A University of Oregon-initiated project using tiny roundworms has identified defects tied to infertility that result when too much DNA is exchanged in the formation of sperm and eggs.
The fundamental research, detailed in a paper placed online in PLOS Genetics, probed what happens when too many DNA exchanges, called crossover events, between chromosomes get past the normal controls of the molecular machinery that help assure fertility.
Chromosomes in a developing egg, in green, left, struggle to organize properly amid too many crossovers versus normal segregation in the egg to the right (Courtesy of Diana Libuda, University of Oregon)
“Over the past century, research has focused on making sure enough crossovers are made during sperm and egg development,” said Diana Libuda, a professor in the UO’s Department of Biology and Institute of Molecular Biology. “It was known that developing sperm and eggs had ways to make sure that not too many crossovers are made, but it was unclear why.”
When too many of these exchanges occur, the segregation of chromosomes into eggs is flawed. That can lead to a range of defects.
Inaccurate chromosome segregation in humans is associated with Down syndrome and miscarriages. The defects seen in the new research can lead to increased infertility, Libuda said.
She was the principal investigator of the new study, which was done across three labs in a National Institutes of Health-supported project: her own, that of UO colleague Bruce Bowerman and Sadie Wignall at Northwestern University.
The researchers identified two mechanisms that help counteract defects triggered by excess crossover activity in developing eggs and, thus, assist the coordination of the process that helps assure genomic integrity in new generations.
Libuda had reported in the Oct. 9, 2013, issue of Nature the discovery of a mechanism that inhibits the overproduction of crossovers in roundworms. However, she said, at that time it was not possible to study the downstream effects in cases where too many crossovers did occur.
Since then, her lab developed a way to generate extra crossovers on a single chromosome.
That ability led to a collaboration with Wignall, an expert on high-resolution imaging of structures involved in segregation of chromosomes into developing eggs. What Wignall found led Libuda back to Bowerman’s lab to take a look at chromosome segregation in live developing eggs.
“Overall, it was a great joining of scientific strengths to take a multipronged approach to answer this important question,” Libuda said.
The research using the roundworms Caenorhabditis elegans provides fundamental insights that can guide research in other organisms to better understand the mechanisms and, eventually, lead to potential clinical applications, she said.
“The same proteins that we are studying in C. elegans are also in humans,” Libuda said. “In fact, most proteins required for fertility are used across organisms that include yeast, fruit flies, nematodes, zebrafish, mice and humans. Research using these microscopic worms has been shown in numerous contexts to have relevance in human health. “
Source: University of Oregon