Research Overview

Programmed DNA Elimination

Genome maintenance and stability are essential, and an organism’s genome rarely changes. Genome instability typically leads to inviability and disease. However, examples are known where genome instability through developmentally regulated DNA loss or rearrangements is integral in the biology of the organism. Programmed DNA elimination leads to the loss of specific sequences from chromosomes. DNA elimination in nematodes occurs during differentiation of the somatic lineages early in embryonic development. In the parasitic nematode, Ascaris, we have shown that 15% of the genome is eliminated in the somatic lineages during the 3rd through 5th cleavage (4 to 16 cell stage), while the germline genome remains intact. Specific repetitive and unique sequences (including 1000 genes) are lost during DNA elimination to form the somatic genome. Notably, analysis of DNA elimination is several other parasitic nematodes demonstrates a high fidelity of DNA elimination where the DNA breaks and seqeunces lost are the same in a species. In the three nematode genera examined, repetitive sequences (that differ among all three genera and can constitute as much as 89% of the genome) and 1000-2000 genes (representing 5-10% of all the genes )are eliminated. Analysis of the genes eliminated in these nematodes indicates that they are primarily expressed in the germline and early embryo with a core set of eliminated genes conserved in all these nematodes (35%) expressed during spermatogenesis. Overall, these data suggest that DNA elimination in nematodes is an extreme and irreversible mechanism for silencing a subset of germline and early embryo expressed genes in somatic tissues and contributes to the distinction between the germline and soma.

Studies are now underway to determine

  • What is the mechanism of chromosome breakage? What proteins are involved?
  • How are the breakpoints defined?
  • Given that nematodes have holocentric chromosomes (multiple centromeric/kinetochore complexes), what determines which chromosomal regions are retained and which are lost?
  • Are small RNAs involved in chromatin diminution?
  • Are there discrete epigenetic changes associated with chromosome diminution?
  • Given that chromosome breaks are healed by telomere addition, what recruits telomerase and what factors prevent other repair mechanisms, apoptosis, or cell cycle arrest from initiating?
  • What are the somatic consequences of DNA elimination?

RNA Metabolism in Development

Information on Ascaris as a model for nematode studies


Programmed DNA Elimination

Diminution

Chromatin Diminution in 4-cell Embryo

(chromosomes in red will be eliminated)

Diminution

Early Cell Lineage of Ascaris Illustrating Cells Undergoing Chromatin Diminution

(Red dots mark cells that undergo DNA elimination)

CENP-A

CENP-A Localization During DNA Elimination

WAGO

Argonaute WAGO-2 Localization During DNA Elimination

(red arrows point to DNA that will be eliminated)

denver

This page created and maintained by
Richard E. Davis
Department of Biochemistry and Molecular Genetics
University of Colorado School of Medicine
Aurora, CO 80045

Last updated: September 2017