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Reinventing Human genome
By Nature Publishing Group,
Nov 23, 2006 - 4:26:42 PM
Nearly six years after the sequence of the human genome was sketched out, one might assume that researchers had worked out what all that DNA means. But a new investigation has left them wondering just how similar one person's genome is to another's.
Geneticists have generally assumed that your string of DNA 'letters' is 99.9% identical to that of your neighbour's, with differences in the odd individual letter. These differences make each person genetically unique — influencing everything from appearance and personality to susceptibility to disease.
But hold on, say the authors of a new study published in Nature1. They have identified surprisingly large chunks of the genome that can differ dramatically from one person to the next. "Everyone has a unique pattern," says one of the lead authors, Matthew Hurles at the Wellcome Trust Sanger Institute in Cambridge, UK.
The differences in question - made up of stretches of DNA that span tens to hundreds of thousands of chemical letters — are called 'copy-number variants', or CNVs. Within a given stretch of DNA, one person may carry one copy of a DNA segment, another may have two, three or more. The region might be completely absent from a third person's genome. And sometimes the segments are shuffled up in different ways.
These variable regions received short shrift for many years. When the human genome sequence was pieced together, they were largely glossed over, because researchers were focused on finding one overarching reference sequence — and because the repetitive nature of the segments makes them hard to sequence. "It was swept under the rug," says Michael Wigler who is also mapping CNVs at Cold Spring Harbor Laboratory, New York.
The new study, led by Hurles and Stephen Scherer of the Hospital for Sick Children in Toronto, Canada, and their colleagues is the most detailed attempt to find how CNVs are scattered across the whole human genome. To do this, they compared genome chunks from 270 people of European, African or Asian ancestry.
They found nearly 1,500 such regions, taking up some 12% of the human genome. That doesn't mean that your DNA is 12% different from mine (or 88% similar), because any two people's DNA will differ at only a handful of these spots.
According to the team's back-of-the-envelope calculations, one person's DNA is probably 99.5% similar to their neighbour's. Or a bit less. "I've tried to do the calculation and it's very complicated," says Hurles. "It all depends on how you do the accounting."
The answer is also unclear because researchers think that there are many more variable blocks of sequence that are 10,000 or 1,000 letters long and were excluded from the current study. Because of limits with their methods, the new map mainly identified variable chunks larger than 50,000 letters long.
Many of these CNVs are thought to be important in our biology. The team found that 10% of human genes are spanned by these regions, meaning that they might be doubled, deleted or otherwise jumbled in a way that could help to determine whether and when we develop diseases.
CNVs have already been linked with susceptibility to Alzheimer's disease, kidney disease and HIV, among others, and the new map will help researchers to make connections to other conditions. "There's a general expectation that these things are quite influential," Wigler says.
The new map adds to a whole library of genetic cartography that already points out other landmarks in the human genome. A lot of attention has focused on mapping the places where single letters vary between individuals (single-nucleotide polymorphisms, or SNPs). Other researchers are identifying hard-to-spot regions where a segment can be flipped around so it runs backwards.
But there is plenty more for geneticists to navigate and undoubtedly more maps to come. Some will reveal the smaller regions of variation excluded from Hurle's map. Other projects are attempting to mark every single sequence that does something biologically useful, such as making proteins or packaging up DNA into chromosomes.
The precise degree to which each person's DNA differs from another may not become clear until geneticists devise a way to read through the entire genome of many different people and compare them all in detail, something that is far too expensive and time consuming today but may become possible with the advent of faster, cheaper sequencing machines.
Scherer and his team have already lined up the only two complete human genome sequences produced by the publicly funded Human Genome Project and the private company Celera. They identified both single-letter changes and small and large regions of variation and report their results in Nature Genetics
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