November 24, 2006
Friday PM

Humans are considerably more genetically diverse than once thought, individually different not just by pairs of genes here and there, but in huge clusters of DNA segments missing or excessively duplicated across many parts of our chromosomes.

The new, more sophisticated map of human genes, published in a group of research papers this week in the journals Nature, Nature Genetics and Genome Research, suggests that the work of finding genetic causes of disease - and related ways to diagnose and prevent or treat them - may be more much complex than scientists thought even a few years ago.

An international team of scientists went back to a reference map for human genetic diversity - specifically, the DNA samples of 270 individuals from Africa, Asia and North America.

Previous screening had looked only at the differences in specific pairs of genes - single base-pairs equivalent to a single letter on a written page. The new search essentially looked for differences in whole sentences, paragraphs and pages. Those differences were found in about 3,000 genes, or 10 percent of the total genes that make up a "normal" human.

The studies aren't the final word, of course. But the researchers suggest that there may be five to 10 times more variations in the genes between any two randomly chosen individuals than once thought. The earlier estimates were based on individual gene matchups that concluded all humans were 99.9 percent genetically alike.

"We need to stop thinking about people as being so genetically similar. We're really a patchwork of DNA sequences that are a lot more individualized compared to one another than we had thought," said Charles Lee, a genetic researcher at Brigham and Women's Hospital in Boston and at Harvard Medical School, one of the leaders of the project.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA, and one of the real surprises of these results was just how much our DNA varies in copy number," said Dr. Matthew Hurles, a leader in research on gene-copy-number variation at the Wellcome Trust Sanger Institute in Cambridge, England.

The researchers found that, in some instances, a segment was deleted, but in other cases was copied as many as 14 times.

At least 285 of the 3,000 genes involved in copy variation are already linked to disease. "A recent review lists 17 conditions of the nervous system alone, including Parkinson's disease and Alzheimer's disease - that can result from copy-number changes," Lee said.

In general, genes that are involved in the immune system and in brain development and activity - functions that have evolved rapidly in humans - tend to have more variation in the number of copies from person to person, the researchers found.

Genes that play a role in early development and cell division - essential to fundamental biology - are less likely to vary.

On the one hand, most of the research into genetic origins of disease in the past decade has focused on mutations or deletions involving one or a few genetic differences. The notion that bigger patches of DNA are involved may, in some cases, force medical researchers to broaden their scope, and makes the concept of gene-replacement therapy more daunting.

However, the knowledge that genetic targets may be bigger, more varied and perhaps clustered in specific spots aids the hunt for the origins of many conditions, from rare disorders and birth defects to cancer, heart disease and diabetes.

The bigger map of human variation also makes clear that studies of disease or drugs that only involve a few hundred subjects of mainly one ethnic background may not adequately reflect what's really going on in our species.

The new research indicates that only about 11 percent of the variations follow specific populations, but many of those also appear to be related to susceptibility to disease.

For instance, a gene called CCL3L1 has been linked to greater resistance to the human immunodeficiency virus (HIV). And the new study showed that the African subjects from Nigeria were much more likely to have extra copies of that gene than were those of European ancestry now living in Utah. Genomes from Asian populations fell somewhere in between.

Technology has been racing ahead so that it may soon be possible for scientists to do a personalized genome sequence of everyone on the planet.

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