Sanger research radically overhauls understanding of disease
Experts believe that the findings of an international research project led by Cambridge’s Sanger Institute will “change forever the field of human genetics,” transforming the way scientists investigate the causes of disease.
The work overhauls the widely-held notion, not least by scientists, that the ‘spellings’ of our genetic code differs ever so slightly.
It is common knowledge that everyone's DNA is different. Just watch any ‘cop show’ on television and you'll find the culprits being identified by their DNA ‘fingerprint;’ that is, their unique sequence of nucleotides. But it was felt that aside from small deviations in the reference code for humans, mapped by the Human Genome Project, that the 99 per cent of the sequences were the same.
The new report by the Sanger and its international collaborators, published in the journal ‘Nature', shows that the differences are more extreme, owing to the previously overlooked phenomenon of the deletion or repetition of large portions of the sequence of nucleotides.
This new development could have a seismic effect on the search for genes involved in disease.
Nuances in the genome have been identified before now in the form of single nucleotide polymorphisms (SNPs), in which a single letter in the genetic code is altered in individuals.
While conducting the search for SNPs, in the HapMap Project for example, it was not readily apparent that another form of variation occurred that could have even more scope for the identification of genetic disease.
This other code alteration, called copy number variation (CNV), comes in the form of huge swathes of genetic code being repeated or completely omitted. “Each one of us has a unique pattern of gains and losses of complete sections of DNA” said Dr Matthew Hurles, project leader at the Wellcome Trust Sanger Institute.
The extent of the variation in copy number surprised the researchers; “We estimate this to be at least 12 per cent of the genome, similar in extent to SNPs. This has never been shown before” Hurles continued.
This new genetic map created by the research will change the way disease-related genes are tracked. Multiple copies of the gene CCL3L1 have been found to bring about HIV resistance, an example of how CNVs could revolutionise the field.
“While the SNP maps produced by the HapMap and other work are invaluable, most CNVs are missed by these maps” according to the Sanger.
“Many examples of diseases resulting from changes in copy number are emerging,” said Charles Lee, one of the project’s leaders from Harvard Medical School in Boston.
“A recent review lists 17 conditions of the nervous system alone, including Parkinson’s Disease and Alzheimer Disease, that can result from such copy number changes.
‘Online Mendelian Inheritance in Man’ is the authoritative database of disease-related genes. When the team compared their results with this data, they found that 10 per cent of the genes in the database were associated with CNVs
Prof Lupski, from Baylor College of Medicine in Houston said; “I believe this paper will change forever the field of human genetics.”
The four main areas in which the CNV is changing medical research are: hunting genes behind common disease; to study familial genetic conditions; the study of severe developmental defects; and also the discovery of variations that protect against infectious diseases, such as AIDS and malaria.
“The wide variation between individuals in the number of repeated or deleted portions of our DNA has not been appreciated until now,” said Dr Mark Walport, director of the Wellcome Trust. The partners in the study team have created a database of CNVs associated with clinical conditions, called DECIPHER. Importantly, any researcher around the world can submit clinical information about patients with CNV-linked disorders over the internet.
This patient information is then mapped onto the human genome in the public ENSEMBL browser, which enables collaborative investigations of rare disorders. In this way, DECIPHER has already helped in the identification of new syndromes “with subsequent improvements in care and genetic advice for affected individuals and families,” the Wellcome Trust said.
The new information is to be made publicly available in order to benefit humanity, rather than to garner huge profits, the researchers stressed. “All of the new data is in the public domain emphasizing the commitment of research funders in making the results of research accessible to all” Dr Walport said.
The causes of copy number variations are not yet well understood. Evidence suggests that CNVs occur near segments of the genome that are next to, or contain, repeated DNA sequences. When these sections are rearranged during the passing of genetic information from parent to child they can be mutated, but smaller CNVs do not appear to follow the same rule.
While a massive breakthrough in understanding has already been achieved, the ongoing research aims to “advance understanding of what is perhaps the most poorly understood mutational process operating in the human genome,” the Sanger Institute said.