The importance of large genomic differences

The published sequence of the human genome is essentially a really long sequence of letters. Individual genomes differ from this sequence, and from each other, because they substitute one letter for another. However, these polymorphisms are quite rare, and hence humans are usually said to be genetically 99.9% the same.

However, two genomes may differ in other ways as well. Entire segments of DNA may be duplicated in some, or missing in others, or they could exist, but written "backwards".

Until recently, it was generally assumed that differences between individuals and populations were due to the really small changes in our genes. But, as reported in Nature, scientists are discovering that the large differences in which big chunks of DNA are duplicated, missing, or inverted, may be even more important for explaining human variation.

Two years ago, a group of researchers led by Michael Wigler at Cold Spring Harbor Laboratory found the first evidence that some of us have more copies of certain genes than do others (R. Lucito et al. Genome Res. 13, 2291−2305; 2003). And at last week's meeting, Evan Eichler of the University of Washington in Seattle reported that this is just the beginning: not only do we carry different copy numbers of parts of our DNA, we also have varying numbers of deletions, insertions and other major rearrangements in our genomes.

In fact, Eichler found at least 297 places in the genome where different individuals have different forms of these major structural variations. At these spots, some of us might carry a major deletion, for example, or an extra hundred bases of DNA.

But do such differences mean anything? Here, too, fresh evidence paints an intriguing picture. In January, scientists at the Iceland-based company deCODE Genetics found a long inversion — a stretch of DNA that is flipped around backwards — that is common in Europeans, but not in Asians and Africans (H. Stefánsson et al. Nature Genet. 37, 129−137; 2005). They also found that women who have this inversion bear more children than those who don't — a classic sign that the inversion confers an evolutionary advantage.

At the Cold Spring Harbor meeting, scientists presented more evidence that structural differences are important in human evolution. Duc-Quang Nguyen, a postdoctoral fellow in Chris Ponting's laboratory at the University of Oxford, UK, reported an analysis of areas where there are different numbers of copies of DNA stretches. Nguyen found that natural selection is actively working on these genes.

What's more, he found that many of these genes belong to groups that seem to help us interact with our environment. For instance, many work in the immune system, and affect how we fight off disease. These are exactly the sort of genes that could explain our diversity — why some of us get asthma when exposed to air pollution, or why some of us can eat plenty of cheeseburgers without gaining weight.

"We knew these variations existed, but this year we're asking, do they matter?" says Ewan Birney, head of bioinformatics for the European Molecular Biology Laboratory, based in Cambridge, UK. "The answer seems to be yes."