Genetics and Genomics Commons^™

Identifying Environmental And Genetic Risk Factors Of Diseases In Case-Control Studies, Siting Li

Dartmouth College Ph.D Dissertations

In response to the increasing efforts in disease prevention and treatment, this thesis applies statistical methods to investigate environmental and genetic risk factors associated with two diseases: bladder cancer and amyotrophic lateral sclerosis (ALS). For bladder cancer, we investigated the association between toenail metal mixture and bladder cancer risk, along with gene expression levels associated with bladder cancer risk. For ALS, our investigation involves identifying genetic variants and gene expression levels associated with ALS risk and exploring gene-smoking interactions linked to ALS risk.

In chapter two, we developed an adaptive-mixture-categorization (AMC)-based g-computation method combining g-computation with optimized exposure categorization. We …

Role Of Non-Chromosomal Birth Defects On The Risk Of Developing Childhood Hodgkin Lymphoma: A Children’S Oncology Group Study, Erin C Peckham-Gregory, Lucas Maschietto Boff, Jeremy M Schraw, Logan G Spector, Amy M Linabery, Erik B Erhardt, Karina B Ribeiro, Carl E Allen, Michael E Scheurer, Philip J Lupo

Faculty, Staff and Students Publications

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk.

Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including …

Genetic Drivers Of Heterogeneity In Type 2 Diabetes Pathophysiology, Ken Suzuki, Konstantinos Hatzikotoulas, Lorraine Southam, Henry J Taylor, Xianyong Yin, Kim M Lorenz, Ravi Mandla, Alicia Huerta-Chagoya, Giorgio E M Melloni, Stavroula Kanoni, Nigel W Rayner, Ozvan Bocher, Ana Luiza Arruda, Kyuto Sonehara, Shinichi Namba, Simon S K Lee, Michael H Preuss, Lauren E Petty, Philip Schroeder, Brett Vanderwerff, Mart Kals, Fiona Bragg, Kuang Lin, Xiuqing Guo, Weihua Zhang, Jie Yao, Young Jin Kim, Mariaelisa Graff, Fumihiko Takeuchi, Jana Nano, Amel Lamri, Masahiro Nakatochi, Sanghoon Moon, Robert A Scott, James P Cook, Jung-Jin Lee, Ian Pan, Daniel Taliun, Esteban J Parra, Jin-Fang Chai, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Gudmar Thorleifsson, Niels Grarup, Tamar Sofer, Matthias Wuttke, Chloé Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Soo-Heon Kwak, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Suraj S Nongmaithem, Raymond Noordam, Victor J Y Lim, Claudia H T Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Jennifer A Brody, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, K Alaine Broadaway, Alice Williamson, Zoha Kamali, Jinrui Cui, Manonanthini Thangam, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Tarunveer S Ahluwalia, Sonia S Anand, Alain Bertoni, Jette Bork-Jensen, Ivan Brandslund, Thomas A Buchanan, Charles F Burant, Adam S Butterworth, Mickaël Canouil, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, John Danesh, Swapan K Das, H Janaka De Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Penny Gordon-Larsen, Myron Gross, Lindsay A Guare, Sophie Hackinger, Liisa Hakaste, Sohee Han, Andrew T Hattersley, Christian Herder, Momoko Horikoshi, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Torben Jørgensen, Frederick K Kamanu, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Kyung Min Lee, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Julie A Lynch, Valeriya Lyssenko, Shiro Maeda, Vasiliki Mamakou, Sohail Rafik Mansuri, Koichi Matsuda, Thomas Meitinger, Olle Melander, Andres Metspalu, Huan Mo, Andrew D Morris, Filipe A Moura, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Snehal Patil, Pei Pei, Mark A Pereira, Annette Peters, Fraser J Pirie, Hannah G Polikowsky, Bianca Porneala, Gauri Prasad, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Kevin Sandow, Alagu Sankareswaran, Naveed Sattar, Sebastian Schönherr, Mohammad Shahriar, Botong Shen, Jinxiu Shi, Dong Mun Shin, Nobuhiro Shojima, Jennifer A Smith, Wing Yee So, Alena Stančáková, Valgerdur Steinthorsdottir, Adrienne M Stilp, Konstantin Strauch, Kent D Taylor, Barbara Thorand, Unnur Thorsteinsdottir, Brian Tomlinson, Tam C Tran, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M Van Dam, Jan B Van Klinken, Rohit Varma, Niels Wacher-Rodarte, Eleanor Wheeler, Ananda R Wickremasinghe, Ko Willems Van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Kenichi Yamamoto, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Matthew Zawistowski, Liang Zhang, Wei Zheng, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Myriam Fornage, Craig L Hanis, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Mitsuhiro Yokota, Sharon L R Kardia, Patricia A Peyser, James S Pankow, James C Engert, Amélie Bonnefond, Philippe Froguel, James G Wilson, Wayne H H Sheu, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald C W Ma, Tien-Yin Wong, Dennis O Mook-Kanamori, Tiinamaija Tuomi, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Yii-Der Ida Chen, Stephen S Rich, Roberta Mckean-Cowdin, Harald Grallert, Ching-Yu Cheng, Mohsen Ghanbari, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Donald W Bowden, Colin N A Palmer, Jaspal S Kooner, Charles Kooperberg, Simin Liu, Kari E North, Danish Saleheen, Torben Hansen, Oluf Pedersen, Nicholas J Wareham, Juyoung Lee, Bong-Jo Kim, Iona Y Millwood, Robin G Walters, Kari Stefansson, Emma Ahlqvist, Mark O Goodarzi, Karen L Mohlke, Claudia Langenberg, Christopher A Haiman, Ruth J F Loos, Jose C Florez, Daniel J Rader, Marylyn D Ritchie, Sebastian Zöllner, Reedik Mägi, Nicholas A Marston, Christian T Ruff, David A Van Heel, Sarah Finer, Joshua C Denny, Toshimasa Yamauchi, Takashi Kadowaki, John C Chambers, Maggie C Y Ng, Xueling Sim, Jennifer E Below, Philip S Tsao, Kyong-Mi Chang, Mark I Mccarthy, James B Meigs, Anubha Mahajan, Cassandra N Spracklen, Josep M Mercader, Michael Boehnke, Jerome I Rotter, Marijana Vujkovic, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Student Publications

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Bi-Allelic Variants In Celsr3 Are Implicated In Central Nervous System And Urinary Tract Anomalies, Jil D Stegmann, Jeshurun C Kalanithy, Gabriel C Dworschak, Nina Ishorst, Enrico Mingardo, Filipa M Lopes, Yee Mang Ho, Phillip Grote, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Steve Seltzsam, Shirlee Shril, Friedhelm Hildebrandt, Felix Boschann, André Heinen, Angad Jolly, Katherine Myers, Kim Mcbride, Mir Reza Bekheirnia, Nasim Bekheirnia, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Annalaura Torella, Tudp Consortium, Michele Pinelli, Valeria Capra, Andrea Accogli, Silvia Maitz, Alice Spano, Rory J Olson, Eric W Klee, Brendan C Lanpher, Se Song Jang, Jong-Hee Chae, Philipp Steinbauer, Dietmar Rieder, Andreas R Janecke, Julia Vodopiutz, Ida Vogel, Jenny Blechingberg, Jennifer L Cohen, Kacie Riley, Victoria Klee, Laurence E Walsh, Matthias Begemann, Miriam Elbracht, Thomas Eggermann, Arzu Stoppe, Kyra Stuurman, Marjon Van Slegtenhorst, Tahsin Stefan Barakat, Maureen S Mulhern, Tristan T Sands, Cheryl Cytrynbaum, Rosanna Weksberg, Federica Isidori, Tommaso Pippucci, Giulia Severi, Francesca Montanari, Michael C Kruer, Somayeh Bakhtiari, Hossein Darvish, Heiko Reutter, Gregor Hagelueken, Matthias Geyer, Adrian S Woolf, Jennifer E Posey, James R Lupski, Benjamin Odermatt, Alina C Hilger

Faculty, Staff and Students Publications

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an …

Novel Avenues Of Tau Research, Claire E Sexton, Gal Bitan, Kathryn R Bowles, Miroslaw Brys, Luc Buée, Mahmoud Bukar Maina, Claire D Clelland, Ann D Cohen, John F Crary, Jeffrey L Dage, Kristophe Diaz, Bess Frost, Li Gan, Alison M Goate, Lawrence I Golbe, Oskar Hansson, Celeste M Karch, Hartmuth C Kolb, Renaud La Joie, Suzee E Lee, Diana Matallana, Bruce L Miller, Chiadi U Onyike, Yakeel T Quiroz, Jessica E Rexach, Jonathan D Rohrer, Amy Rommel, Ghazaleh Sadri-Vakili, Suzanne E Schindler, Julie A Schneider, Reisa A Sperling, Charlotte E Teunissen, Stacie C Weninger, Susan L Worley, Hui Zheng, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years.

METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.

RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.

DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration …

Cub Domains Are Not Required For Ovch2 Function In Sperm Maturation In The Mouse Epididymis, Katarzyna Kent, Kaori Nozawa, Courtney Sutton, Frey Daniel, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Ovochymase 2 (Ovch2) is an epididymis-specific gene that is required for male fertility. While a multitude of reproductive tract-specific genes required for male fertility have been identified, OVCH2 is thus far the first protein required for male fertility that contains Complement C1r/C1s, Uegf, Bmp1 (CUB) domains located in tandem in the C-terminus of the protein. Identifying the functional significance of this unique domain has implications in better understanding fertility and infertility and as a potential contraceptive target.

OBJECTIVE: The goals of these studies were to understand the influence and requirement of OVCH2 CUB domains in the localization and functional …

Biallelic Variants In Slc4a10 Encoding A Sodium-Dependent Bicarbonate Transporter Lead To A Neurodevelopmental Disorder, Reza Maroofian, Mina Zamani, Rauan Kaiyrzhanov, Lutz Liebmann, Ehsan Ghayoor Karimiani, Barbara Vona, Antje K Huebner, Daniel G Calame, Vinod K Misra, Saeid Sadeghian, Reza Azizimalamiri, Mohammad Hasan Mohammadi, Jawaher Zeighami, Sogand Heydaran, Mehran Beiraghi Toosi, Javad Akhondian, Meisam Babaei, Narges Hashemi, Rhonda E Schnur, Mohnish Suri, Jonas Setzke, Matias Wagner, Theresa Brunet, Christopher M Grochowski, Lisa Emrick, Wendy K Chung, Ute A Hellmich, Miriam Schmidts, James R Lupski, Hamid Galehdari, Mariasavina Severino, Henry Houlden, Christian A Hübner

Faculty, Staff and Students Publications

PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness.

METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles.

RESULTS: The families harbor 8 segregating ultra-rare biallelic SLC4A10 …

Foxp1 Haploinsufficiency Contributes To The Development Of Congenital Diaphragmatic Hernia, Katherine E Pendleton, Andres Hernandez-Garcia, Jennifer M Lyu, Ian M Campbell, Chad A Shaw, Julie Vogt, Frances A High, Patricia K Donahoe, Wendy K Chung, Daryl A Scott

Faculty, Staff and Students Publications

FOXP1 encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of FOXP1 is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous FOXP1 variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias. In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion. Based on this deletion, and deletions …

Tex46 Knockout Male Mice Are Sterile Secondary To Sperm Head Malformations And Failure To Penetrate Through The Zona Pellucida, Yoshitaka Fujihara, Haruhiko Miyata, Ferheen Abbasi, Tamara Larasati, Kaori Nozawa, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. It is assumed that sperm head shape is important for sperm-zona pellucida (ZP) penetration but research has yet to elucidate why. We generated testis expressed 46 (Tex46) knockout mice to investigate the essential roles of TEX46 in mammalian reproduction. We used RT-PCR to demonstrate that Tex46 was expressed exclusively in the male reproductive tract in mice and humans. We created Tex46−/− mice using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system and analyzed their fertility. Tex46 null spermatozoa …

Hmzdupfinder: A Robust Computational Approach For Detecting Intragenic Homozygous Duplications From Exome Sequencing Data, Haowei Du, Zain Dardas, Angad Jolly, Christopher M Grochowski, Shalini N Jhangiani, He Li, Donna Muzny, Jawid M Fatih, Gozde Yesil, Nursel H Elçioglu, Alper Gezdirici, Dana Marafi, Davut Pehlivan, Daniel G Calame, Claudia M B Carvalho, Jennifer E Posey, Tomasz Gambin, Zeynep Coban-Akdemir, James R Lupski

Faculty, Staff and Students Publications

Homozygous duplications contribute to genetic disease by altering gene dosage or disrupting gene regulation and can be more deleterious to organismal biology than heterozygous duplications. Intragenic exonic duplications can result in loss-of-function (LoF) or gain-of-function (GoF) alleles that when homozygosed, i.e. brought to homozygous state at a locus by identity by descent or state, could potentially result in autosomal recessive (AR) rare disease traits. However, the detection and functional interpretation of homozygous duplications from exome sequencing data remains a challenge. We developed a framework algorithm, HMZDupFinder, that is designed to detect exonic homozygous duplications from exome sequencing (ES) data. The …

Loss Of The Endoplasmic Reticulum Protein Tmem208 Affects Cell Polarity, Development, And Viability, Debdeep Dutta, Oguz Kanca, Rishi V Shridharan, Paul C Marcogliese, Benjamin Steger, Marie Morimoto, F Graeme Frost, Ellen Macnamara, Michael F Wangler, Shinya Yamamoto, Andreas Jenny, David Adams, May C Malicdan, Hugo J Bellen

Faculty, Staff and Students Publications

Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog

African Swine Fever Virus Early Protein Pi73r Suppresses The Type-I Ifn Promoter Activities, Danh C. Lai, Jayeshbhai Chaudhari, Hiep L.X. Vu

Department of Animal Science: Faculty Publications

African swine fever virus is known to suppress type-I interferon (IFN) responses. The main objective of this study was to screen early-expressed viral genes for their ability to suppress IFN production. Out of 16 early genes examined, I73R exhibited robust suppression of cGAS-STING-induced IFN-β promoter activities, impeding the function of both IRF3 and NF-κB transcription factors. As a result, I73R obstructed IRF3 nuclear translocation following the treatment of cells with poly(dA:dT), a strong inducer of the cGAS-STING signaling pathway. Although the I73R protein exhibits structural homology with the Zα domain binding to the left-handed helical form of DNA known as …

Current Strategies For Increasing Knock-In Efficiency In Crispr/Cas9-Based Approaches, Andrés Felipe Leal, Angelica María Herreno-Pachón, Eliana Benincore-Flórez, Amali Karunathilaka, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Since its discovery in 2012, the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) system has supposed a promising panorama for developing novel and highly precise genome editing-based gene therapy (GT) alternatives, leading to overcoming the challenges associated with classical GT. Classical GT aims to deliver transgenes to the cells via their random integration in the genome or episomal persistence into the nucleus through lentivirus (LV) or adeno-associated virus (AAV), respectively. Although high transgene expression efficiency is achieved by using either LV or AAV, their nature can result in severe side effects in humans. For instance, …

Inhibition Of Csf1r And Kit With Pexidartinib Reduces Inflammatory Signaling And Cell Viability In Endometriosis, Timothy N Dunn, Dominique I Cope, Suni Tang, Tirupataiah Sirupangi, Sydney E Parks, Zian Liao, Fei Yuan, Chad J Creighton, Ramya P Masand, Linda Alpuing Radilla, Xiaoming Guan, Laura Detti, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved …

The Impact Of The Turkish Population Variome On The Genomic Architecture Of Rare Disease Traits, Zeynep Coban-Akdemir, Xiaofei Song, Francisco C Ceballos, Davut Pehlivan, Ender Karaca, Yavuz Bayram, Tadahiro Mitani, Tomasz Gambin, Tugce Bozkurt-Yozgatli, Shalini N Jhangiani, Donna M Muzny, Richard A Lewis, Pengfei Liu, Eric Boerwinkle, Ada Hamosh, Richard A Gibbs, V Reid Sutton, Nara Sobreira, Claudia M B Carvalho, Chad A Shaw, Jennifer E Posey, David Valle, James R Lupski

Faculty, Staff and Student Publications

PURPOSE: The variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated for insights on the genomic architecture of disease.

METHODS: We generated and analyzed a database of variants derived from exome sequencing data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits and 643 unaffected relatives.

RESULTS: Using uniform manifold approximation and projection, we showed that the TK genomes are more similar to those of Europeans and consist of 2 main subpopulations: clusters 1 and 2 (

CONCLUSION: Our findings support the notion that …

Relationship Of Tissue Dimensions And Three Captive Bolt Application Sites On Cadaver Heads From Mature Swine (Sus Scrofa Domesticus) < 200 Kg Body-Weight, Karly N. Anderson, Ashlynn A. Kirk, Jennifer Berger, Arquimides A. Reyes, Ruth Woiwode, Perle E. Zhitnitskiy, Kurt D. Vogel

Department of Animal Science: Faculty Publications

Penetrating captive bolt (PCB) is a common method of euthanasia for swine but has not been evaluated for mature swine < 200 kg body weight (BW). The objectives were to determine tissue depth, brain contact plane, and visible brain tissue damage (brain damage[BD]) for the common FRONTAL (F) and alternative TEMPORAL (T) and BEHIND EAR (BE) placements for PCB use on sows and boars weighing < 200 kg. Cadaver heads were obtained from 30 sows and 30 boars (estimated BW, mean ± SD; sows: 165.8 ± 22.4 kg; boars: 173.6 ± 21.4 kg) from a slaughter establishment after electrical stunning and exsanguination. Heads were cooled at 2 to 4 °C for approximately 64 h. A Jarvis PAS-Type P 0.25R PCB with a Long Stunning Rod Nosepiece Assembly and a 3.5 GR power load was used for all PCB applications at the following placements: F–3.5 cm superior to the optic orbits at midline, T–at the depression posterior to the lateral canthus of the eye within the plane between the lateral canthus and the base of the ear, or BE–directly caudal to the pinna of the ear on the same plane as the eyes and targeting the middle of the opposite eye. For sows, the bolt path was in the brain for 10/10 (100.0%, 95% CI: 69.2% to 100.0%) F, T, and BE heads. In heads that could reliably be assessed for BD, BD was detected in 10/10 (100.0%, 95% CI: 69.2% to 100.0%) F heads, 9/9 (100.0%, 95% CI: 66.4% to 100.0%) T heads, and 0/10 (0.0%, 95% CI: 0.0% to 30.1%) BE heads. For boars, the bolt path was in the plane of the brain for 8/9 (88.9%, 95% CI: 51.8% to 99.7%) F heads, 9/10 (90.0%, 95% CI: 55.5% to 99.7%) T heads, and 11/11 (100.0%, 95% CI: 71.5% to 100.0%) BE heads. In heads that could reliably be assessed for BD, BD was detected in 8/9 (88.9%, 95% CI: 51.7% to 99.7%) F heads, 7/10 (70.0%, 95% CI: 34.8% to 93.3%) T heads, and 4/11 (36.4%, 95% CI: 10.9% to 69.2%) BE heads. Tissue depth was reported as mean ± SE followed by 95% one-sided upper reference limit (URL). For sows, total tissue thickness differed (P < 0.05) between placements (F: 49.41 ± 2.74 mm, URL: 70.0 mm; T: 62.83 ± 1.83 mm, URL: 76.6 mm; BE: 84.63 ± 3.67 mm; URL: 112.3 mm). Total tissue thickness differed (P < 0.05) between placements for boars (F: 54.73 ± 3.23 mm, URL: 77.6 mm; T: 70.72 ± 3.60 mm, URL: 96.3 mm; BE: 92.81 ± 5.50 mm; URL: 135.3 mm). For swine between 120 and 200 kg BW, the F placement may have the greatest likelihood for successful euthanasia due to the least total tissue thickness and may present less risk for failure than the T and BE placements.

Matrin3 Mediates Differentiation Through Stabilizing Chromatin Loop-Domain Interactions And Yy1 Mediated Enhancer-Promoter Interactions, Tianxin Liu, Qian Zhu, Yan Kai, Trevor Bingham, Stacy Wang, Hye Ji Cha, Stuti Mehta, Thorsten M Schlaeger, Guo-Cheng Yuan, Stuart H Orkin

Faculty, Staff and Students Publications

Although emerging evidence indicates that alterations in proteins within nuclear compartments elicit changes in chromosomal architecture and differentiation, the underlying mechanisms are not well understood. Here we investigate the direct role of the abundant nuclear complex protein Matrin3 (Matr3) in chromatin architecture and development in the context of myogenesis. Using an acute targeted protein degradation platform (dTAG-Matr3), we reveal the dynamics of development-related chromatin reorganization. High-throughput chromosome conformation capture (Hi-C) experiments revealed substantial chromatin loop rearrangements soon after Matr3 depletion. Notably, YY1 binding was detected, accompanied by the emergence of novel YY1-mediated enhancer-promoter loops, which occurred concurrently with changes in …

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 …

Unraveling The Genetic Architecture Of Congenital Vertebral Malformation With Reference To The Developing Spine, Sen Zhao, Hengqiang Zhao, Lina Zhao, Xi Cheng, Zhifa Zheng, Mengfan Wu, Wen Wen, Shengru Wang, Zixiang Zhou, Haibo Xie, Dengfeng Ruan, Qing Li, Xinquan Liu, Chengzhu Ou, Guozhuang Li, Zhengye Zhao, Guilin Chen, Yuchen Niu, Xiangjie Yin, Yuhong Hu, Xiaochen Zhang, Deciphering Disorders Involving Scoliosis And Comorbidities (Disco) Study, Pengfei Liu, Guixing Qiu, Wanlu Liu, Chengtian Zhao, Zhihong Wu, Jianguo Zhang, Nan Wu

Faculty, Staff and Students Publications

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord …