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1 Evolution of Genetic and Gene Regulatory Sex Differences In Evolution of genetic and gene regulatory sex differences in mammals By Sahin Naqvi A.B. Molecular Biology Princeton University, 2012 Submitted to the Department of Biology In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY JUNE 2019 © Sahin Naqvi. All rights reserved. The author hereby grants to MIT permission to reproduce and to distribute publically paper and electronic copies of this thesis document in whole or in part in any medium now known or hereafter created. Signature of author:………………………………………………………………………………… Department of Biology April 4, 2019 Certified by:……………………………………………………………………………………….. David C. Page Professor of Biology Thesis Advisor Accepted by:……………………………………………………………………………………….. Amy E. Keating Professor of Biology Co-Chair, Biology Graduate Committee 1 2 Evolution of genetic and gene regulatory sex differences in mammals by Sahin Naqvi Submitted to the Department of Biology on April 4, 2019 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology Abstract Sex differences are widespread in mammalian health, development, and disease. Ultimately, sex differences derive from the sex chromosomes; males are XY and females are XX, but the mammalian X and Y chromosomes evolved from an ancestral pair of ordinary autosomes. These genetic sex differences, through a variety of regulatory mechanisms, give rise to sex differences in gene expression across the genome, which in turn result in the observed phenotypic differences between males and females. In this thesis, I take an evolutionary perspective on this pathway, using computational analysis of both publically available and newly generated data to provide insight into the molecular basis of mammalian sex differences. First, to better understand the selective forces underlying the evolution of the amniote sex chromosomes from ordinary autosomes, we reconstructed gene-by-gene dosage sensitivities on the ancestral autosomes through phylogenetic analysis of microRNA target sites, finding that preexisting heterogeneities in dosage sensitivity shaped the evolution of both the mammalian XY and avian ZW sex chromosomes. Second, to understand the extent to which genome-wide sex differences are conserved across both tissues and species, we conducted a five-species, twelve- tissue survey of sex differences in gene expression, finding that most sex bias in gene expression has arisen during since the last common ancestor of boroeutherian mammals, and that evolutionary gains or losses of regulation by sex-biased transcription factors likely drove a significant fraction of lineage-specific changes in sex bias. Third, we used the results of this survey to show that conserved sex bias in gene expression contributes to the male bias in height and body size observed in a range of mammalian species, including humans. Together, these studies suggest that dosage sensitivity played a key role in both the evolution of mammalian sex chromosomes and their contribution to phenotypic sex differences, as well revealing the widespread nature and phenotypic impact of sex differences in gene expression across the genome. Thesis Supervisor: David C. Page Title: Professor of Biology 3 Acknowledgements I would like to thank my thesis advisor, David Page, for his support and mentorship. I am fortunate to have chosen a thesis advisor who constantly has my best interests in mind. While I am sure my interactions with David over the years have impacted me in ways that I don’t even realize yet, working with him has fundamentally shaped how I communicate scientific ideas and has shown me that one must take risks to continue moving forwards. He has also instilled in me a deep appreciation for the use of the comma. My thesis committee members, Dave Bartel and Peter Reddien, have provided me with invaluable advice, both related to science and beyond, throughout graduate school. I thank both present and past members of the Bartel lab for tolerating many unannounced visits and fielding my relatively uninformed questions about microRNAs (Vikram Agarwal, Sean McGeary, Jeff Morgan, Stephen Eichhorn), and for being valuable collaborators in a more official capacity (Kathy Lin). A special thanks to my outside committee member Christine Diesteche, who very graciously agreed to travel to Boston from Seattle to attend my thesis defense. This work would have not been possible without the assistance, advice, and friendship of the members of the Page lab, both past and present. I am grateful to Susan Tocio and Jorge Adarme, who do an incredible job of keeping the lab running efficiently. Between the two of them, Winston Bellott and Alex Godfrey have likely read every formal document I have written during my time in the lab. As both unofficial and official collaborators, their generosity with their time, critical feedback and creative ideas has contributed immensely to this work. Jenn Hughes has played an invaluable role in shaping the direction of the lab and helping with strategic and logistical planning of projects and publications. I thank Pete Nicholls for being the only other lab member to understand cricket, and for also introducing me to the intricacies of early germ cell development through a very enjoyable collaboration. Mary Goodheart volunteered many hours to ensure that my incompetency in handling rodents did not derail my thesis work too drastically. I would also like to thank the entire Sex Differences Subgroup for providing a stimulating intellectual environment and a diverse set of perspectives for me to learn from. I couldn’t have asked for a better group of friends, both at and outside of MIT, who have offered both support and distraction from graduate school when needed. I would like to thank Leah Dodell for bringing the best out in me. Above all, I thank my family for constantly believing in my abilities, even when I doubted them the most, and for always encouraging me to pursue my interests, no matter where they might take me. I thank my parents for all that they have sacrificed for my education, and my sisters for making sure that I never took myself too seriously. 4 Table of contents Abstract .......................................................................................................................................... 3 Acknowledgements ....................................................................................................................... 4 Chapter 1. Introduction ............................................................................................................... 7 Part 1. The evolution of the mammalian and avian sex chromosomes ....................................... 9 The sex-specific chromosome as a degenerating autosome ................................................. 10 Dosage compensation of the sex-shared chromosome ......................................................... 14 Exceptions to the rules: Gene survival on the sex-specific chromosome a lack of dosage compensation on the sex-shared chromosome ...................................................................... 19 Part 2. Phenotypic and physiological sex differences in mammals .......................................... 23 Reproductive tract ................................................................................................................. 23 Height and body size ............................................................................................................. 24 Immune system ...................................................................................................................... 26 Cardiovascular system .......................................................................................................... 27 Metabolism ............................................................................................................................ 28 Part 3. Sex-biased gene expression as an intermediary from sex chromosomes to phenotypic sex differences .......................................................................................................................... 30 Prior studies of sex bias in autosomal gene expression ....................................................... 33 Upstream causes of sex-biased gene expression: sexually dimorphic hormonal environments ......................................................................................................................... 36 Upstream causes of sex-biased gene expression: sex chromosome complement outside the reproductive tract .................................................................................................................. 41 Linking sex-biased gene expression to phenotypic sex differences ...................................... 44 Evolutionary causes of sex-biased gene expression: sexual conflict and sexually antagonistic selection ............................................................................................................ 46 Part 4. Concluding remarks ....................................................................................................... 47 References ................................................................................................................................. 49 Chapter 2. Conserved microRNA targeting reveals preexisting heterogeneities in dosage sensitivity that shaped amniote sex chromosome evolution .................................................... 64 Summary ..................................................................................................................................
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