November 23, 2006
Many More Human Genetic Differences Than Previously Reported

Early DNA sequencing and testing technology made it easier to find single point mutations where just a single DNA letter is different. Now scientists are employing techniques that allow identification of larger scale differences where big sections of the genome show up as multiple copies and the number of copies varies between people. At least 10% of human genes vary between people in the number of internal sequences or whole genes that are found in each person.

New research shows that at least 10 percent of genes in the human population can vary in the number of copies of DNA sequences they contain—a finding that alters current thinking that the DNA of any two humans is 99.9 percent similar in content and identity.

I never bought into the politically correct claims from figures around the human genome project a few years ago about how genetically similar we all are. Humans have evolved in too many local environments with unique selective pressures for that to be the case. Even this paper does not uncover the full extent of genetic variation in the human species. Expect to see more such reports.

This discovery of the extent of genetic variation, by Howard Hughes Medical Institute (HHMI) international research scholar Stephen W. Scherer, and colleagues, is expected to change the way researchers think about genetic diseases and human evolution.

The idea that large copy variations exist is not new news. Reports have been coming out over the last few years suggesting that copy variations play a big role. But this is the first report I'm aware of that tries to more comprehensively measure the extent of human genetic variation due to copy variations. Note again that Scherer's group has not discovered all such genetic variations. Their sample size of only 270 people from 3 races doesn't begin to capture the extent of the variation within each race let alone the variations in Amerinds, Australian Aborigines, and other groups. Plus, their technique for detecting copy variations probably has limitations that caused them to miss some even in the samples they studied.

Discovery of large numbers of functionally significant variations is good news for a number of reasons. The greater number of variations allows even more comparisons of humans to see how variations on each gene affect how human metabolism functions. Also, it provides indication that we need more methods of DNA testing in order to do personal genome testing.

This group found copy variations that affected 10% of all genes. But, again, this represents a lower bound on the total. The variations that are going to be harder to find are the ones that are rarer. Every person alive probably has genetic variations unique to them. We need really cheap personal DNA sequencing and DNA testing to uncover all the variations that exist.

Genes usually occur in two copies, one inherited from each parent. Scherer and colleagues found approximately 2,900 genes—more than 10 percent of the genes in the human genome—with variations in the number of copies of specific DNA segments. These differences in copy number can influence gene activity and ultimately an organism's function.

Scherer's team used DNA samples from 270 people who have given DNA to the International Hap Map project. That project is aimed at identifying single letter genetic variations and how groups of single letter variations tend to occur together. Their goal is not only to map the extent of genetic variation but also to look for ways to predict some variations due to the presence of other variations.

To get a better picture of exactly how important this type of variation is for human evolution and disease, Scherer's team compared DNA from 270 people with Asian, African, or European ancestry that had been compiled in the HapMap collection and previously used to map the single nucleotide changes in the human genome. Scherer's team mapped the number of duplicated or deleted genes, which they call copy number variations (CNVs). They reported their findings in the November 23, 2006, issue of the journal Nature.

Scherer, a geneticist at the Hospital for Sick Children and the University of Toronto, and colleagues searched for CNVs using microarray-based genome scanning techniques capable of finding changes at least 1,000 bases (nucleotides) long. A base, or nucleotide, is the fundamental building block of DNA. They found an average of 70 CNVs averaging 250,000 nucleotides in size in each DNA sample. In all, the group identified 1,447 different CNVs that collectively covered about 12 percent of the human genome and six to 19 percent of any given chromosome—far more widespread than previously thought.

Many genes linked to a variety of diseases have copy number variations (CNVs).

Not only were the changes common, they also were large. "We'd find missing pieces of DNA, some a million or so nucleotides long," Scherer said. "We used to think that if you had big changes like this, then they must be involved in disease. But we are showing that we can all have these changes."

The group found nearly 16 percent of known disease-related genes in the CNVs, including genes involved in rare genetic disorders such as DiGeorge, Angelman, Williams-Beuren, and Prader-Willi syndromes, as well as those linked with schizophrenia, cataracts, spinal muscular atrophy, and atherosclerosis.

In related research published November 23, 2006, in an advance online publication in Nature Genetics, Scherer and colleagues also compared the two human genome maps—one assembled by Celera Genomics, Inc., and one from the public Human Genome Project. They found thousands of differences.

"Other people have [compared the two human genome sequences]," Scherer said, "but they found so many differences that they mostly attributed the results to error. They couldn't believe the alterations they found might be variants between the sources of DNA being analyzed."

A lot of the differences are indeed real, and they raise a red flag, he said.

Doing individual DNA testing on copy variations is probably harder than doing it for single letter differences. But this research paper will probably cause more scientists to work on better and cheaper techniques for measuring copy variations.

Personalized genome sequencing—for individualized diagnosis, treatment, and prevention of disease—is not far off, Scherer pointed out. "The idea [behind comparing the human genome sequences] was to come up with a good understanding of what we're going to get when we do [personalized sequencing]," he explained. "This paper helps us think about how complex it will be."

Copy variations can deliver a few benefits. First off, having more copies of a gene can allow it to get expressed more rapidly. There's a limit to how fast a gene can get transcribed (read) to make messenger RNA. If more copies of the gene exist then they can get read in parallel to produce more copies of messenger RNA (mRNA) in a given amount of time. Then the mRNA gets translated into chains of amino acids which form peptides which, in turn, make up proteins or serve other roles.

Copy variations also make it possible for each copy to take get mutated to make custom versions of peptides that can do different things under different circumstances. One copy can serve the old purpose for which the gene exists and another copy can mutate to better serve some new need that has arisen.

Share |      Randall Parker, 2006 November 23 08:14 AM  Human Population Genetics

Kurt said at November 24, 2006 11:45 AM:

The Howard Hughes Medical research center has consistantly out-performed the NIH in terms of real medical discovery even though its budget is much less than that of the NIH. Both this genetic variation as well as the posting with regards to the protein signalling in stem cells illustrate this point.

Do a general search through PubMed on just about any topic you can think of. You will find that 90-95% of the research papers cited on any particular topic are complete junk. This is your tax dollars at work.

Randall Parker said at November 24, 2006 11:50 AM:


Yes, I continue to be thoroughly impressed by the quality of research coming out from the labs of researchers funded by HHMI. Not only the quality though. The appropriateness is great. They attack the most important problems.

Is this mainly due to the quality of the researchers HHMI funds, the direction HHMI gives them, or the choices that the researchers make when allowed to choose their own priorities? I'd love to know.

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