Matthew Hurles: The Copy Number Variation Project
At the Wellcome Trust Sanger Institute, Dr Matthew Hurles and his colleagues worked on the first ever CNV map, and remain at the forefront of research to help explain how this kind of variation makes us who we are.
Background
The genetic basis of human diversity is one of the major questions confronting geneticists today. Matthew Hurles led a landmark study of a previously underestimated source of genetic variation in humans: copy number variation. This and subsequent work by the team has shown that CNVs contribute to human diversity on a scale previously unanticipated.
Single nucleotide polymorphisms (SNPs) in the genome sequences of healthy individuals have long been known to be associated with variations between individuals, and had been thought to account for almost all genetic differences between people. Major alterations in chromosomes that are visible under the microscope also occur, but they are very rare.
Relatively little has been known about variations in the genome that are intermediate in size between SNPs and large-scale chromosomal changes. These intermediate-sized differences - known as copy number variations (CNVs) - involve changes to the genome such as deletions, inversions and repetitions of pieces of DNA that range in size from 1000s of bases to tens of thousands of bases.
Studies of individual CNVs show that they can underlie human variation, and can cause disease, but their frequency throughout the human genome was unknown. Scientists at the Wellcome Trust Sanger Institute and 12 other centres around the world - the Structural Genomic Variation Consortium - have collaborated on a genome-wide study of CNVs.
Advance
The consortium studied the genomes of the 270 people in the International HapMap collection, who come from four populations, with European, African and Asian ancestry, and compared them with a reference genome sequence. In this way, in 2006, they compiled the first CNV map of the human genome. They identified 1447 CNV regions, and found that they cover 12 per cent of the genome. Although there are many more SNPs in the human genome, they cover only 0.4 per cent of the sequence.
The group also looked at 2000 genes in which mutations are known to cause diseases and found that 285 vary in copy number in the people studied. They also found previously unidentified variants in genes linked to disease including schizophrenia, Charcot-Marie-Tooth syndrome and coronary heart disease.
The CNVs identified in this study tended to be at least 5000 base pairs in size. As such, this first map was thought to have captured just the largest five per cent of the CNVs present in the genome.
CNVs are known to affect phenotype by altering how many copies of certain genes are in the genome, by disrupting the coding sequences of genes and by upsetting the regulation of genes. A further study in 2007 led by Matthew Hurles and Emmanouil Dermitzakis at the Wellcome Trust Sanger Institute looked at the relative contributions of SNPs and CNVs to gene activity and found that SNPs correlated with altered gene activity in 900 out of a total of 14 000 genes studied, while CNVs did so in 240 of the genes studied.
The comparison of whole gene sequences is now being encouraged as a worldwide effort to improve the mapping of copy number variations throughout the genome. The Wellcome Trust Sanger Institute has set up a central database called DECIPHER, to which clinicians are being encouraged to contribute CNV and phenotype data on their patients. This data can then be compared with the CNV map from healthy individuals to help define disease-causing variants.
Making a difference
One of the most striking findings from the work of Dr Hurles and his colleagues is how much copy number variation there seems to be throughout the genome. This, combined with the group's finding that CNVs can affect how genes work (for example, by turning them on or off), provides compelling evidence that CNVs play a crucial and substantial role in human diversity.
The importance of CNVs in diversity and disease means that the search for them is now integrated into many large-scale, human genetic studies from the start, including the 1000 Genomes Project and the Wellcome Trust Case Control Consortium (WTCCC).
The 1000 Genomes Project is an international consortium formed to create a detailed and medically useful catalogue of human genetic variation. The new sequencing technology used in this project means that, rather than just CNVs, other structural variants (including inversions, translocations and jumping repeats) can be detected. Recent research suggests that structural variants could be linked to susceptibility to mental retardation and autism.
Dr Hurles' team, in collaboration with other WTCCC members, published the results of the hunt for CNVs from the WTCCC in April 2010. The study hoped to find an association between commonly occurring CNVs and eight common human diseases, including diabetes, heart disease and bipolar disorder. However, any role played by common CNVs in the genetic basis of these eight diseases was, disappointingly, found to be unlikely.
The result suggests that rare variation, which hasn’t been well captured by the approaches that are available, is responsible for the heritability of these diseases. The next step is to find them.
References
- Redon R et al. Global variation in copy number in the human genome. Nature 2006;444(7718)444-54.
- Stranger BE et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007;315(5813)848-53.
- The Wellcome Trust Case Control Consortium. Genome-wide association study of CNV in 16 000 cases of eight common diseases and 3000 shared controls. Nature 2010; 464:713-720.
See also
- DECIPHER database
- Common CNVs unlikely to contribute towards common diseases
- Q&A: Copy number variants with Matt Hurles