What makes people different may not just be their different genes, but how many copies they have of each one, and how many stretches of DNA are “missing”.

Two separate studies of the human genome have revealed an unsuspected amount of variation between people in the number of copies of genes they have. Such variations appear to involve as much as 12% of our DNA, and raise questions about what constitutes a “normal” genome.

Originally, the differences between individuals were thought simply to be the result of mutations, whereby single bases in a DNA strand change, which can cause small changes in the proteins the DNA codes for.

Then in the 1990s scientists discovered that people also differed in the number of copies of genes they had, with large chunks of one person’s DNA being duplicated or deleted when compared to another’s. Extra copies of identical genes can even cause disease with no mutation involved (see Genomics: We are all numbers).


What is normal?

How much of this duplication and deletion occurs is not clear, but now two separate groups of researchers have found that it involves more of the genome than anyone suspected.

Stephen Scherer at the Hospital for Sick Children in Toronto, Canada, and colleagues sought out differently deleted or duplicated chunks of DNA in the two complete human genome sequences so far produced. They discovered that nearly 24 million nucleotides are involved in such “copy number variants” (CNVs).

They conclude that adding this kind of variation to the single-base mutations we already knew about means “significantly more variation exists between humans than was previously estimated”.As personalised genetic sequencing becomes more common, they say, questions will be raised as to whose genome will be considered “normal”.

Immense contribution

Meanwhile, Matt Hurles at the Wellcome Trust Sanger Institute in Cambridge, UK, and colleagues compared genomes from 270 people in four ethnic groups: Yoruba in Nigeria; European descendants in the US; Han Chinese in Beijing; and Japanese in Tokyo. They measured the number of copies of genes by looking at how well chunks of the genomes bonded to each other.

They found 1447 CNVs, covering about 12% of the human genome. “One of the real surprises of these results was just how much of our DNA varies in copy number. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals,” says Hurles. “Each one of us has a unique pattern of gains and losses of complete sections of DNA.”

“This research paper will change forever the field of human genetics,” says James Lupski at the Baylor College of Medicine in Houston in the US, an independent CNV expert. Now, when seeking genetic causes for diseases, scientists will have to look, not just for mutations, but for CNVs, he says. The new data have been placed in the public domain to help researchers do this.

Journal reference: Nature Genetics (DOI: 10.1038/ng1921) Nature (vol 444, p 444)