Functional Analysis of Programmed Genome Rearrangement

University Of Kentucky, Lexington KY

Investigators

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Abstract

My laboratory’s research interests are focused on understanding how changes in genome sequence, structure, and function arise: both in the context of changes that accumulate over deep evolutionary time and in the context of changes that occur during the development of cell lineages. An individual’s genome provides a complete set of instructions for completing development, regulating physiology and passing heritable information to the next generation. These instructions are encoded in the linear sequence of DNA molecules and are modulated by epigenetic modifications in the context of higher-order structures. Alterations at any scale can severely impact an individual’s health or ability to reproduce. It is therefore not surprising that life has evolved a variety of molecular pathways that contribute to the maintenance of genome integrity. Studying these diverse mechanisms can provide critical comparative perspective on the cellular, molecular and evolutionary underpinnings of human genome biology and has the potential to reveal new approaches to modulating related pathways in human. Following this philosophy, my lab has sought to understand the functional and evolutionary mechanisms that underlie the remarkable diversity of genome biologies that exist among deep vertebrate lineages. This work takes advantage of the deep evolutionary history of key vertebrate groups (including lamprey, hagfish and salamander) and exceptional aspects of their genome biologies (e.g. programmed DNA loss and reprogramming during development/regeneration) to gain new inroads toward understanding vertebrate genome biology. Our recent work has largely focused on dissecting the causes and consequences of programmed genome rearrangement (PGR) in the sea lamprey (Petromyzon marinus). In lampreys, PGR involves changes in the physical structure (and content) of the genome that occur in a highly predictable and programmatic manner during early development. These changes result in the reproducible loss of a specific subset of genes from all somatic cell lineages. In total, ~20% of the lamprey’s genome is eliminated from somatic cells and retained only by germ cells. Recent progress in this line of research has substantially improved our understanding of the structure of eliminated chromosomes, allowed us to trace the origins and evolution of eliminated genes, provided a more integrative understanding of PGR in the context of early embryonic reprogramming, and identified cellular/developmental pathways that contribute to later stages of PGR. However, the pathways that achieve initial targeting of sequences for elimination and their differential behavior during cell division remain elusive. Proposed studies aim to further this line of research address several outstanding challenges with respect to PGR. These include identification of the pathways that that mediate 1) the targeting of sequences for elimination, 2) the differential migration of eliminated chromatin, and 3) the stable packaging of eliminated DNA. In addition, our recent work has highlighted the necessity of 4) resolving how PGR integrates with other mechanisms of embryonic reprogramming that direct the early development of germline and soma.