Mutant Sperm Map Guides to Deadly Mutations

Those little naughty sperms seem to have an increased vulnerability to mutation. The team at the Wellcome Trust Sanger Institute focused on four unstable areas in the DNA where rearrangements cause genetic diseases called genomic disorders, and discovered that some of these mutations were more frequent in sperm than believed.

In 2006, the same team led by Dr Matt Hurles revealed that losses or duplication of DNA stretches of the human genome were common in apparently healthy people. These rearrangements called Copy Number Variants (CNVs) are encountered in the DNA of any person. Some processes creating CNVs come with one duplication for each deletion, but investigations revealed a few duplications for hundreds of deletions.

"There was no direct, global measure of the relative rate at which human DNA is gained or lost, a study that requires many thousands of human genomes, so we carried out a study on four clinically important regions using human sperm cells as our population of genomes. Sperm cells give us an unbiased snapshot of CNVs: using our new highly-sensitive assays we can detect one rearrangement in a million cells." explained Hurles.

The team focused on DNA stretches prone to rearrangement in Williams-Beuren Syndrome, Charcot-Marie-Tooth disease Type 1A, Smith-Magenis Syndrome, and AZFa deletion that causes male infertility. Duplications seemed to represent just 50% of the deletions' number. The two types of CNV appeared to be similarly common in healthy adults, as some deletions could be too harmful for the individual's life.

"It is likely that deletions are more harmful than duplications, perhaps because a vital gene is removed, and so less likely to survive. However, for some of the genomic regions we looked at, duplications can cause milder symptoms." said Hurles. In Williams-Beuren Syndrome, loss of a variable DNA stretch can induce very severe effects, like narrowing of arteries, facial and bone deficiencies and mental illness. Duplications of the same area seem to cause a milder effect, usually delayed speech development.

"Although some of these CNVs arise much more frequently than anyone thought, they are still comfortingly rare: we see them in about 1 in 50,000 sperm cells. These are unfortunate accidents of the essential shuffling of our genetic deck of cards, a process essential to human life." said Hurles.

The method could find CNVs in unsuspected situations and forecast new harmful mutations. One of the sperm duplications was new and could be harmful, as smaller duplications in the same area can cause Potocki-Lupski syndrome.
Clinical DNA analyses take long to observe sperm mutations, while the new CNV research could identify more rapidly disease-causing mutations.