The evolution of longevity in the context of epigenetic regulation and genetic sequence evolution

Abstract

Modern-day humans enjoy an elongated lifespan relative to chimpanzees, even when accounting for environmental factors such as healthcare. This suggests that genetic changes to the biological processes underlying longevity have taken place over the course of human evolution, changes resultant from the forces of natural selection. The goal of this dissertation is to explore the potential means by which these forces of natural selection may operate to shape the human genome, and the implications of genetic changes for the manifestation of ageing phenotypes – in particular, focusing on the incidence of late-onset diseases such as osteoarthritis. Over three data chapters, I will approach this goal in several ways: (1) considering the role for selection acting on development of a derived human trait in influencing the genetic risk for development of late-onset disease, (2) how shifts in epigenetic regulation over the course of development and aging influence the sequence properties and disease associations of genetic variants, and (3) how selection operating across long-lived species may act at the protein-coding level to alter the activity and function of aging-associated proteins.

In the second chapter, I characterize the regulatory landscape of early knee development in mouse and human fetal tissues and consider the role that modifications to regulatory elements may have not only in the development of the knee, but in the potential for far-reaching consequences on knee disease later in life. Through my analyses, I develop an evolutionary model to describe the relationship between development, natural selection, and heritable risk for osteoarthritis incidence later in life. Ancient directional, and subsequent purifying, selection acts on developing knee regulatory regions, establishing and maintaining the derived human knee configuration; this imposes strong functional sequence constraint. More recently, genetic variants arising in these constrained regions via the effects of antagonistic pleiotropy or random genetic drift contribute to a ‘violation of constraint’. This violation can lead to slight changes to knee morphology which may eventually contribute to knee dysfunction in late-life. Evidence in support of this model is established through the demonstration of changes to knee morphology, and incidence of spontaneous osteoarthritis, via functional experiments within the GDF5 locus, and the finding that human osteoarthritis patients have elevated mutational load within these constrained knee regulatory regions relative to background populations.

In the third chapter I consider the interactions between developmental and aging processes more broadly, focusing on shifts in epigenetic regulation occurring across tissues as they transition from fetal to adult forms, and subsequently mature from a young-adult to old-adult state. I find that epigenetic trends occurring over development are continued across ageing, and that the genetic sequences subject to these trends have markedly divergent sequence properties depending on their directionality – suggesting that evolutionary pressures and regulatory activities act in a context-dependent manner. Furthermore, these sequences also diverge in their associations with heritable risk for late-onset diseases. I develop an evolutionary model in which sequences most epigenetically active in early adulthood have the strongest association with heritable risk for late-onset disease, while the behaviour of sequences most active during early development or far later in life suggest limitations to previously established evolutionary models of aging.

In the fourth chapter I consider the potential for natural selection favouring longevity to act at the level of protein-sequence changes. Building upon previous studies, which take a cross-species approach to identifying amino acid substitutions which stratify across long/short-lived organisms, I explore the nature of these sequence changes in terms of their potential effects on protein structures and functions, as well as their distribution across the proteome. I find that these amino acid substitutions are over-represented in protein complexes, and in particular the interfaces between interacting proteins. I go on to develop an evolutionary model in which natural selection favouring longevity may act at the level of complex formation, rather than modifying the catalytic activities of proteins themselves, so as to avoid the prohibitive sequence constraints imposed by pleiotropic effects.

Overall, this thesis establishes three evolutionary models to describe the results of findings made throughout the three data chapters, and in the discussion of the thesis we integrate these three models into a more general framework. These models are not mutually exclusive and instead may be complementary in explaining different aspects of the broader evolutionary program underlying the extension of lifespan along the human lineage.