malik, Firdaus A A Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A Smith, Kent D Taylor, James G Terry, Jeroen Van Der Grond, Joyce Van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A Young, Nuno R Zilhão, Robert Zweiker, Themistocles L Assimes, Lewis C Becker, Daniel Bos, J Jeffrey Carr, L Adrienne Cupples, Dominique P V De Kleijn, Menno De Winther, Hester M Den Ruijter, Myriam Fornage, Barry I Freedman, Vilmundur Gudnason, Aroon D Hingorani, John E Hokanson, M Arfan Ikram, Ivana Išgum, David R Jacobs, Mika Kähönen, Leslie A Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T Raitakari, Helena Schmidt, P Eline Slagboom, André G Uitterlinden, Meike W Vernooij, Joshua C Bis, Nora Franceschini, Bruce M Psaty, Wendy S Post, Jerome I Rotter, Johan L M Björkegren, Christopher J O'Donnell, Lawrence F Bielak, Patricia A Peyser, Rajeev Malhotra, Sander W Van Der Laan, Clint L Miller

Faculty, Staff and Student Publications

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci …

Collagene Enables Privacy-Aware Federated And Collaborative Genomic Data Analysis, Wentao Li, Miran Kim, Kai Zhang, Han Chen, Xiaoqian Jiang, Arif Harmanci

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Growing regulatory requirements set barriers around genetic data sharing and collaborations. Moreover, existing privacy-aware paradigms are challenging to deploy in collaborative settings. We present COLLAGENE, a tool base for building secure collaborative genomic data analysis methods. COLLAGENE protects data using shared-key homomorphic encryption and combines encryption with multiparty strategies for efficient privacy-aware collaborative method development. COLLAGENE provides ready-to-run tools for encryption/decryption, matrix processing, and network transfers, which can be immediately integrated into existing pipelines. We demonstrate the usage of COLLAGENE by building a practical federated GWAS protocol for binary phenotypes and a secure meta-analysis protocol. COLLAGENE is available at https://zenodo.org/record/8125935 …

Early Onset Horizontal Gaze Palsy And Progressive Scoliosis Due To A Noncanonical Splicing-Site Variant And A Missense Variant In The Robo3 Gene, Sheng Yi, Zailong Qin, Xunzhao Zhou, Junjie Chen, Shang Yi, Qiuli Chen, Limei Huang, Qinle Zhang, Biyan Chen, Jingsi Luo

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BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.

METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.

RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention …

Beyond The Exome: What’S Next In Diagnostic Testing For Mendelian Conditions, Monica H Wojcik, Chloe M Reuter, Shruti Marwaha, Medhat Mahmoud, Michael H Duyzend, Hayk Barseghyan, Bo Yuan, Philip M Boone, Emily E Groopman, Emmanuèle C Délot, Deepti Jain, Alba Sanchis-Juan, Genomics Research To Elucidate The Genetics Of Rare Diseases (Gregor) Consortium, Lea M Starita, Michael Talkowski, Stephen B Montgomery, Michael J Bamshad, Jessica X Chong, Matthew T Wheeler, Seth I Berger, Anne O'Donnell-Luria, Fritz J Sedlazeck, Danny E Miller

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Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. …

Ancestral Diversity In Lipoprotein(A) Studies Helps Address Evidence Gaps, Moa P Lee, Sofia F Dimos, Laura M Raffield, Zhe Wang, Anna F Ballou, Carolina G Downie, Christopher H Arehart, Adolfo Correa, Paul S De Vries, Zhaohui Du, Christopher R Gignoux, Penny Gordon-Larsen, Xiuqing Guo, Jeffrey Haessler, Annie Green Howard, Yao Hu, Helina Kassahun, Shia T Kent, J Antonio G Lopez, Keri L Monda, Kari E North, Ulrike Peters, Michael H Preuss, Stephen S Rich, Shannon L Rhodes, Jie Yao, Rina Yarosh, Michael Y Tsai, Jerome I Rotter, Charles L Kooperberg, Ruth J F Loos, Christie Ballantyne, Christy L Avery, Mariaelisa Graff

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INTRODUCTION: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.

METHODS: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.

RESULTS: Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R

CONCLUSIONS: …

Genome-Wide Crispr-Cas9 Screen Analyzed By Slider Identifies Network Of Repressor Complexes That Regulate Trim24, Lalit R Patel, Sabrina A Stratton, Megan Mclaughlin, Patrick Krause, Kendra Allton, Andrés López Rivas, Daniela Barbosa, Traver Hart, Michelle C Barton

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TRIM24 is an oncogenic chromatin reader that is frequently overexpressed in human tumors and associated with poor prognosis. However, TRIM24 is rarely mutated, duplicated, or rearranged in cancer. This raises questions about how TRIM24 is regulated and what changes in its regulation are responsible for its overexpression. Here, we perform a genome-wide CRISPR-Cas9 screen by fluorescence-activated cell sorting (FACS) that nominated 220 negative regulators and elucidated a regulatory network that includes the KAP1 corepressor, CNOT deadenylase, and GID/CTLH E3 ligase. Knocking out required components of these three complexes caused TRIM24 overexpression, confirming their negative regulation of TRIM24. Our findings …

Minimal Positional Substring Cover Is A Haplotype Threading Alternative To Li And Stephens Model, Ahsan Sanaullah, Degui Zhi, Shaojie Zhang

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The Li and Stephens (LS) hidden Markov model (HMM) models the process of reconstructing a haplotype as a mosaic copy of haplotypes in a reference panel. For small panels, the probabilistic parameterization of LS enables modeling the uncertainties of such mosaics. However, LS becomes inefficient when sample size is large, because of its linear time complexity. Recently the PBWT, an efficient data structure capturing the local haplotype matching among haplotypes, was proposed to offer a fast method for giving some optimal solution (Viterbi) to the LS HMM. Previously, we introduced the minimal positional substring cover (MPSC) problem as an alternative …

Genotype-Degree Of Hemolysis Correlation In Hereditary Spherocytosis, Yimeng Shi, Yuan Li, Xiawan Yang, Xiaoxia Li, Guangxin Peng, Xin Zhao, Xu Liu, Yufei Zhao, Jing Hu, Xiangrong Hu, Baohang Zhang, Kang Zhou, Yang Yang, Youzhen Xiong, Jianping Li, Huihui Fan, Wenrui Yang, Lei Ye, Liping Jing, Li Zhang, Fengkui Zhang

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BACKGROUND: Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood cell (RBC) lifespan could directly reflect the degree of hemolysis. In the present cohort of 23 patients with HS, we performed next-generation sequencing (NGS) and Levitt's carbon monoxide (CO) breath test to investigate the potential genotype-degree of hemolysis correlation.

RESULTS: In the present cohort, we identified 8 ANK1,9 SPTB,5 SLC4A1 and 1 SPTA1 mutations in 23 patients with HS, and the median RBC lifespan was 14(8-48) days. The median RBC lifespan of patients with ANK1, …

The Integrative Studies On The Functional A-To-I Rna Editing Events In Human Cancers, Sijia Wu, Zhiwei Fan, Pora Kim, Liyu Huang, Xiaobo Zhou

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Adenosine-to-inosine (A-to-I) RNA editing, constituting nearly 90% of all RNA editing events in humans, has been reported to contribute to the tumorigenesis in diverse cancers. However, the comprehensive map for functional A-to-I RNA editing events in cancers is still insufficient. To fill this gap, we systematically and intensively analyzed multiple tumorigenic mechanisms of A-to-I RNA editing events in samples across 33 cancer types from The Cancer Genome Atlas. For individual candidate among ∼ 1,500,000 quantified RNA editing events, we performed diverse types of downstream functional annotations. Finally, we identified 24,236 potentially functional A-to-I RNA editing events, including the cases …

Physio-Psycho-Social Interaction Mechanism In Dyadic Health Of Young And Middle-Aged Stroke Survivors And Their Spousal Caregivers: A Longitudinal Observational Study Protocol, Dandan Xiang, Zhen-Xiang Zhang, Song Ge, Wen Na Wang, Bei-Lei Lin, Su-Yan Chen, Er-Feng Guo, Peng-Bo Zhang, Zhi-Wei Liu, Hui Li, Yong-Xia Mei

Faculty, Staff and Student Publications

Introduction: In recent years, stroke has become more common among young people. Stroke not only has a profound impact on patients' health but also incurs stress and health threats to their caregivers, especially spousal caregivers. Moreover, the health of stroke survivors and their caregivers is interdependent. To our knowledge, no study has explored dyadic health of young and middle-aged stroke survivors and their spousal caregivers from physiological, psychological and social perspectives. Therefore, this proposed study aims to explore the mechanism of how physiological, psychological and social factors affect dyadic health of young and middle-aged stroke survivors and their spousal caregivers. …

Renal-Hepatic-Pancreatic Dysplasia Type 2: Perinatal Lethal Condition Or A Multisystemic Disorder With Variable Expressivity, Kathryn Gunther, Essam M Imseis, Joyce P Samuel, Elizabeth A Hillman, Tiina H Ojala, Timo Jahnukainen, Paul R Hillman

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BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data.

METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the …

Rare Variant Enrichment Analysis Supports Greb1l As A Contributory Driver Gene In The Etiology Of Mayer-Rokitansky-Küster-Hauser Syndrome, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Faculty, Staff and Student Publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was …