Thursday, June 25, 2009

INSIGHTS INTO MALE FERTILITY: NEW RESEARCH SHOWS POTENTIAL FOR A MALE CONTRACEPTIVE

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Researchers have known for more than half a century that sperm is able to fertilize an egg only after it has resided for a period of time in the female reproductive tract. Without this specific interaction with the female body, the sperm is incapable of producing offspring. But until now there was very little understanding of what changes occur within the sperm that suddenly allows it to fertilize an egg.

In the Journal of Proteome Research, Rensselaer Polytechnic Institute Assistant Professor of Chemistry and Chemical Biology Mark Platt reveals the molecular-level changes that occur within sperm after it enters the female reproductive tract. His findings provide important clues into the still-mysterious process of capacitation, the process by which sperm acquire the ability to fertilize an egg, including why some otherwise healthy males might encounter fertility issues. His research may also offer insight required to develop an entirely new contraceptive, even a male version of the birth control pill.

“Much has been done to understand capacitation, but with the tools that we have within the lab we can now identify how specific sites on individual proteins are modified during this process,” said Platt. “With this knowledge we can develop a deeper understanding of the molecular mechanisms required to provide sperm with fertilizing competence.”

“Based upon some of our additional work, a few of these sites appear to be essential to carrying out the process of capacitation,” Platt said.

Phosphorylation can be thought of as a light switch, which can be used to turn on or turn off a step in the chain of reactions, known as a signal transduction cascade, that leads to capacitation. Just like the initial flicking of a light switch quickly moves electricity through the wires to turn on a lamp across the room, phosphorylation provides the initial trigger that moves a cellular signal through the cell that turns “on” its ability to fertilize an egg. According to Platt, by interfering with a just a single site of phosphorylation, scientists could entirely switch off the fertilization process. It is this ability that has the strongest potential for the development of a novel contraceptive.

“If phosphorylation on a particular amino acid is absolutely required for sperm capacitation, a drug could be developed which prevents phosphorylation from occurring at that specific site, thereby preventing the entire capacitation process,” Platt said. This turning off of the phosphorylation switch could then prevent fertilization entirely.

“These applications are currently hypothetical at this point, but the implications for contraceptives resulting from this research are promising,” he said. He noted that there could be several different options that could be developed using this and future research, including a drug for males that specifically targets the individual sites of protein phosphorylation in the developing sperm or a novel spermicide that prevents capacitation from occurring in sperm residing in the female reproductive tract.

In addition, the research provides important insight into male infertility. “Certain types of male infertility could be caused by a mutation of a single amino acid on a critical protein that prevents the sperm from ever undergoing the capacitation process,” Platt said. “If you could correct that specific mutation or design a drug which mimics phosphorylation on that particular amino acid, for example, you might be able to improve fertility.”

To locate the specific site of phosphorylation, Platt and his colleagues first induced capacitation in sperm. Proteins from the capacitated sperm and proteins from a non-capacitated population were then extracted and digested into smaller segments called peptides. Using tandem mass spectrometry (MS/MS), an analytical technique utilized in his laboratory, Platt was able to determine the amino acid sequence of each peptide and to determine where each was phosphorylated. By comparing the phosphorylation status of the samples, Platt and his colleagues were able to identify 55 specific sites whose level of modification changed as a result of the capacitation process.

(Photo: Rensselaer/Mark Platt)

Rensselaer Polytechnic Institute

GENETIC DIFFERENCES IN HUMANS SHAPED BY GEOGRAPHY, HISTORY

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Local pressures such as climate or diet that affect natural selection are only partly responsible for differences in the genetic makeup of human populations, a new study finds. Migrations, the expansions and contractions of populations and the vagaries of genetic chance also play a role.

“It’s easy to imagine that natural selection could have led to human populations strongly diverging from each other as they adapted to the different environments they encountered as they spread around the world,” said Graham Coop, an assistant professor of evolution and ecology at the University of California, Davis, and lead author of the paper describing the study. “But what excites me about this work is that we’re showing that a population’s history and migrations between groups have had a strong role in limiting and shaping how populations adapted to their environments.”

The study, led by Jonathan Pritchard, a Howard Hughes Medical Institute investigator at the University of Chicago, was published June 5 in the online journal PLoS Genetics.

Other collaborators in the work are Joseph Pickrell at the University of Chicago and Marcus Feldman, Richard Myers and Luca Cavalli-Sforza, all at Stanford University.

Natural selection occurs when a particular genetic difference — known as a variant — gives an individual a greater opportunity to have children and pass on his or her genes to future generations. A good example are the variants responsible for light skin color. As modern humans moved out of Africa and spread into northern latitudes, dark skin became a disadvantage, possibly because it blocked too much of the sunlight necessary for synthesis of vitamin D for healthy bones. Genetic variants for light skin, then, conferred a small survival edge, and today those variants are common in people of European and northern Asian ancestry.

Yet genetic variants do not always help populations adapt to their environments, Pritchard said. For example, if a small population undergoes a rapid expansion — because it has entered new territory, perhaps, or developed a technology that supports larger numbers — some of the genetic variants carried by that population can increase rapidly in number, even if they do not provide a reproductive advantage. The pool of genes within a population also tends to fluctuate due to chance events and random differences in the number of children people have and the particular genes they pass on to their offspring.

Thus, one of the fundamental questions facing human geneticists is: Is it possible to determine which genetic variants have increased because of selection and which have increased because of population changes or genetic chance?

Pritchard, Coop and their collaborators decided to tackle this question when new genetic data became available last year from the Human Genome Diversity Project at Stanford University. These data provided a much more in-depth sampling of worldwide genetic differences than had previously been available, allowing the research team to carry out a new and more rigorous test for selection.

To determine whether a variant’s frequency resulted from natural selection, the team compared the distribution of variants in two parts of the genome: in regions that affect the structure and regulation of proteins, and in neutral regions that have no effect on proteins. Because neutral regions are less likely to be affected by natural selection, they should reflect the demographic history of populations, the team reasoned. In contrast, regions that have been influenced by selection — the protein-regulating regions — should show different patterns of distribution.

The analysis immediately identified known examples of selection, including those involved in determining skin pigmentation, resistance to pathogens, and the ability to digest milk as an adult, a trait that arose in Europe, the Middle East and Africa following the domestication of dairy animals.

Interestingly, it also revealed several genes of unknown function that appear to have been under strong selective pressures. “We’re keen to learn what these genes are and how they work,” said Coop.

Yet the team also found that many genetic signals that other researchers have attributed to selection may actually have been created by historical and demographic factors. When the group compared closely related populations — those that recently came from the same ancestral population or those that have exchanged many migrants throughout history — it found few large genetic differences. If these populations’ environments were exerting strong selective pressure, such differences should have been more apparent.

Even with genetic variants where evidence of selection is strong, such as those for skin color, Pritchard noted, the movements of populations have powerfully influenced current patterns of variation.
“A handful of selective signals are clear,” he said, “but it’s hard to be confident about individual cases beyond the top ten or so that we understand well right now.” (Photo: Karin Higgins/UC Davis)

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