Genetics and Genomics Commons^™

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

Student and Faculty 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 …

Rewiring The Sex-Determination Pathway During The Evolution Of Self-Fertility., Yongquan Shen, Shin-Yi Lin, Jonathan Harbin, Richa Amin, Allison Vassalotti, Joseph Romanowski, Emily Schmidt, Alexis Tierney, Ronald E Ellis

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show …

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

Student and Faculty 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 …

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, …

Single-Cell Multiomics Decodes Regulatory Programs For Mouse Secondary Palate Development, Fangfang Yan, Akiko Suzuki, Chihiro Iwaya, Guangsheng Pei, Xian Chen, Hiroki Yoshioka, Meifang Yu, Lukas M Simon, Junichi Iwata, Zhongming Zhao

Student and Faculty Publications

Perturbations in gene regulation during palatogenesis can lead to cleft palate, which is among the most common congenital birth defects. Here, we perform single-cell multiome sequencing and profile chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. We construct five trajectories representing continuous differentiation of cranial neural crest-derived multipotent cells into distinct lineages. By linking open chromatin signals to gene expression changes, we characterize the underlying lineage-determining transcription factors. In silico perturbation analysis identifies transcription factors SHOX2 and MEOX2 as important regulators …

Armc5 Controls The Degradation Of Most Pol Ii Subunits, And Armc5 Mutation Increases Neural Tube Defect Risks In Mice And Humans, Hongyu Luo, Linjiang Lao, Kit Sing Au, Hope Northrup, Xiao He, Diane Forget, Marie-Soleil Gauthier, Benoit Coulombe, Isabelle Bourdeau, Wei Shi, Lucia Gagliardi, Maria Candida Barisson Villares Fragoso, Junzheng Peng, Jiangping Wu

Student and Faculty Publications

BACKGROUND: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).

RESULTS: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized …

Failure To Mate Enhances Investment In Behaviors That May Promote Mating Reward And Impairs The Ability To Cope With Stressors Via A Subpopulation Of Neuropeptide F Receptor Neurons, Julia Ryvkin, Liora Omesi, Yong-Kyu Kim, Mali Levi, Hadar Pozeilov, Lital Barak-Buchris, Bella Agranovich, Ifat Abramovich, Eyal Gottlieb, Avi Jacob, Dick R Nässel, Ulrike Heberlein, Galit Shohat-Ophir

Student and Faculty Publications

Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward …

Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor …

Hite: A Fast And Accurate Dynamic Boundary Adjustment Approach For Full-Length Transposable Element Detection And Annotation, Kang Hu, Peng Ning, Minghua Xu, You Zou, Jianye Chang, Xin Gao, Yaohang Li, Jue Ruan, Bin Hu, Jianxin Wang

Computer Science Faculty Publications

Recent advancements in genome assembly have greatly improved the prospects for comprehensive annotation of Transposable Elements (TEs). However, existing methods for TE annotation using genome assemblies suffer from limited accuracy and robustness, requiring extensive manual editing. In addition, the currently available gold-standard TE databases are not comprehensive, even for extensively studied species, highlighting the critical need for an automated TE detection method to supplement existing repositories. In this study, we introduce HiTE, a fast and accurate dynamic boundary adjustment approach designed to detect full-length TEs. The experimental results demonstrate that HiTE outperforms RepeatModeler2, the state-of-the-art tool, across various species. Furthermore, …