rDNA and Heterochromatin in the Genome: Experiments in Drosophila and implications for human health
MetadataShow full item record
AbstractGenomic DNA is generally comprised of two types of chromatin: euchromatin, associated with active gene transcription, and heterochromatin, associated with silenced and often repetitive DNA. Heterochromatin comprises not only DNA and histones, but heterochromatin-associated proteins, as well. Heterochromatin silences the genes to which it is associated, and also displays trans regulatory capabilities. Research in Drosophila has been fundamental in demonstrating the trans effects of heterochromatin and characterizing the ways in which it manifests. The Y chromosome in particular has been well-studied, as the chromosome is completely heterochromatic in Drosophila melanogaster. Evidence of its causal role in modifying heterochromatin expansion into white, an eye-color gene, was documented by Dmitri and Pisano in 1989. More recently, Lemos et al showed that polymorphic Y chromosomes can differentially regulate thousands of genes in both males and in XXY females. This dissertation encompasses these and other Y-chromosome effects.
In Chapter 1, I investigate the phenotypic responses, in males and females, to the addition of a free Y chromosome. I utilized attached sex chromosomes (denoted X^X and X^Y) to manipulate these strains so that a free Y chromosome could be stably maintained. I observed that males exhibited few effects of Y-chromosome aneuploidy, but X^X/Y females exhibited increased fitness and fertility compared to X^X/0 females. The X^X-carrying offspring of X^X/Y females, however, exhibited phenotypes mimicking those of bobbed mutants. bobbed phenotypes occur when the ribosomal DNA (rDNA) locus – a repetitive array of the 45S rDNA operon located on the X and Y chromosomes in D. melanogaster – contains fewer than the necessary number of copies to support development. We found that the X^X chromosome loses rDNA copies when maintained with a free Y chromosome. In Chapter 2, I elaborate on these findings, observing that additional strains of X^X/Y females can also produce bobbed X^X offspring. I identify inversion-carrying attached-X chromosomes as prerequisites for the development of the phenotype, as X^X/Y females whose X^X chromosome did not carry inversions showed no adverse responses in F1 X^X offspring. In Chapter 3, I examine gene expression changes at the rDNA-adjacent whitemottled4 locus in response to environmental chemical exposures. I found that multiple chemicals can act as enhancers or suppressors of heterochromatin at the locus, and I focus particularly on responses to cadmium chloride. Finally, in Chapter 4, I review the role of sex chromosomes as potential causes and mediators of human diseases, focusing principally on the potential for X- and Y-linked heterochromatin to modify gene regulation and downstream phenotypes.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:37925664