Mechanisms and Phenotypic Consequences of Structural Genomic Variation

Structural genomic variation has only recently come into focus as a major source of genetic diversity in
humans, and in biology in general. Despite its critical importance, we still have a very limited understanding of
the processes that cause the structure of genomes to change over time, and of the consequences of these
large-scale changes to living organisms. Over the last four years of MIRA support, my laboratory has been
using two parallel and integrated approaches to study this problem, taking advantage of the unique research
tools available in the budding yeast model system. Our work has been fruitful. We have significantly advanced
the boundaries of our research field, while also contributing to the development of a new generation of
rigorously trained, creative young scientists. In the next funding cycle (1), we will continue to investigate the
forces that cause chromosomes to break, and the cellular mechanisms that are responsible for preventing,
surveying, and repairing this damage. To do so, we will use custom and highly sensitive cell-based assays to
measure the rate of gene copy number variation (CNV), Loss-of-Heterozygosity (LOH), and whole
chromosome gains and losses (aneuploidy), both in mitotic and meiotic cells. We will also deploy advanced
genomic analysis tools to characterize the associated structural changes. In addition, we will continue to
expand on a brand-new investigation front we opened through work carried out during the current funding
cycle. Specifically, we recently reported on a new form of structural mutagenesis (systemic genomic instability,
SGI), through which cells can acquire multiple rearrangements simultaneously, and thus radically reconfiguring
their genomes. In addition (2), we will also investigate the phenotypic consequences associated with
chromosomal rearrangements in a diploid yeast strain that shares many of the properties that characterize the
complex human genome. These include a high degree of heterozygosity, structural chromosomal
polymorphisms between homologs, gene redundancy, and CNVs; all the while retaining the small and
manageable genome of S. cerevisiae. I strongly believe that by opening these new and integrated avenues of
investigation, in close partnership with the talented junior colleagues I mentor in my laboratory, we will
contribute much needed insight into how structural genomic variation arises and how it affects all aspects of
life, from the evolution of species to human health.

Grant Number: 5R35GM119788-10
NIH Institute/Center: NIH
Principal Investigator: Juan Lucas Argueso