Genetic Structures Commons^™

Predicting The Impact Of Rare Variants On Rna Splicing In Cagi6, Jenny Lord, Carolina Jaramillo Oquendo, Htoo A Wai, Andrew G L Douglas, David J Bunyan, Yaqiong Wang, Zhiqiang Hu, Zishuo Zeng, Daniel Danis, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Yuchen Chang, Richard D Bagnall, Stephen M Mount, Brynja Matthiasardottir, Chiaofeng Lin, Thomas Van Overeem Hansen, Raphael Leman, Alexandra Martins, Claude Houdayer, Sophie Krieger, Constantina Bakolitsa, Yisu Peng, Akash Kamandula, Predrag Radivojac, Diana Baralle

Faculty, Staff and Students Publications

Variants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant's impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact. The performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 56 functionally validated variants. The maximum accuracy achieved was …

Assessing Predictions On Fitness Effects Of Missense Variants In Hmbs In Cagi6, Jing Zhang, Lisa Kinch, Panagiotis Katsonis, Olivier Lichtarge, Milind Jagota, Yun S Song, Yuanfei Sun, Yang Shen, Nurdan Kuru, Onur Dereli, Ogun Adebali, Muttaqi Ahmad Alladin, Debnath Pal, Emidio Capriotti, Maria Paola Turina, Castrense Savojardo, Pier Luigi Martelli, Giulia Babbi, Rita Casadio, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Matsvei Tsishyn, Alexey Strokach, Zhiqiang Hu, Warren Van Loggerenberg, Frederick P Roth, Predrag Radivojac, Steven E Brenner, Qian Cong, Nick V Grishin

Faculty, Staff and Students Publications

This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the …

Genomic Balancing Act: Deciphering Dna Rearrangements In The Complex Chromosomal Aberration Involving 5p152, 2q311, And 18q2132, Zain Dardas, Dana Marafi, Ruizhi Duan, Jawid M Fatih, Omnia F El-Rashidy, Christopher M Grochowski, Claudia M B Carvalho, Shalini N Jhangiani, Weimin Bi, Haowei Du, Richard A Gibbs, Jennifer E Posey, Daniel G Calame, Maha S Zaki, James R Lupski

Faculty, Staff and Students Publications

Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses …

Analysis And Benchmarking Of Small And Large Genomic Variants Across Tandem Repeats, Adam C English, Egor Dolzhenko, Helyaneh Ziaei Jam, Sean K Mckenzie, Nathan D Olson, Wouter De Coster, Jonghun Park, Bida Gu, Justin Wagner, Michael A Eberle, Melissa Gymrek, Mark J P Chaisson, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits and are linked to over 60 disease phenotypes. However, they are often excluded from at-scale studies because of challenges with variant calling and representation, as well as a lack of a genome-wide standard. Here, to promote the development of TR methods, we created a catalog of TR regions and explored TR properties across 86 haplotype-resolved long-read human assemblies. We curated variants from the Genome in a Bottle (GIAB) HG002 individual to create a TR dataset to benchmark existing and future TR analysis methods. We …

Meeting Report: 1st International Conference On Polyploid Giant Cancer Cells-Biology, Clinical Applications, And The Birth Of A New Field In Cancer Research, Tao P Wu, Xiaoran Li, Sujuan Ba, Phil Jones, Donna E Hansel, Jinsong Liu

Faculty, Staff and Students Publications

No abstract provided.

Genomics And Multiomics In The Age Of Precision Medicine, Srinivasan Mani, Seema R Lalani, Mohan Pammi

Faculty, Staff and Students Publications

Precision medicine is a transformative healthcare model that utilizes an understanding of a person's genome, environment, lifestyle, and interplay to deliver customized healthcare. Precision medicine has the potential to improve the health and productivity of the population, enhance patient trust and satisfaction in healthcare, and accrue health cost-benefits both at an individual and population level. Through faster and cost-effective genomics data, next-generation sequencing has provided us the impetus to understand the nuances of complex interactions between genes, diet, and lifestyle that are heterogeneous across the population. The emergence of multiomics technologies, including transcriptomics, proteomics, epigenomics, metabolomics, and microbiomics, has enhanced …

Evaluation Of Enzyme Activity Predictions For Variants Of Unknown Significance In Arylsulfatase A, Shantanu Jain, Marena Trinidad, Thanh Binh Nguyen, Kaiya Jones, Santiago Diaz Neto, Fang Ge, Ailin Glagovsky, Cameron Jones, Giankaleb Moran, Boqi Wang, Kobra Rahimi, Sümeyra Zeynep Çalıcı, Luis R Cedillo, Silvia Berardelli, Buse Özden, Ken Chen, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Sadhna Rana, Swatantra Pradhan, Rajgopal Srinivasan, Rakshanda Sajeed, Dinesh Joshi, Eshel Faraggi, Robert Jernigan, Andrzej Kloczkowski, Jierui Xu, Zigang Song, Selen Özkan, Natàlia Padilla, Xavier De La Cruz, Rocio Acuna-Hidalgo, Andrea Grafmüller, Laura T Jiménez Barrón, Matteo Manfredi, Castrense Savojardo, Giulia Babbi, Pier Luigi Martelli, Rita Casadio, Yuanfei Sun, Shaowen Zhu, Yang Shen, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Daniele Raimondi, Pauline Hermans, Sofia Kwee, Ella Chen, Courtney Astore, Akash Kamandula, Vikas Pejaver, Rashika Ramola, Michelle Velyunskiy, Daniel Zeiberg, Reet Mishra, Teague Sterling, Jennifer L Goldstein, Jose Lugo-Martinez, Sufyan Kazi, Sindy Li, Kinsey Long, Steven E Brenner, Constantina Bakolitsa, Predrag Radivojac, Dean Suhr, Teryn Suhr, Wyatt T Clark

Faculty, Staff and Students Publications

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning …

Assessing The Contribution Of Rare Protein-Coding Germline Variants To Prostate Cancer Risk And Severity In 37,184 Cases, Jonathan Mitchell, Niedzica Camacho, Patrick Shea, Konrad H Stopsack, Vijai Joseph, Oliver S Burren, Ryan S Dhindsa, Abhishek Nag, Jacob E Berchuck, Amanda O'Neill, Ali Abbasi, Anthony W Zoghbi, Jesus Alegre-Díaz, Pablo Kuri-Morales, Jaime Berumen, Roberto Tapia-Conyer, Jonathan Emberson, Jason M Torres, Rory Collins, Quanli Wang, David Goldstein, Athena Matakidou, Carolina Haefliger, Lauren Anderson-Dring, Ruth March, Vaidehi Jobanputra, Brian Dougherty, Keren Carss, Slavé Petrovski, Philip W Kantoff, Kenneth Offit, Lorelei A Mucci, Mark Pomerantz, Margarete A Fabre

Faculty, Staff and Students Publications

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P <  1×10−8), and CHEK2 at the suggestive threshold (P <  2.6×10−6). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75–3.83], …

Rna Methyltransferase Spout1/Cenp-32 Links Mitotic Spindle Organization With The Neurodevelopmental Disorder Spadmiss, Avinash V Dharmadhikari, Maria Alba Abad, Sheraz Khan, Reza Maroofian, Tristan T Sands, Farid Ullah, Itaru Samejima, Yanwen Shen, Martin A Wear, Kiara E Moore, Elena Kondakova, Natalia Mitina, Theres Schaub, Grace K Lee, Christine H Umandap, Sara M Berger, Alejandro D Iglesias, Bernt Popp, Rami Abou Jamra, Heinz Gabriel, Stefan Rentas, Alyssa L Rippert, Christopher Gray, Kosuke Izumi, Laura K Conlin, Daniel C Koboldt, Theresa Mihalic Mosher, Scott E Hickey, Dara V F Albert, Haley Norwood, Amy Feldman Lewanda, Hongzheng Dai, Pengfei Liu, Tadahiro Mitani, Dana Marafi, Hatice Koçak Eker, Davut Pehlivan, Jennifer E Posey, Natalie C Lippa, Natalie Vena, Erin L Heinzen, David B Goldstein, Cyril Mignot, Jean-Madeleine De Sainte Agathe, Nouriya Abbas Al-Sannaa, Mina Zamani, Saeid Sadeghian, Reza Azizimalamiri, Tahere Seifia, Maha S Zaki, Ghada M H Abdel-Salam, Mohamed S Abdel-Hamid, Lama Alabdi, Fowzan Sami Alkuraya, Heba Dawoud, Aya Lofty, Peter Bauer, Giovanni Zifarelli, Erum Afzal, Faisal Zafar, Stephanie Efthymiou, Daniel Gossett, Meghan C Towne, Raey Yeneabat, Belen Perez-Duenas, Ana Cazurro-Gutierrez, Edgard Verdura, Veronica Cantarin-Extremera, Ana Do Vale Marques, Aleksandra Helwak, David Tollervey, Sandeep N Wontakal, Vimla S Aggarwal, Jill A Rosenfeld, Victor Tarabykin, Shinya Ohta, James R Lupski, Henry Houlden, William C Earnshaw, Erica E Davis, A Arockia Jeyaprakash, Jun Liao

Faculty, Staff and Students Publications

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are …

Genetic And Environmental Contribution To Phenotypic Resemblance Between Iranian Couples: Tehran Cardiometabolic And Genetic Study (Tcgs), Parisa Riahi, Amir Hossein Saeidian, Albert Tenesa, Carolyn T Hogan, Michael March, Kamran Guity, Mahmoud Amiri Roudbar, Asieh Zahedi, Maryam Zarkesh, Farideh Neshati, Mehdi Hedayati, Fereidoun Azizi, Hakon Hakonarson, Maryam S Daneshpour, Mahdi Akbarzadeh

Faculty, Staff and Students Publications

Objective: To provide an applied framework for assessing the genetic contribution to assortative mating (AM) using height as a model trait and disclose the trace of certain pieces of evidence of AM in the form of the shared environmental effects from long-term cohabitation on spouses' anthropometric traits and lipid serum levels.

Methods: 2315 genotyped couples were extracted from the Tehran Cardiometabolic Genetic Study (TCGS). Pearson correlation analysis was used to assess the relationship between spouses' height. The GCTA-GREML was used to assess the SNP-based heritability of individual and spousal heights with AM adjustments. We used a recent GWAS meta-analysis of …

Long-Read Sequencing Of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity And Disease Susceptibility, Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Chinese Pangenome Consortium (Cpc), Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan

Faculty, Staff and Students Publications

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could …

Bi-Allelic Kics2 Mutations Impair Kicstor Complex-Mediated Mtorc1 Regulation, Causing Intellectual Disability And Epilepsy, Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack

Faculty, Staff and Students Publications

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Characterizing Features Affecting Local Ancestry Inference Performance In Admixed Populations, Jessica Honorato-Mauer, Nirav N Shah, Adam X Maihofer, Clement C Zai, Sintia Belangero, Caroline M Nievergelt, Marcos Santoro, Elizabeth G Atkinson

Faculty, Staff and Students Publications

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR). Simulating linkage-disequilibrium-informed admixed haplotypes under a variety of 2- and 3-way admixture models, we implemented a standard LAI pipeline, testing the impact of reference panel composition, DNA data type, demography, and …

Dna-Binding Affinity And Specificity Determine The Phenotypic Diversity In Bcl11b-Related Disorders, Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar De La Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Undiagnosed Diseases Network, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel

Faculty, Staff and Students Publications

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Update On Cancer Screening In Children With Syndromes Of Bone Lesions, Hereditary Leiomyomatosis And Renal Cell Carcinoma Syndrome, And Other Rare Syndromes, Orli Michaeli, Sun Young Kim, Sarah G Mitchell, Marjolijn C J Jongmans, Jonathan D Wasserman, Melissa R Perrino, Anirban Das, Suzanne P Macfarland, Sarah R Scollon, Mary-Louise C Greer, Nara Sobreira, Bailey Gallinger, Philip J Lupo, David Malkin, Kami Wolfe Schneider, Kris Ann P Schultz, William D Foulkes, Emma R Woodward, Douglas R Stewart

Faculty, Staff and Students Publications

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline …

Historical Demography And Species Distribution Models Shed Light On Speciation In Primates Of Northeast India, Mihir Trivedi, Kunal Arekar, Shivakumara Manu, Lukas F K Kuderna, Jeffrey Rogers, Kyle Kai-How Farh, Tomas Marques Bonet, Govindhaswamy Umapathy

Faculty, Staff and Students Publications

Past climate change is one of the important factors influencing primate speciation. Populations of various species could have risen or declined in response to these climatic fluctuations. Northeast India harbors a rich diversity of primates, where such fluctuations can be implicated. Recent advances in climate modeling as well as genomic data analysis has paved the way for understanding how species accumulate at a particular geographic region. We utilized these methods to explore the primate diversity in this unique region in relation to past climate change. To ascertain the population level changes, we inferred the demographic history of nine species of …

Unprecedented Female Mutation Bias In The Aye-Aye, A Highly Unusual Lemur From Madagascar, Richard J Wang, Yadira Peña-García, Muthuswamy Raveendran, R Alan Harris, Thuy-Trang Nguyen, Marie-Claude Gingras, Yifan Wu, Lesette Perez, Anne D Yoder, Joe H Simmons, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality-without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascariensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to …

Exome Sequencing In Asian Populations Identifies Low-Frequency And Rare Coding Variation Influencing Parkinson’S Disease Risk, Elaine Gy Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y Ng, Louis Cs Tan, Wee Ling Chng, Tiak Ju Tan, Esther Kl Peh, Ying Swan Ho, Xiao Yin Chen, Erin Yt Lim, Chu Hua Chang, Jonavan J Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Yy Chan, Juei-Jueng Lin, Beom S Jeon, Kyuyoung Song, Clement C Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B Makarious, Cornelis Blauwendraat, Mike A Nalls, Laurie A Robak, Roy N Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo

Faculty, Staff and Students Publications

Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest …