Tiny Disparities in Human Genes Go a Long Way, Studies Find
The first detailed survey of the human genetic code is revealing many striking things about the blueprint for making a human being. Among them: how similar we all are to each other. And how different.
The findings, to be formally announced today and published later this week, reveal for instance that members of two different racial groups can be more alike than members of the same group.
The studies also reveal that two unrelated people are unexpectedly alike, differing on average at just 1 out of every 1,000 sites in our DNA.
Yet even that small difference adds up to roughly 3 million places in DNA where tiny disparities exist between two people’s genetic codes. That’s enough to create all the known genetic variety, from simple traits such as eye color to more complicated ones such as higher risks for depression or heart disease, according to the new findings published by two groups, the Human Genome Project and a privately funded effort by Celera Genomics Corp. The genome project was funded largely by the U.S. government and a British charity.
Today, because of the genome effort, places in our DNA where those differences occur have been cataloged to a degree of detail unimaginable just a few years ago. This new information will have a huge effect on biology and medicine, scientists say. It will allow them to track down genes for medical conditions and other human traits that have proved elusive up until now.
“Everyone wants to do these studies, but so far we’ve been doing them in a very incomplete way, sort of like old-time prospectors who go someplace and pan, look hard, then move on,” says Aravinda Chakravarti, director of the Institute for Genetic Medicine at Johns Hopkins School of Medicine in Baltimore. “This is the first time we’ve had a chance to look at the genome in a comprehensive way.”
Both Celera and the genome project announced in June that they had completed efforts to describe the chemical structure of all but a fraction of the human genetic code.
This week, the journals Science and Nature report the genome’s “sequence”--the long strings of chemical building blocks known as A’s, Cs, Ts and Gs that comprise our DNA. They also describe what scientists have learned so far from scrutinizing the reams of data.
They report several million places where people’s genomes can differ from those of others, changes researchers refer to as “SNPs.” This catalog is as yet incomplete; there could be as many as 10 million such sites.
SNPs--which stands for “single nucleotide polymorphism”--are not the only kind of variability that exists in the human genome. But they represent about 85% of the differences that exist.
Some of those SNPs occur directly in the middle of genes. In those cases, there’s a good chance that an SNP may alter that gene--giving us blue eyes or a brain that’s a tad more prone to depression, says Dr. David Altshuler, a researcher at Harvard and the Center for Genome Research at the Whitehead Institute in Cambridge, Mass. Altshuler is senior author of a Nature paper that reports this week on 1.4 million SNPs found by the public genome effort.
However, “the overwhelming majority of these SNPs do nothing,” Altshuler says. They’re sitting in parts of the genome that do not code for genes.
That does not mean they are rubbish, though--not for scientists. They are more like gold. If a particular SNP is close enough to a gene that is involved in a genetically based malady, such as diabetes, it serves as a very useful signpost for that gene.
In one sense there is nothing new about SNPs. The whole science of genetics, covering more than a century, has been based on tracking differences in inherited traits, be they in molds, plants, flies or human beings.
For instance, pea plants tended over a century ago by the Austrian monk Gregor Mendel were tall or short due to a difference in a single gene (although only in 1997 was the actual genetic difference discovered). And human blood groups, first described in 1901, differ from each other because of differences in a blood protein gene.
With the advent of molecular biology, researchers in recent years have been working with known SNPs, hopeful that they could find genes predisposing people to depression, alcoholism, schizophrenia, autism, diabetes, heart disease and more.
The general idea has been to compare groups of people who have an ailment with groups that don’t--and look for certain patterns of SNPs that crop up in the group with the disease.
But though there have been successes, their quarry has too often proved elusive, says Dr. Nelson Freimer, director of UCLA’s center for neurobehavioral genetics. Even though traits such as depression and schizophrenia are known to be highly influenced by genes, there have never been enough of these SNPs, covering enough of the genome, for scientists to use in their efforts.
“We just have not had the tools before,” Freimer says.
Now they have an abundance of riches, and the challenge becomes figuring out ways to quickly and efficiently discover the patterns of thousands and thousands of SNPs in the people being studied.
Another huge challenge is devising ways to number-crunch the data to figure out which patterns of SNPs are related to diseases or other traits, such as susceptibility to medication side effects.
Though most researchers are enthusiastic, a few believe that scientists are promising and expecting too much.
Even if traits such as diabetes have in part a genetic basis, if there are too many genes acting in too complicated a manner, it may never be possible to find them, says Kenneth Weiss, geneticist at Pennsylvania State University in University Park.
Some proponents are “promising near immortality from genetic research,” he says. “Are people dreaming about powerful public health solutions from genetic research that aren’t realistic? I’m skeptical--but I could be wrong, of course.”
Others counter that this, the very dawn of the post-genome age, is hardly the moment to be pessimistic, even if the promise of the genome has been overly hyped.
“For God’s sake, this has only just been published,” Freimer says. “Let’s not either throw cold water on it or proclaim that the day in which we’re all going to be carrying our disease chips in our handbags is coming right around the corner.”
SNPs, meanwhile, are not only invaluable for medicine, they should help shore up knowledge of evolution and human history, scientists say. Though people cannot be clearly divided into “races,” scientists can still detect certain patterns of SNPs that crop up more in some parts of the world than others. This should give researchers clues to the movements of different peoples during history.
By charting these subtle differences, researchers have already learned much about human migration patterns. Their findings are often buttressed by other fields of science such as anthropology or archeology.
They have learned, for instance, that people in Finland are far more similar to each other than are people in America, implying that the Finnish population was very small thousands of years ago, and that members of the Jewish diaspora still retain patterns of SNPs in common, despite all their years of living in far-flung places around the world.
They have also learned that humans appear to be far more similar to one another than some of our close relatives. Chimps, for instance, are about two to three times more genetically variable than we are, and gorillas are maybe five times more so, says Chakravarti. The fact that we are so similar implies that we are descended from a relatively small number of people--maybe 10,000--as little as 100,000 years ago.
The new crop of SNPs reinforces such findings and promises to make future tracking of human movements easier, geneticists say.
“This kind of data is going to make possible a very complete description of the history of the human race--who went where and when,” Altshuler says. “It is an unparalleled data set to explore the population history of the human race.”
