|
Mutant sperm guide clinicians to new diseases
December 03, 2007Disease, DNA, deletions and duplications in human sperm
Research published today in Nature Genetics shows that some rearrangements of the human genome occur more frequently than previously thought. The work is likely to lead to new identification of genes involved in disease and to improve diagnosis of genomic disease.
The scientists from the Wellcome Trust Sanger Institute looked at four unstable regions in the genome where rearrangements cause genetic diseases, so-called 'genomic disorders', and found that some of these rearrangements were found in sperm much more frequently than expected.
In work published in November 2006, the team, led by Dr Matt Hurles, showed that losses or duplication of 'chunks' of the human genome occurred frequently in apparently healthy people. These losses or gains of DNA regions are called Copy Number Variants (CNVs), and can be found all over the genome in every individual.
Some of the mechanisms thought to produce CNVs would be expected to produce about one duplication for every deletion: however, clinical records for genomic disorders show only a few duplications, compared with 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," explained Dr Matt Hurles, Investigator at the Wellcome Trust Sanger Institute, "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."
The team looked at regions known to be affected by rearrangement in Williams-Beuren Syndrome, Charcot-Marie-Tooth disease Type 1A, Smith-Magenis Syndrome, and a deletion (AZFa) that causes male infertility. Their study showed that duplications are about half as frequent as deletions. By contrast, the two types of CNV are similarly common in healthy adults, suggesting that some deletions are too detrimental for the genome to tolerate.
"It is likely that deletions are more harmful than duplications, perhaps because a vital gene is removed, and so less likely to survive," explained Dr Hurles. "However, for some of the genomic regions we looked at, duplications can cause milder symptoms. Perhaps we can improve diagnosis with improved understanding of the possible consequences of duplications."
In Williams-Beuren Syndrome, loss of a genomic region (which can vary in size) can have very severe effects, including narrowing of arteries, facial and other skeletal deficiencies and impaired mental development. By contrast, duplications of the same regions have a milder effect, resulting most commonly in delay of speech development. With the results of this study, the team suggest that improved diagnosis might result from examining speech-delay for CNVs in this region.
"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," explained Dr Hurles. "These are unfortunate accidents of the essential shuffling of our genetic deck of cards, a process essential to human life. We need a new deal for each new person."
The method should also be able to detect rearrangements where none was suspected and to predict new disease-causing variants. Indeed one of the duplications that was detected in sperm has not yet been observed in the clinic, and yet it can be expected to cause disease, because smaller duplications of the same region cause Potocki-Lupski syndrome. Clinical genetics usually proceeds from observations in a patient down a long road to identify the gene involved. The new CNV work opens a new and possibly quicker, route of using new mutations found in sperm to lead to disease-causing mutations in patients.
In their work in 2006, the team has developed the CNV map for apparently healthy people: many of these are unlikely to cause disease. By looking across the entire genome for novel CNVs in human sperm, they will be able to predict where CNVs are likely to play a possible undiscovered role. In this 'reverse genetics', the new methods move from genome to prediction of consequences for patients.
This work complements the systematic cataloguing of CNVs that do cause disease by the Institute's DECIPHER consortium.
Wellcome Trust Sanger Institute
In work published in November 2006, the team, led by Dr Matt Hurles, showed that losses or duplication of 'chunks' of the human genome occurred frequently in apparently healthy people. These losses or gains of DNA regions are called Copy Number Variants (CNVs), and can be found all over the genome in every individual.
Some of the mechanisms thought to produce CNVs would be expected to produce about one duplication for every deletion: however, clinical records for genomic disorders show only a few duplications, compared with 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," explained Dr Matt Hurles, Investigator at the Wellcome Trust Sanger Institute, "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."
The team looked at regions known to be affected by rearrangement in Williams-Beuren Syndrome, Charcot-Marie-Tooth disease Type 1A, Smith-Magenis Syndrome, and a deletion (AZFa) that causes male infertility. Their study showed that duplications are about half as frequent as deletions. By contrast, the two types of CNV are similarly common in healthy adults, suggesting that some deletions are too detrimental for the genome to tolerate.
"It is likely that deletions are more harmful than duplications, perhaps because a vital gene is removed, and so less likely to survive," explained Dr Hurles. "However, for some of the genomic regions we looked at, duplications can cause milder symptoms. Perhaps we can improve diagnosis with improved understanding of the possible consequences of duplications."
In Williams-Beuren Syndrome, loss of a genomic region (which can vary in size) can have very severe effects, including narrowing of arteries, facial and other skeletal deficiencies and impaired mental development. By contrast, duplications of the same regions have a milder effect, resulting most commonly in delay of speech development. With the results of this study, the team suggest that improved diagnosis might result from examining speech-delay for CNVs in this region.
"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," explained Dr Hurles. "These are unfortunate accidents of the essential shuffling of our genetic deck of cards, a process essential to human life. We need a new deal for each new person."
The method should also be able to detect rearrangements where none was suspected and to predict new disease-causing variants. Indeed one of the duplications that was detected in sperm has not yet been observed in the clinic, and yet it can be expected to cause disease, because smaller duplications of the same region cause Potocki-Lupski syndrome. Clinical genetics usually proceeds from observations in a patient down a long road to identify the gene involved. The new CNV work opens a new and possibly quicker, route of using new mutations found in sperm to lead to disease-causing mutations in patients.
In their work in 2006, the team has developed the CNV map for apparently healthy people: many of these are unlikely to cause disease. By looking across the entire genome for novel CNVs in human sperm, they will be able to predict where CNVs are likely to play a possible undiscovered role. In this 'reverse genetics', the new methods move from genome to prediction of consequences for patients.
This work complements the systematic cataloguing of CNVs that do cause disease by the Institute's DECIPHER consortium.
Wellcome Trust Sanger Institute
Human Genome News and Current Human Genome Events RSSHebrew University study opening new route for combating viruses
A unique technique for analyzing the function of microRNAs developed by a Hebrew University of Jerusalem doctoral student has led to the discovery of a new mechanism by which viruses evade the human immune system.
DNA study unlocks mystery to diverse traits in dogs
What makes a pointer point, a sheep dog herd, and a retriever retrieve? Why do Yorkshire terriers live longer than Great Danes? And how can a tiny Chihuahua possibly be related to a Great Dane?
Genome sequence of lancelet shows how genes quadrupled during vertebrate evolution
The newly sequenced genome of a dainty, quill-like sea creature called a lancelet provides the best evidence yet that vertebrates evolved over the past 550 million years through a four-fold duplication of the genes of more primitive ancestors.
Woolly-Mammoth Gene Study Changes Extinction Theory
A large genetic study of the extinct woolly mammoth has revealed that the species was not one large homogenous group, as scientists previously had assumed, and that it did not have much genetic diversity.
Scientist study bacterial communities inside us to better understand health and disease
The number of bacteria living within the body of the average healthy adult human are estimated to outnumber human cells 10 to 1. Changes in these microbial communities may be responsible for digestive disorders, skin diseases, gum disease and even obesity.
UNC medical geneticist cautions against rushing into genetic testing
Just because scientific advances now allow individuals to learn their genetic make-up doesn't mean they should rush into genetic testing in hopes of making revolutionary improvements to their health, cautions a geneticist and practicing physician at the University of North Carolina at Chapel Hill.
Statistical tool could explain gene study variations
While scientists are using the human genome to associate certain genes with disease, Dr. Hongyan Xu wants to ensure they are accounting for natural variations in those genes.
Leiden scientists sequence first female DNA
Geneticists of Leiden University Medical Centre (LUMC) are the first to determine the DNA sequence of a woman. She is also the first European whose DNA sequence has been determined. This has been announced by the researchers this morning, during a special press conference at 'Bessensap', a yearly meeting of scientists and the press in the Netherlands.
New cheaper method for mapping disease genes
Scientists at the Swedish medical university Karolinska Institutet have developed a new DNA-sequencing method that is much cheaper than those currently in use in laboratories. They hope that this new method will make it possible to map disease genes in large patient groups, which in turn can mean quicker breakthroughs for new treatments for a wide variety of diseases.
New statistical method reveals surprises about our ancestry
A statistical approach to studying genetic variation promises to shed new light on the history of human migration.
More Human Genome News Articles
 | Genome: The Autobiography of a Species in 23 Chapters (P.S.) by Matt Ridley |
 | A Life Decoded: My Genome: My Life by J. Craig Venter |
 | Human Origins: What Bones and Genomes Tell Us about Ourselves by Rob Desalle, Ian Tattersall |
 | Welcome to the Genome: A User's Guide to the Genetic Past, Present, and Future by Rob DeSalle, Michael Yudell, American Museum of Natural History |
 | The Genome War: How Craig Venter Tried to Capture the Code of Life and Save the World by James Shreeve |
 | Genetic Entropy & the Mystery of the Genome by John C. Sanford |
 | The LIVES TO COME by Philip Kitcher |
 | Short Guide to the Human Genome by Stewart Scherer |
 | ISCN 2005: An International System for Human Cytogenetic Nomenclature (Cytogenetic & Genome Research) by Lisa G. Shaffer, Niels Tommerup |
 | It Ain't Necessarily So: The Dream of the Human Genome and Other Illusions by Richard Lewontin |
| © 2008 BrightSurf.com |