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University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. With an updated set of EGs, I characterized the genetic and functional properties of EGs and demonstrated the association between EGs and human diseases. Next I provided evidence for a stronger contribution of EGs to ASD risk, compared to non-essential genes (NEGs). By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, I demonstrated a significantly higher burden of damaging mutations in EGs in ASD probands compared to their non-ASD siblings. Analysis of EGs in the developing brain identified clusters of co-expressed EGs implicated in ASD, among which I proposed a priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Finally, I developed the essentiality burden score (EBS), which captures the burden of rare mutations in EGs as a novel polygenic predictor of individual ASD risk and a useful addition to the current tools for understanding the polygenic architecture of ASD. Overall, I show that large-scale studies of gene function in model organisms and human cell lines provide a powerful approach for prioritization of genes and pathogenic variants identified yb sequencing studies of complex human disease. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Genomics & Computational Biology First Advisor Maja Bucan Keywords Autism spectrum disorder, Essential genes, Mouse knockout, Mutational burden Subject Categories Bioinformatics | Genetics This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2369 ESSENTIAL GENES AND THEIR ROLE IN AUTISM SPECTRUM DISORDER Xiao Ji A DISSERTATION in Genomics and Computational Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation ______________ Maja Bucan, Ph.D., Professor of Genetics Graduate Group Chairperson ______________ Li-San Wang, Ph.D., Associate Professor of Pathology and Laboratory Medicine Dissertation Committee Hakon Hakonarson, M.D., Ph.D., Professor of Pediatrics Christopher D. Brown, Ph.D., Assistant Professor of Genetics Nancy Zhang, Ph.D., Associate Professor of Statistics Santhosh Girirajan, Ph.D., Assistant Professor of Biochemistry & Molecular Biology and Assistant Professor of Anthropology ESSENTIAL GENES AND THEIR ROLE IN AUTISM SPECTRUM DISORDER COPYRIGHT 2017 Xiao Ji This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ ACKNOWLEDGMENT It would not have been possible to complete this dissertation without the support that I received from many people. I would like to express my appreciation and thanks to my advisor Dr. Maja Bucan. Since I joined her lab six years ago as an inexperienced student looking for initial research experiences, she began to take me hand in hand through everything that I needed to learn to be a real scientist. She is always encouraging and supportive during every step I took. It is fortunate for me to have her as my dissertation advisor and mentor. I would like to thank my thesis committee members, Dr. Hakon Hakonarson, Dr. Christopher Brown, Dr. Nancy Zhang and Dr. Santhosh Girirajan for devoting their time for our regular meetings and providing invaluable guidance to the development of this dissertation. Special thanks go to Dr. Christopher Brown for our one-on-one seminar on the history of genome-wide association study, from which I gained in-depth perspective on my dissertation proposal. I would also like to thank Dr. Rachel Kember. During the years in the lab, she was like a co-mentor to me and she was always there whenever I needed help. In addition to all of our discussions in research, she was an excellent English teacher of me. I am grateful to my parents, who encouraged me to pursue a Ph.D. degree and offered me their support without restraint. Finally I thank my wife, Dr. Lu Chen, who has been always together with me through the ups and downs during these years. She also provided important insights into a number of statistical problems in the dissertation. iii ABSTRACT ESSENTIAL GENES AND THEIR ROLE IN AUTISM SPECTRUM DISORDER Xiao Ji Maja Bucan Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific role in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. With an updated set of EGs, I characterized the genetic and functional properties of EGs and demonstrated the association between EGs and human diseases. Next I provided evidence for a stronger contribution of EGs to ASD risk, compared to non-essential genes (NEGs). By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, I demonstrated a significantly higher burden of iv damaging mutations in EGs in ASD probands compared to their non-ASD siblings. Analysis of EGs in the developing brain identified clusters of co-expressed EGs implicated in ASD, among which I proposed a priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Finally, I developed the essentiality burden score (EBS), which captures the burden of rare mutations in EGs as a novel polygenic predictor of individual ASD risk and a useful addition to the current tools for understanding the polygenic architecture of ASD. Overall, I show that large- scale studies of gene function in model organisms and human cell lines provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of complex human disease. v TABLE OF CONTENTS ACKNOWLEDGMENT ........................................................................................................ III ABSTRACT ................................................................................................................................ IV TABLE OF CONTENTS......................................................................................................... VI LIST OF TABLES ..................................................................................................................... X LIST OF ILLUSTRATIONS ................................................................................................. XI CHAPTER 1: INTRODUCTION ........................................................................................... 1 Figures .................................................................................................................................................. 12 Figure 1.1 Distinct mutational spectrums of variants in essential and non-essential genes. ..................... 12 CHAPTER 2: CHARACTERIZATION OF ESSENTIAL
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