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ABSTRACT RAJAB, SARAH, A. S.. an Integrated Metabolomic And ABSTRACT RAJAB, SARAH, A. S.. An Integrated Metabolomic and Transcriptomic Approach for Understanding White Muscle Growth Regulation in Hybrid Striped Bass Aquaculture. (Under the direction of Dr. Harry V. Daniels and Dr. Benjamin J. Reading). Farming of hybrid striped bass (HSB) (striped bass x white bass) is the fourth largest finfish aquaculture industry in the U.S., behind catfish, salmon and tilapia, however several knowledge gaps remain, particularly in regards to the cellular processes that underlie growth performance of these fish. Insight into these processes is critical for improvement of breeding and rearing methodologies geared towards foodfish production. Here, we describe a novel combinatorial machine learning analysis of transcriptomic and metabolomic data generated from white muscle and liver tissues to identify discrete molecular processes that underlie the regulation of enhanced growth and muscle accretion of HSB. HSB were reared in tanks and ponds according to standard two-phase culture procedures until harvest at market size. Individuals of the top and bottom 10% body size in weight and total length relative to the cohort were sampled (N = 10 fish per group) as representatives of fish that grow good and poorly, respectively. These cutoffs were chosen as they represent a body size that is typically larger and smaller than that desired at market and therefore represent extremes of the distribution. The data were linked to corresponding changes in metrics of growth including body weight, total length, hepatosomatic index, and gonadosomatic index. Transverse sections of white muscle tissue were taken to evaluate differences in muscle growth patterns and revealed that good- growth group fish trended towards hyperplastic growth and that poor-growth group fish had switched to hypertrophic growth. Additionally, muscle and liver samples were subjected to metabolomics analysis and a total of 469 and 464 metabolites, in muscle and liver, respectively were identified and analyzed by decision tree, where 30 metabolites were classified as the top most important growth predictors. As metabolites are the end products of gene and protein activities within the cell, they therefore underlie the physiological response of the animal. A determination of differential gene expression between groups was completed with Illumina-based RNA-Seq data generated from muscle tissue and a total of 72,893 genes were identified and ranked by importance using statistical inference, based on adjusted p-value, and machine learning (Support Vector Machines). Two reduced gene lists, 143 from inferential statistics and 150 from Class SVMAttributeEval machine learning model, were selected as a cutoff for pathway analysis and only eleven genes were found to be shared between the two lists. To ascertain the biological processes that determine size differences in the two groups of fish, Ingenuity Pathway Analysis (IPA) was conducted on the two differentially expressed gene lists and the top 30 metabolites. The IPA results, identified potential candidates and pathways that influence growth performance for guiding future experimental testing and feed design. In particular, pathways such as cell proliferation and cell differentiation, apoptosis, and inflammation may possibly underly the growth performance of the fish. Furthermore, combined with application of genetic improvement technology, manipulation of these pathways may enhance animal growth and body size. These studies combined, for the first time, two powerful approaches (metabolomics and transcriptomics), along with a novel machine learning-based model analysis tool using Support Vector Machines (SVMAttributeEval), to generate an informative list of the most important metabolite and gene biomarkers and their likely integrated pathways associated with HSB growth performance. These approaches, which ten years ago were neither available nor accessible, provide the most practical predictors of growth performance in fish and identify key metabolites and gene transcripts that may be indicators of growth performance. The integrated pathways of these components provide a great insight into the mechanisms of muscle development, which will inform future breeding and nutrition studies to help improve HSB aquaculture production and assure the successful continuation of the industry. © Copyright 2020 Sarah A. S. Rajab All Rights Reserved An Integrated Metabolomic and Transcriptomic Approach for Understanding White Muscle Growth Regulation in Hybrid Striped Bass Aquaculture By Sarah A. S. Rajab A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Zoology Raleigh, North Carolina 2020 APPROVED BY: _____________________________________ _____________________________________ Dr. Harry V. Daniels Dr. Benjamin J. Reading Co-Chair of Advisory Committee Co-Chair of Advisory Committee _______________________________________ _____________________________________ Dr. Peter Ferket Dr. Christopher Ashwell DEDICATION This thesis work is wholeheartedly dedicated to my beloved parents, Ahmad and Batoul, for encouraging my pursuit in sciences from a young age. For loving me unconditionally and whose good examples have taught me to work hard for the things that I aspire to achieve. They have been my source of inspiration and gave me strength when I thought of giving up, and have continuously provided their moral, spiritual, emotional, and finical support. This work is also dedicated to my beloved husband, Yousef. Yousef is also my best friend for being my constant source of support and encouragement during the challenges of graduate school and life. I am thankful that you have always believed in me and I am genuinely grateful for having you in my life. ii BIOGRAPHY Sarah Ahmad Sayed Rajab was born during the year 1984 to Ahmad Rajab and Batoul Haji. She has been passionate for science from a very young age and was mostly fascinated in nature and explicitly in animals. This led her to obtain a zoology degree with a minor in marine sciences from Kuwait University. She was awarded an honor student certificate for two consecutive years 2005-2006 during her undergraduate studies. Throughout her undergraduate career she had the opportunity to be involved in variety of different research projects all which were integrated with Kuwait marine environment. From that point onward, Sarah’s passion for the marine environment grow more and she contained to peruse her love for the sea by working during the summer at Lothan Youth Achievement Centre (LOYAC). Shortly after her graduation in 2006, she joined Kuwait Institute for Scientific Research (KISR) as a Research Assistant specializing in fish age determination and stock assessment. During that time, she participated in collaborated projects with The Gulf Cooperation Council (GCC). While there, she mastered several laboratorial techniques such a tissue and bone histology for fish age determination, Principles of Polymerase Chain Reaction (PCR), fish anatomy and classification , image analysis using highly advanced motorized compound, stereo, and scanning electron microscopy. Additionally, she was given the opportunity to attend a stock assessment modeling training course arranged by the International Council for the Exploration of the Sea (ICES) in Copenhagen, Denmark. Also she participated in the world 5th fisheries congress in Yokohama, Japan. iii In KISR, Sarah was granted a scholarship to continue her path in the field. She was awarded a Master Degree in “Applied Marine and Fishers Ecology an Implementation to Marine Protected Areas” at Aberdeen University in Scotland, the United Kingdom. Throughout her time in Scotland, Sarah also worked in Marine Scotland Science (MSS) where she refined her skills in the fish age determination laboratory, until her graduation in 2010. After graduation, Sarah continued working for KISR until August 2014 where she was matriculated to Kuwait University and granted a scholarship to pursue a doctorate degree at the North Carolina State University (NCSU). During her time in NSCU, she was able to work with a number of undergraduate and graduate students and present her research at several national scientific symposia. As of the writing of this dissertation, Sarah currently lives in Raleigh, NC with her Husband Yousef, her Mother Batoul, and her newly born son Mohammed. She has five siblings, two older brothers, Hashem and Mohammed, two older sisters, Saja and Sakeena, and one younger brother, Ibraheem. Sarah’s hobbies include watercolor painting, photography, reading National Geographic, and exploring the world. iv ACKNOWLEDGMENTS First and foremost, praises and thanks to God, the Almighty, for His showers of blessings throughout my research work to complete the research successfully. I offer my sincerest gratitude to my committee advisors, Dr. Benjamin Reading and Dr. Harry Daniels, my mentors, and trusted guides for their unending support and encouragement throughout my Northern Carolina State University experience. Dr. Benjamin Reading nurtured and refined my scientific research talents by encouraging me to be bold and creative, not afraid to “think outside the box.” I will forever be indebted to him for how he enriched my understanding of science, the scientific research process, and the ability to approach problem-solving with precision and clarity. It was a great privilege and honor to work and study under his guidance. I am incredibly
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