CNVs

DNA Varies More Widely From Person to Person, Genetic Maps Reveal
James Owen for National Geographic News
November 22, 2006

The genetic makeup of the human race is much more varied than previously believed, new research shows.

Scientists say that surprisingly many large chunks of human DNA differ among individuals and ethnic groups.

Here, superimposed profiles of different human genomes reveal the magnitude of differences, with green segments showing DNA gains, red areas representing losses, and yellow portions indicating no difference.
Image courtesy Matthew Hurles/Nature

The research also suggests that humans have less DNA in common with chimpanzees, our closest living relative, than is widely supposed.

The new findings, based on several studies, will have dramatic implications for research into deadly diseases, the researchers add.

In the lead study, reported tomorrow in the journal Nature, scientists created the first map of the human genome that shows that large segments of DNA are missing or duplicated between normal, healthy people.

Known as copy number variants (CNVs), some of these altered DNA sequences can be responsible for increased susceptibility to cancers and many other diseases, the study team says.

"Astonishing" Results

The new map provides a much clearer picture of human genetic variation, says geneticist and co-researcher Charles Lee of the Harvard Medical School in Boston, Massachusetts.

"This evidence is showing that we are more genetically unique from one another — we all have individualized genomes," he said.

The team analyzed the DNA of 270 people with ancestry in Europe, Africa, and Asia. (Get an overview of human genetics.)

More than 1,400 CNVs were detected, covering 12 percent of the human genome — the complete set of chromosomes, present in almost every human cell, that contains a person's genetic code.

Until now only relatively small amounts of genetic difference between people had been identified.

"The number and magnitude of this type of variation was totally unexpected," said Huntington F. Willard, director of the Institute for Genome Sciences and Policy at Duke University in Durham, North Carolina.

"The variation among seemingly 'normal' human genomes is quite astonishing," added Willard, who was not involved in the study.

Huge Variation

Previous human genome studies such as the HapMap Project mapped only single base pair changes between individuals.    Base pairs make up each rung of the "DNA ladder," representing the "letters" of the genetic code.

The new research, however, looked at much larger DNA sequences, employing powerful experimental methods called microarrays.

Details of these new methods, which allow scientists to scan the human genome accurately for CNVs, are published concurrently in the journal Nature Genetics.

CNVs occur when existing genes are deleted or duplicated or when parts of genes fuse together to form new DNA structures.

The phenomenon results from various mechanisms, some of which remain poorly understood, researchers say.

Studies suggest that larger CNVs occur in regions of the genome that are prone to errors during crossover, when chromosomes exchange pieces before being passed from parent to offspring.

Previously known copy number variation in humans was "was simply the tip of the iceberg," says co-leader of the DNA mapping project, Matthew Hurles of the Wellcome Trust Sanger Institute in Cambridge, England.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," he said.

The findings "will change forever the field of human genetics," commented James Lupski, professor of molecular and human genetics at Baylor College of Medicine, Houston, Texas.

"One can no longer consider human traits as resulting primarily from single base pair changes," he said.    "This is perhaps the most important breakthrough in human and medical genetics in several decades.

"I would say it rivals finally knowing the number of chromosomes [50 years ago] that makes us humans and showing that some syndromes can result from an abnormal number of chromosomes."

Disease Breakthrough?

The study team says their genome map will provide new ways for scientists to identify genes involved in disease.

Many examples of diseases known to result from changes in DNA copy number are emerging, the team points out.

Yet current tests for mutated genes that cause diseases won't detect most CNVs, the researchers warn.

CNVs revealed in the study are associated with a wide variety of diseases, including AIDS, cataracts, heart disease, and schizophrenia.

"Medical research will benefit enormously from this map," team member Lee said.

The study also highlighted genetic differences among the population groups tested, with 11 percent of copy number variations not being shared between people of European, African, and East Asian ancestry.

Some of these differences may relate to how different ethnic groups adapted to their specific environments, according to Hurles of the Wellcome Trust Sanger Institute.

For instance, he says, the African group was found to have higher copy numbers of a gene associated with increased resistance to HIV infection.

The team says an understanding of how such genetic variation is distributed around the world can reveal much about human prehistory and help in tracking down disease genes.    (Related: National Geographic's Genographic Project.)

The findings also suggest "more genetic variation between human genomes and chimpanzee genomes than we had previously appreciated," Lee said.

Past studies suggest chimps share around 99 percent of their DNA with humans.

"If you add on CNVs, you do see a lot more differences between the two species," Lee added.

The researchers say their findings suggest a figure in the region of 96 to 97 percent similarity.

Willard, of Duke University, said the research raises new questions "about what makes our genome the 'human' genome and about the events that have shaped our genome over the past few million years and even today.

"I suspect we're just seeing the very early stages of a new way to think about evolution."