Scientists hail genetic discovery that will change human understanding
By Steve Connor, Science Editor
Published: 23 November 2006
Scientists have discovered a dramatic variation in the genetic make-up of humans that could lead to a fundamental reappraisal of what causes incurable diseases and could provide a greater understanding of mankind.
The discovery has astonished scientists studying the human genome - the genetic recipe of man. Until now it was believed the variation between people was due largely to differences in the sequences of the individual "letters" of the genome.
It now appears much of the variation is explained instead by people having multiple copies of some key genes that make up the human genome.
Until now it was assumed that the human genome, or "book of life", is largely the same for everyone, save for a few spelling differences in some of the words. Instead, the findings suggest that the book contains entire sentences, paragraphs or even whole pages that are repeated any number of times.
The findings mean that instead of humanity being 99.9 per cent identical, as previously believed, we are at least 10 times more different between one another than once thought - which could explain why some people are prone to serious diseases.
The studies published today have found that instead of having just two copies of each gene - one from each parent - people can carry many copies, but just how many can vary between one person and the next.
The studies suggest variations in the number of copies of genes is normal and healthy. But the scientists also believe many diseases may be triggered by an abnormal loss or gain in the copies of some key genes.
Another implication of the finding is that we are more different to our closest living relative, the chimpanzee, than previously assumed from earlier studies. Instead of being 99 per cent similar, we are more likely to be about 96 per cent similar.
The findings, published simultaneously in three leading science journals by scientists from 13 different research centres in Britain and America, were described as ground-breaking by leading scientists.
"I believe this research will change for ever the field of human genetics," said Professor James Lupski, a world authority on medical genetics at the Baylor College of Medicine in Houston, Texas.
Professor Lupski said the findings superseded the basic principles of human genetics that have been built up since the days of Gregor Mendel, the 19th century "father" of Mendelian genetics, and of Jim Watson and Francis Crick, who discovered the DNA double helix in 1953.
"One can no longer consider human traits as resulting primarily from [simple DNA] changes... With all respect to Watson and Crick, many Mendelian and complex traits, as well as sporadic diseases, may indeed result from structural variation of the genome," Professor Lupski said.
Deciphering the three billion letters in the sequence of the human genome was once likened to landing on the Moon. Having now arrived, scientists have found the "lunar landscape" of the genome is very different from what they expected.
Matthew Hurles, one of the project's leaders at the Wellcome Trust Sanger Institute in Cambridge, said the findings show each one of us has a unique pattern of gains and losses of entire sections of our DNA.
"One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12 per cent of the genome - that has never been shown before," Dr Hurles said.
Scientists have detected variation in the "copy number" of genes in some individuals before but the sheer scale of the variation now being discovered is dramatic.
"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected," Dr Hurles said.
"We now appreciate the immense contribution of this phenomenon to genetic differences between individuals," he said.
The studies involved a detailed and sophisticated analysis of the genomes of 270 people with Asian, African or European ancestry. It was important to include as wide a sample of the human gene pool as possible.
They found that 2,900 genes could vary in the number of copies possessed by the individuals. The genes involved multiple copies of stretches of DNA up to a million letters of the genetic code long.
"We used to think that if you had big changes like this, then they must be involved in disease. But we are showing that we can all have these changes," said Stephen Scherer of the Howard Hughes Medical Institute in Chevy Chase, Maryland.
But it is also becoming apparent that many diseases appear to be influenced by the number of copies of certain key genes, said Charles Lee, another of the project's leaders at the Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.
"Many examples of diseases resulting from changes in copy number are emerging. A recent review lists 17 conditions of the nervous system alone, including Parkinson's disease and Alzheimer's, that can result from such copy number changes," Professor Lee said.
"Indeed, medical research will benefit enormously from this map, which provides new ways for identifying genes involved in common diseases," he said.
Mark Walport, director of the Wellcome Trust, the medical charity that funded much of the research, said: "This important work will help to identify genetic causes of many diseases."
The key questions answered
What have scientists discovered today?
They have found that each of us is more different genetically than we previously believed. Instead of being 99.9 per cent identical, it may turn out to be more like 99 per cent identical - enough of a difference to explain many variations in human traits. Instead of having just two copies of every gene - one from each parent - we have some genes that are multiplied several times. Furthermore these "multiple copy numbers" differ from one person to another, which could explain human physical and even mental variation.
Why does this matter?
One practical benefit is that it could lead to a new understanding of some of the most difficult, incurable diseases. Although it adds an extra layer of complexity to our understanding of the human genome, the discovery could lead eventually to new insights and medical treatments of conditions ranging from childhood disorders to senile dementia. Scientists are predicting for instance that the knowledge could lead to new diagnostic tests for such diseases as cancer.
How was this discovery made?
Scientists have developed sophisticated methods of analysing large segments of DNA over recent years. "In some ways the methods we have used are 'molecular microscopes', which have transformed the techniques used since the foundation of clinical genetics where researchers used microscopes to look for visible deletions and rearrangements in chromosomes," explained Nigel Carter of the Sanger Institute in Cambridge.
What genes are copied many times and why?
There are just under 3,000 genes in the human genome, which consists of about 3 billion "letters" of the DNA code. The scientists found that more than 10 per cent of these genes appear to be multiplied in the 270 people who took part in the study. They do not know why some genes are copied and some are not. One gene, called CCL3L1, which is copied many times in people of African descent, appears to confer resistance to HIV. Another gene involved in making a blood protein is copied many times in people from south-east Asia and seems to help against malaria. Other research has shown that variation in the number of copies of some genes is involved in Alzheimer's and Parkinson's disease.
Are there any other practical applications?
The scientists looked at people from three broad racial groups - African, Asian and European. Although there was an underlying similarity in terms of how common it was for genes to be copied, there were enough racial differences to assign every person bar one to their correct ethnic origin. This might help forensic scientists wishing to know more about the race of a suspect.
Who made the discovery and where can we read more about it?
Scientists from 13 research centres were involved, including Britain's Sanger Institute in Cambridge, which also took a lead role in deciphering the human genome. The research is published in Nature, Nature Genetics and Genome Research.