Harvard researchers map newform of genetic diversity

A new map of human genetic diversity provides a powerful tool for understanding how each person is unique.

Created by researchers at Harvard Medical School, Brigham and Women’s Hospital, and other institutions around the world, the map focuses on the number of copies of large segments of DNA present in each individual. Though humans normally have two copies of their DNA, researchers found that some people have three, four, five, or more copies of certain DNA segments, while others have just one copy or are even missing them entirely.

Working as part of an international consortium, the group identified 1,447 DNA segments that vary from the normal number of two copies. Included in those DNA segments, called copy number variants (CNVs), are the DNA that make up 3,000 genes, including 285 genes known to be associated with disease.

Researchers believe that variations in the number of copies of these disease genes may explain disease susceptibility and why, for example, one person develops cataracts in old age while another doesn’t. Among those 285 are genes linked to AIDS, schizophrenia, inflammatory bowel disease, lupus, and arterial disease.

The work, detailed in the Nov. 23 edition of the journal Nature, involved researchers from 13 institutions. Principal investigators included Charles Lee, assistant professor of pathology at Harvard Medical School and a cytogeneticist at Brigham and Women’s Hospital; Stephen Scherer of the Hospital for Sick Children in Toronto; Matthew Hurles, Nigel Carter, and Chris Tyler-Smith of the Wellcome Trust Sanger Institute; Hiroyuki Aburatani of the University of Tokyo; and Keith Jones of Affymetrix Inc.

The focus on structural DNA variation, such as gains, losses, and rearrangements of large chains of DNA, represents a relatively new front in the battle to understand the unimaginably complex workings of the genetic code.

Scientists have long known that differences in DNA are the primary determinant for why humans are different from dogs, robins, and sharks, for example. Scientists have also known that DNA is made up of essentially four different components, called bases, joined in pairs and repeated over and over in a dizzying array of combinations. It’s these different combinations of base pairs that contain the blueprint for each individual.

Until recently, scientists have focused much of their attention on single base pair differences to explain individual variation. However, in recent years, research led by Lee has highlighted the fact that the number of copies of DNA segments can also serve as another major source for genetic diversity.

“Two years ago, we made the first observation that copy number variants were widespread,” Lee said.

Lee used a literary analogy to explain the development. If all the DNA in the human genome represents the book of life, so far scientists have been looking for single letter spelling mistakes. The CNV work is looking for larger errors.

“We’re finding sentences can be duplicated or completely deleted in some individuals, sometimes paragraphs, sometimes whole chapters,” Lee said.

The CNV segments found by Lee and colleagues are extraordinarily variable in size, each ranging from as few as a thousand base pairs in length to more than 2 million. The CNVs were found in DNA samples from 270 individuals representing four different populations of the world. These individuals were originally selected by the International HapMap Project, a scientific collaboration focused on finding and characterizing single base pair changes in the human genome.

Researchers examining the human genome letter by letter have estimated that humans share 99.9 percent of their DNA, leaving just 0.1 percent to explain all the individual differences among us. Lee and colleagues, however, found that copy number variants cover as much as 12 percent of the genome and may be the source of a large portion of human genetic diversity.

Copy number variation can also provide new insight into what makes humans human, Lee said. Recent research comparing human and chimpanzee genomes have determined that humans and chimps share 96 percent of their DNA. Copy number variants can potentially add greatly to that diversity. In fact, recent studies examining copy number variants uncovered an unknown gene, active in the brain, which is copied in primates more times as species get closer to humans, who have 212 copies.

Lee said he hopes that publishing the CNV map, available on the Internet, will be a helpful and important resource for interested researchers. For example, scientists that are conducting disease association studies, which aim to determine which DNA segments are linked to specific human diseases, currently scan human genomes to identify single base pair changes that recur in individuals with a certain disease. Such studies will now also need to identify and incorporate CNV data.

Similarly, in the field of pharmacogenomics, which studies how genetic variation causes individuals to react differently to drugs, will also need to take into account CNVs. Lee said he hopes that a more comprehensive understanding of human genetic variation will ultimately help physicians prescribe medication in a more individualized manner, resulting in maximum therapeutic effects to each patient, with minimal side effects.

As for the consortium of researchers that has developed this new map of human genetic variation, Lee said the next phase of their mapping effort will examine CNVs in other human populations with higher resolution technologies that will help them identify even smaller lengths of DNA that are copy number variable. Their analysis of currently available data has already revealed CNV patterns that differ from population to population.

“It’s only the beginning,” Lee said. “There is still so much out there waiting to be discovered.”