Genetic Processes Commons^™

Pathogen-Driven Crispr Screens Identify Trex1as A Regulator Of Dna Self-Sensing During Influenza Virus Infection, Cason R King, Yiping Liu, Katherine A Amato, Grace A Schaack, Clayton Mickelson, Autumn E Sanders, Tony Hu, Srishti Gupta, Ryan A Langlois, Judith A Smith, Andrew Mehle

Faculty, Staff and Student Publications

Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the …

Cell-Type-Specific Alternative Polyadenylation Promotes Oncogenic Gene Expression In Non-Small Cell Lung Cancer Progression, Kexin Huang, Yun Zhang, Xiaorui Shi, Zhiqin Yin, Weiling Zhao, Liyu Huang, Fu Wang, Xiaobo Zhou

Faculty, Staff and Student Publications

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and …

A Single Dominant Locus Restricts Retrovirus Replication In Ybr/Ei Mice, Helen A Beilinson, Amanda Sevilleja, Jessica Spring, Fernando Benavides, Vera Beilinson, Nickolas Neokosmidis, Tatyana Golovkina

Faculty, Staff and Student Publications

Differential responses to viral infections are influenced by the genetic makeup of the host. Studies of resistance to retroviruses in human populations are complicated due to the inability to conduct proof-of-principle studies. Inbred mouse lines, which have a range of susceptible phenotypes to retroviruses, are an ideal tool to identify and characterize mechanisms of resistance and define their genetic underpinnings. YBR/Ei mice become infected with Mouse Mammary Tumor Virus, a mucosally transmitted murine retrovirus, but eliminate the virus from their pedigrees. Virus elimination correlates with a lack of virus-specific neonatal oral tolerance, which is a major mechanism for blocking the …

Genetic Control Of Mrna Splicing As A Potential Mechanism For Incomplete Penetrance Of Rare Coding Variants, Jonah Einson, Dafni Glinos, Eric Boerwinkle, Peter Castaldi, Dawood Darbar, Mariza De Andrade, Patrick Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Craig P Hersh, Jill Johnsen, Robert Kaplan, Barbara A Konkle, Charles Kooperberg, Rami Nassir, Ruth J F Loos, Deborah A Meyers, Braxton D Mitchell, Bruce Psaty, Ramachandran S Vasan, Stephen S Rich, Michael Rienstra, Jerome I Rotter, Aabida Saferali, Moore Benjamin Shoemaker, Edwin Silverman, Albert Vernon Smith, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium; Pejman Mohammadi, Pejman Mohammadi, Stephane E Castel, Ivan Iossifov, Tuuli Lappalainen

Faculty, Staff and Student Publications

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce …

Federated Generalized Linear Mixed Models For Collaborative Genome-Wide Association Studies, Wentao Li, Han Chen, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

Federated association testing is a powerful approach to conduct large-scale association studies where sites share intermediate statistics through a central server. There are, however, several standing challenges. Confounding factors like population stratification should be carefully modeled across sites. In addition, it is crucial to consider disease etiology using flexible models to prevent biases. Privacy protections for participants pose another significant challenge. Here, we propose distributed Mixed Effects Genome-wide Association study (dMEGA), a method that enables federated generalized linear mixed model-based association testing across multiple sites without explicitly sharing genotype and phenotype data. dMEGA employs a reference projection to …

Fast Inference Of Genetic Recombination Rates In Biobank Scale Data, Ardalan Naseri, William Yue, Shaojie Zhang, Degui Zhi

Faculty, Staff and Student Publications

Although rates of recombination events across the genome (genetic maps) are fundamental to genetic research, the majority of current studies only use one standard map. There is evidence suggesting population differences in genetic maps, and thus estimating population-specific maps, are of interest. Although the recent availability of biobank-scale data offers such opportunities, current methods are not efficient at leveraging very large sample sizes. The most accurate methods are still linkage disequilibrium (LD)-based methods that are only tractable for a few hundred samples. In this work, we propose a fast and memory-efficient method for estimating genetic maps from population genotyping data. …

Deep Single-Cell Rna-Seq Data Clustering With Graph Prototypical Contrastive Learning, Junseok Lee, Sungwon Kim, Dongmin Hyun, Namkyeong Lee, Yejin Kim, Chanyoung Park

Faculty, Staff and Student Publications

MOTIVATION: Single-cell RNA sequencing enables researchers to study cellular heterogeneity at single-cell level. To this end, identifying cell types of cells with clustering techniques becomes an important task for downstream analysis. However, challenges of scRNA-seq data such as pervasive dropout phenomena hinder obtaining robust clustering outputs. Although existing studies try to alleviate these problems, they fall short of fully leveraging the relationship information and mainly rely on reconstruction-based losses that highly depend on the data quality, which is sometimes noisy.

RESULTS: This work proposes a graph-based prototypical contrastive learning method, named scGPCL. Specifically, scGPCL encodes the cell representations using Graph …

Genome-Wide Association Study Of Lung Adenocarcinoma In East Asia And Comparison With A European Population, Jianxin Shi, Kouya Shiraishi, Jiyeon Choi, Keitaro Matsuo, Tzu-Yu Chen, Juncheng Dai, Rayjean J Hung, Kexin Chen, Xiao-Ou Shu, Young Tae Kim, Maria Teresa Landi, Dongxin Lin, Wei Zheng, Zhihua Yin, Baosen Zhou, Bao Song, Jiucun Wang, Wei Jie Seow, Lei Song, I-Shou Chang, Wei Hu, Li-Hsin Chien, Qiuyin Cai, Yun-Chul Hong, Hee Nam Kim, Yi-Long Wu, Maria Pik Wong, Brian Douglas Richardson, Karen M Funderburk, Shilan Li, Tongwu Zhang, Charles Breeze, Zhaoming Wang, Batel Blechter, Bryan A Bassig, Jin Hee Kim, Demetrius Albanes, Jason Y Y Wong, Min-Ho Shin, Lap Ping Chung, Yang Yang, She-Juan An, Hong Zheng, Yasushi Yatabe, Xu-Chao Zhang, Young-Chul Kim, Neil E Caporaso, Jiang Chang, James Chung Man Ho, Michiaki Kubo, Yataro Daigo, Minsun Song, Yukihide Momozawa, Yoichiro Kamatani, Masashi Kobayashi, Kenichi Okubo, Takayuki Honda, Dean H Hosgood, Hideo Kunitoh, Harsh Patel, Shun-Ichi Watanabe, Yohei Miyagi, Haruhiko Nakayama, Shingo Matsumoto, Hidehito Horinouchi, Masahiro Tsuboi, Ryuji Hamamoto, Koichi Goto, Yuichiro Ohe, Atsushi Takahashi, Akiteru Goto, Yoshihiro Minamiya, Megumi Hara, Yuichiro Nishida, Kenji Takeuchi, Kenji Wakai, Koichi Matsuda, Yoshinori Murakami, Kimihiro Shimizu, Hiroyuki Suzuki, Motonobu Saito, Yoichi Ohtaki, Kazumi Tanaka, Tangchun Wu, Fusheng Wei, Hongji Dai, Mitchell J Machiela, Jian Su, Yeul Hong Kim, In-Jae Oh, Victor Ho Fun Lee, Gee-Chen Chang, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Adeline Seow, Jae Yong Park, Sun-Seog Kweon, Kun-Chieh Chen, Yu-Tang Gao, Biyun Qian, Chen Wu, Daru Lu, Jianjun Liu, Ann G Schwartz, Richard Houlston, Margaret R Spitz, Ivan P Gorlov, Xifeng Wu, Ping Yang, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, Bu-Tian Ji, H-Erich Wichmann, David C Christiani, Gadi Rennert, Susanne Arnold, Paul Brennan, James Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Kjell Grankvist, Mikael Johansson, Angela Cox, Fiona Taylor, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Hyo-Sung Jeon, Shih Sheng Jiang, Jae Sook Sung, Chung-Hsing Chen, Chin-Fu Hsiao, Yoo Jin Jung, Huan Guo, Zhibin Hu, Laurie Burdett, Meredith Yeager, Amy Hutchinson, Belynda Hicks, Jia Liu, Bin Zhu, Sonja I Berndt, Wei Wu, Junwen Wang, Yuqing Li, Jin Eun Choi, Kyong Hwa Park, Sook Whan Sung, Li Liu, Chang Hyun Kang, Wen-Chang Wang, Jun Xu, Peng Guan, Wen Tan, Chong-Jen Yu, Gong Yang, Alan Dart Loon Sihoe, Ying Chen, Yi Young Choi, Jun Suk Kim, Ho-Il Yoon, In Kyu Park, Ping Xu, Qincheng He, Chih-Liang Wang, Hsiao-Han Hung, Roel C H Vermeulen, Iona Cheng, Junjie Wu, Wei-Yen Lim, Fang-Yu Tsai, John K C Chan, Jihua Li, Hongyan Chen, Hsien-Chih Lin, Li Jin, Jie Liu, Norie Sawada, Taiki Yamaji, Kathleen Wyatt, Shengchao A Li, Hongxia Ma, Meng Zhu, Zhehai Wang, Sensen Cheng, Xuelian Li, Yangwu Ren, Ann Chao, Motoki Iwasaki, Junjie Zhu, Gening Jiang, Ke Fei, Guoping Wu, Chih-Yi Chen, Chien-Jen Chen, Pan-Chyr Yang, Jinming Yu, Victoria L Stevens, Joseph F Fraumeni, Nilanjan Chatterjee, Olga Y Gorlova, Chao Agnes Hsiung, Christopher I Amos, Hongbing Shen, Stephen J Chanock, Nathaniel Rothman, Takashi Kohno, Qing Lan

Faculty, Staff and Student Publications

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European …

Mesoporous Silica Nanoparticles As A Gene Delivery Platform For Cancer Therapy, Nisar Ul Khaliq, Juyeon Lee, Joohyeon Kim, Yejin Kim, Sohyeon Yu, Jisu Kim, Sangwoo Kim, Daekyung Sung, Hyungjun Kim

Faculty, Staff and Student Publications

Cancer remains a major global health challenge. Traditional chemotherapy often results in side effects and drug resistance, necessitating the development of alternative treatment strategies such as gene therapy. Mesoporous silica nanoparticles (MSNs) offer many advantages as a gene delivery carrier, including high loading capacity, controlled drug release, and easy surface functionalization. MSNs are biodegradable and biocompatible, making them promising candidates for drug delivery applications. Recent studies demonstrating the use of MSNs for the delivery of therapeutic nucleic acids to cancer cells have been reviewed, along with their potential as a tool for cancer therapy. The major challenges and future interventions …

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A Mcconkey, Marie Zechner, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …

The Potential Regulation Of A-To-I Rna Editing On Genes In Parkinson's Disease, Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD's transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) …

Genomic-Transcriptomic Evolution In Lung Cancer And Metastasis, Carlos Martínez-Ruiz, James R M Black, Clare Puttick, Mark S Hill, Jonas Demeulemeester, Elizabeth Larose Cadieux, Kerstin Thol, Thomas P Jones, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Paulina Prymas, Andrew Rowan, Sophia Ward, Laura Cubitt, Foteini Athanasopoulou, Oriol Pich, Takahiro Karasaki, David A Moore, Roberto Salgado, Emma Colliver, Carla Castignani, Michelle Dietzen, Ariana Huebner, Maise Al Bakir, Miljana Tanić, Thomas B K Watkins, Emilia L Lim, Ali M Al-Rashed, Danny Lang, James Clements, Daniel E Cook, Rachel Rosenthal, Gareth A Wilson, Alexander M Frankell, Sophie De Carné Trécesson, Philip East, Nnennaya Kanu, Kevin Litchfield, Nicolai J Birkbak, Allan Hackshaw, Stephan Beck, Peter Van Loo, Mariam Jamal-Hanjani, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression …

A Multicenter Study Of Clinical Impact Of Variant Of Uncertain Significance Reclassification In Breast, Ovarian And Colorectal Cancer Susceptibility Genes, Sukh Makhnoon, Brooke Levin, Megan Ensinger, Kristin Mattie, Robert J Volk, Zhongming Zhao, Tito Mendoza, Sanjay Shete, Laila Samiian, Generosa Grana, Andrew Grainger, Banu Arun, Brian H Shirts, Susan K Peterson

Faculty, Staff and Student Publications

BACKGROUND: Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences.

METHODS: This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) …

Spatiotemporal View Of Malignant Histogenesis And Macroevolution Via Formation Of Polyploid Giant Cancer Cells, Xiaoran Li, Yanping Zhong, Xudong Zhang, Anil K Sood, Jinsong Liu

Faculty, Staff and Student Publications

To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. The fecundity cells …

The Assembled Genome Of The Stroke-Prone Spontaneously Hypertensive Rat, Theodore S Kalbfleisch, Nahla A Hussien Abouel Ela, Kai Li, Wesley A Brashear, Kelli J Kochan, Andrew E Hillhouse, Yaming Zhu, Isha S Dhande, Eric J Kline, Elizabeth A Hudson, Terence D Murphy, Françoise Thibaud-Nissen, Melissa L Smith, Peter A Doris

Faculty, Staff and Student Publications

BACKGROUND: We report the creation and evaluation of a de novo assembly of the genome of the spontaneously hypertensive rat, the most widely used model of human cardiovascular disease.

METHODS: The genome is assembled from long read sequencing (PacBio HiFi and continuous long read data [CLR]) and scaffolded with long-range structural information obtained from Bionano optical maps and proximity ligation sequencing proximity analysis of the genome. The genome assembly was polished with Illumina short reads. Completeness of the assembly was investigated using Benchmarking Universal Single Copy Orthologs analysis. The genome assembly was also evaluated with the rat reference gene set, …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Janet Van Eersel, Lars M Ittner

Faculty, Staff and Student Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Privacy-Aware Estimation Of Relatedness In Admixed Populations, Su Wang, Miran Kim, Wentao Li, Xiaoqian Jiang, Han Chen, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization.

RESULTS: Here, we present SIGFRIED, which makes …

The Evolving Privacy And Security Concerns For Genomic Data Analysis And Sharing As Observed From The Idash Competition, Tsung-Ting Kuo, Xiaoqian Jiang, Haixu Tang, Xiaofeng Wang, Arif Harmanci, Miran Kim, Kai Post, Diyue Bu, Tyler Bath, Jihoon Kim, Weijie Liu, Hongbo Chen, Lucila Ohno-Machado

Faculty, Staff and Student Publications

Concerns regarding inappropriate leakage of sensitive personal information as well as unauthorized data use are increasing with the growth of genomic data repositories. Therefore, privacy and security of genomic data have become increasingly important and need to be studied. With many proposed protection techniques, their applicability in support of biomedical research should be well understood. For this purpose, we have organized a community effort in the past 8 years through the integrating data for analysis, anonymization and sharing consortium to address this practical challenge. In this article, we summarize our experience from these competitions, report lessons learned from the events …

A Multi-Omics Framework Reveals Strawberry Flavor Genes And Their Regulatory Elements, Zhen Fan, Denise M Tieman, Steven J Knapp, Philipp Zerbe, Randi Famula, Christopher R Barbey, Kevin M Folta, Rodrigo R Amadeu, Manbo Lee, Youngjae Oh, Seonghee Lee, Vance M Whitaker

Faculty, Staff and Student Publications

Flavor is essential to consumer preference of foods and is an increasing focus of plant breeding programs. In fruit crops, identifying genes underlying volatile organic compounds has great promise to accelerate flavor improvement, but polyploidy and heterozygosity in many species have slowed progress. Here we use octoploid cultivated strawberry to demonstrate how genomic heterozygosity, transcriptomic intricacy and fruit metabolomic diversity can be treated as strengths and leveraged to uncover fruit flavor genes and their regulatory elements. Multi-omics datasets were generated including an expression quantitative trait loci map with 196 diverse breeding lines, haplotype-phased genomes of a highly-flavored breeding selection, a …

Complement Component C4 Structural Variation And Quantitative Traits Contribute To Sex-Biased Vulnerability In Systemic Sclerosis, Martin Kerick, Marialbert Acosta-Herrera, Carmen Pilar Simeón-Aznar, José Luis Callejas, Shervin Assassi, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Gisela Orozco, Anne Barton, Ariane L Herrick, Chikashi Terao, Yannick Allanore, Carmen Fonseca, Marta Eugenia Alarcón-Riquelme, Timothy R D J Radstake, Lorenzo Beretta, Christopher P Denton, Maureen D Mayes, Javier Martin

Faculty, Staff and Student Publications

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its …

Svat: Secure Outsourcing Of Variant Annotation And Genotype Aggregation, Miran Kim, Su Wang, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

RESULTS: We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at …

Usp7 Substrates Identified By Proteomics Analysis Reveal The Specificity Of Usp7, Litong Nie, Chao Wang, Xiaoguang Liu, Hongqi Teng, Siting Li, Min Huang, Xu Feng, Guangsheng Pei, Qinglei Hang, Zhongming Zhao, Boyi Gan, Li Ma, Junjie Chen

Faculty, Staff and Student Publications

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of

Nrf1 Association With Auts2-Polycomb Mediates Specific Gene Activation In The Brain, Sanxiong Liu, Kimberly A Aldinger, Chi Vicky Cheng, Takae Kiyama, Mitali Dave, Hanna K Mcnamara, Wukui Zhao, James M Stafford, Nicolas Descostes, Pedro Lee, Stefano G Caraffi, Ivan Ivanovski, Edoardo Errichiello, Christiane Zweier, Orsetta Zuffardi, Michael Schneider, Antigone S Papavasiliou, M Scott Perry, Jennifer Humberson, Megan T Cho, Astrid Weber, Andrew Swale, Tudor C Badea, Chai-An Mao, Livia Garavelli, William B Dobyns, Danny Reinberg

Faculty, Staff and Student Publications

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

Pathway‐Extended Gene Expression Signatures Integrate Novel Biomarkers That Improve Predictions Of Patient Responses To Kinase Inhibitors, Ashis Bagchee‐Clark, Eliseos J. Mucaki, Tyson Whitehead, Peter Rogan

Biochemistry Publications

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi‐gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology‐based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway‐extended SVMs predicted responses in …

Using Active Learning To Build A Foundation For Bioinformatics Training., Stacey E. Wahl Ph.D., Amy L. Olex Ms

Transforming Libraries for Graduate Students

As Health Sciences Libraries evolve, the support they offer graduate students has evolved to incorporate many aspects of the research life cycle. At Tompkins-McCaw Library for the Health Sciences, we have partnered with the Wright Center for Clinical and Translational Research to offer training workshops for graduate students who are interested in using bioinformatics to plan, analyze, or execute scientific experiments. We offer two series: 1) an 8-week, 1-hour per week seminar series providing a general overview of available techniques and 2) a week-long intensive, two hours per session, series on utilizing free databases from the National Center for Biotechnology …

Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

The past two decades have witnessed significant advances in high-throughput ``omics" technologies such as genomics, proteomics, metabolomics, transcriptomics and radiomics. These technologies have enabled simultaneous measurement of the expression levels of tens of thousands of features from individual patient samples and have generated enormous amounts of data that require analysis and interpretation. One specific area of interest has been in studying the relationship between these features and patient outcomes, such as overall and recurrence-free survival, with the goal of developing a predictive ``omics" profile. Large-scale studies often suffer from the presence of a large fraction of censored observations and potential …