mentions CMT1A: Mutant Sperm Guide Clinicians To New Diseases

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Mutant Sperm Guide Clinicians To New Diseases

Some rearrangements of the human genome occur more frequently than

previously thought, according to new research. The work is likely to

lead to new identification of genes involved in disease and to

improve diagnosis of genomic disease.

http://www.sciencedaily.com/releases/2007/12/071202155313.htm

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

-Beuren Syndrome, Charcot-Marie-Tooth disease Type 1A, -

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 -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.

Journal reference: DJ et al. (2007) The rates of de novo

meiotic deletions and duplications causing several genomic disorders

in the male germline. Nature Genetics published online Sunday 2

December 2007.