Genome sequence of one individual is published for first time

The complete genome sequence of one person—one of the US biologists working on the project, J Craig Venter—was published for the first time this week. By enabling scientists to compare the contribution of each of the parental chromosomes, it showed that genetic variation among humans was much greater than previously estimated.

The data indicate that variation from human to human is about 0.5% of the genome, not 0.1%, as previously thought.

The new genome, called HuRef (which stands for human reference), is the first time that the full or diploid genome, consisting of the DNA in both sets of chromosomes (one from each parent), has been published for one individual (PLoS Biol 2007;5(10):e244 doi: 10.1371/journal.pbio.0050254). Two previous versions of the human genome, published by the Human Genome Sequencing Consortium and by Celera Genomics, were mosaics of DNA sequences from several donors.

Data on more than 20 billion base pairs of DNA were analysed to assemble most of Dr Venter's diploid genome. This made it possible to determine the contributions of each of the parental chromosomes and to determine the amount of variation between them. Results showed that at least 44% of the genes differed in the two chromosomes.

Dr Venter, chairman of the J Craig Venter Institute, which is based in Rockville, Maryland, said: “We have shown that human to human variation is five to sevenfold greater than earlier estimates, proving that we are in fact more unique at the individual genetic level than we thought.”

Sequencing the genome also showed a wider variety of DNA variants than previously thought. HuRef contained a total of 4.1 million variants between the two chromosomes, covering 12.3 million base pairs of DNA. Of these, 3.2 million were single nucleotide polymorphisms (SNPs, in which just one nucleotide—the basic unit of the DNA strand—is changed). The researchers said that this was a typical number, but they found at least 1.2 million variants that had not been described before.

They also found a surprisingly high number—nearly one million—of non-SNP variants, including insertions and deletions (where a single DNA unit has been inserted or deleted) and copy number variations (where the same gene occurs in multiple copies).

These non-SNP variants involved a larger portion (74%) than expected of the variable component of the sequenced genome. The research group wrote, “These data suggest that human-to-human variation is much greater than the 0.1% difference found in earlier genome sequencing projects. The new estimate based on this data is that genomes between individuals have at least 0.5% total genetic variation (or are 99.5% similar).” They said that much more research needs to be done on these non-SNP variants to better understand their role in individual genomics.

Sequencing an individual, diploid genome also allowed the researchers to look at haplotypes—groups of linked variations along chromosomes—which may be associated with individual traits and diseases. These indicated that Dr Venter has gene variants that potentially increase his risk of alcoholism, coronary artery disease, obesity, and Alzheimer's disease. He also has genes associated with novelty seeking and blue eyes.

Robert Strausberg, deputy director of the J Craig Venter Institute and one of the co-authors of the new genome, said, “Publishing the first genetic sequence of an individual human is an important first step in the era of individualised medicine.” He predicted that the technology would become available in his lifetime to sequence an individual's genomes at a cost of around $1000 (£500; €725). “Instead of a black box of what DNA encodes, there will be much more complete information to relate to medical care.”

He said that knowledge of an individual's potential risk of conditions, which for most diseases will be associated with several rather than single genes, could be used to build awareness and make decisions about preventive measures, screening tests for early detection, and treatment approaches. However, it is very important to have laws in place that would prevent any discrimination that is based on individual genetic information, he said.

The research group acknowledged concerns about individuals being informed of a predisposition if there was nothing they could do about it. But they argued: “As more individuals put their genomic profiles into the public realm, effective research will be facilitated, and strategies to mitigate the untoward effects of certain genes will emerge. The cycle, in fact, should become self propelling, and reasons to know will soon outweigh reasons to remain uninformed.”