In the Hunt for Useful Genes, a Lot Depends on 'Snips'

August 11, 1998

In the Hunt for Useful Genes, a Lot Depends on 'Snips'

By NICHOLAS WADE

new word is edging into the study of human genetics: the snip.
Snips, variations in the DNA that make each individual unique, are the genetic determinants of health and disease.
Because of machines that rapidly decode DNA, the chemical chain that embodies the genetic instructions, snips are at last becoming widely accessible.
Genetic keys to what makes each person unique.

Snips promise to yield two troves of information, one past and one present.
They will help population geneticists reconstruct the size and timing of the early human migrations that peopled the globe. And they should enable medical geneticists to trace elusive links between genes and disease, particularly the common diseases to which many genes contribute.
With the use of snips, pharmaceutical companies hope to match drugs more precisely to an individual's unique genetic makeup.
The search for snips is an essential counterpart to the human genome project, the attempt to decode or sequence all three billion letters of human DNA in the next five to seven years. The human genome project largely ignores the variations in DNA that make each person unique. Based on analyzing the DNA of just a few individuals, it will provide a consensus sequence, meaning the DNA letter that is most commonly found at each of the three billion positions on the DNA chain.
Though the consensus sequence is of great interest to biologists trying to figure out the operation of the human genetic programming, medical geneticists are interested in the variations from the consensus because in them lies the answer as to why one person may succumb to a disease and another resist it.
The number of variations among six billion humans might seem impossibly large because in principle every letter in the genome can change, whether by chemical decay, a hit from stray radiation or a copying error. But in fact the variation is much more limited, with changes being commonly found only at particular sites in the DNA.
The reason is that by evolution's standards the human species is very young, a mere 100,000 years or so, and at about that time went through a population bottleneck of some 10,000 individuals.
"The blink of an eye since we left Africa hasn't been long enough to build up many common variations," said Dr. Eric S. Lander, a biologist at the Whitehead Institute in Boston and the principal proponent of a remarkable "snip chip" that could someday identify an individual's genetic variations.
"We have the level of variation expected from 10,000 people because we are just a little population that happened to grow big."
Most of the medically interesting variations in DNA are in the form of single changes to a nucleotide, the chemical units that make up the DNA chain.
Changes that are commonly found, meaning in at least 1 percent of a population, are known as SNPs, or single nucleotide polymorphisms.
SNPs, pronounced snips, can exert dramatic effects. Sickle cell anemia is caused solely by the change of an A to a T (A, T, C and G are the symbols for the four chemical letters, or nucleotides, that make up the DNA alphabet) in one of the genes that specifies the hemoglobin protein of the red blood cells. Three variant spellings in the gene known as apolipoprotein E account for much of the risk for Alzheimer's disease.
SNP's occur in roughly one out of every 500 positions along the DNA chain. Because only 3 percent of the genome appears to be active in the body, the rest being generally of no known purpose, there are only some 200,000 snips in the genes that specify the working parts of the body's cells. The effective human genetic repertoire is apparently limited to combinations, very large though their number is, of this finite number of variations.
Biologists pursuing snips in parallel with the decoding of the human genome are headed in two main directions. One is the effort to measure how genetic variation is distributed around the globe, information that will help track prehistoric human migrations.
The Human Genome Diversity Project, headed by Luca Cavalli-Sforza of Stanford University, aims to collect DNA from at least 100 populations on each continent. But the project has been held up by objections that it would exploit the people who donated samples. In a recent review, a panel convened by the National Academy of Sciences endorsed the goals of the project but said more work should be done to address ethical concerns.
The other major use of snips is in tracing the genetic variations that contribute to health and disease. Diseases caused by defects in a single gene have been easy enough to trace because they are inherited in the simple patterns first described by Gregor Mendel, the founder of genetics, in the 19th century. But these Mendelian diseases tend to be quite rare. Most common maladies, like heart disease and schizophrenia, are thought to be caused by the defective versions of many genes acting in concert.
Because each gene makes only a minor contribution to the disease, it is hard for geneticists to trace its effects even when they have large family pedigrees to work with.
The current method of mapping the human genome depends on the same kind of signpost or marker that is used in the forensic technique of DNA fingerprinting.
But these markers, which consist of repetitive bits of DNA repeated a varying number of times in different individuals, are technically difficult to work with.
So far, there has been very little success in digging out the genetic roots of multi-gene diseases.
Hence, considerable interest was aroused by a recent calculation that multi-gene diseases could be cracked through the snip approach.
Its authors, Neil Risch of Stanford University and Kathleen Merikangas of Yale, said that a simple association study -- comparing people with and without a given disease -- would help pinpoint the contributory genes if enough snips could be identified along the DNA chain so that one would probably be in or near the causative genes.
Citing the Risch-Merikangas paper, Dr. Francis S. Collins, director of the human genome project at the National Institutes of Health, persuaded the directors of other N.I.H. divisions to join in financing a grand hunt for snips, based on the premise that genetic factors contribute to almost every human disease.
The hunt began last January, at a cost of $10 million a year and with the goal of locating at least 100,000 snips spread out across the genome, which Dr. Collins calculates is the necessary number to tag most genes of possible interest.
Snips are also the basis of a fashionable new approach to drug design known as pharmacogenomics. The premise is that people respond differently to drugs based on their genetic makeup. With the use of snips, it should be possible to tailor drugs to patients, selecting the drug that works best for a person and excluding from drug trials the people likely to suffer side effects.
If the approach works, drug companies might end up selling fewer drugs, but could charge more for the tailored approach.
Last year Abbott Laboratories made a $20 million deal with Genset, a Paris-based company, to discover 60,000 SNP's spread across the genome.
Once the snips are identified, they can be used for many purposes. A particularly striking application is that of the snip chip.
Made in a similar way to computer chips but incorporating DNA, the chip can be programmed to scan a DNA chain for specific sequences of letters. Chips are being developed by biologists at the Whitehead Institute and at Affymetrix in Santa Clara, Calif., with the ultimate purpose of scanning a person's whole DNA or genome for all medically significant snips.
Lander believes a single chip, or set of chips, could be programmed to sift the six million snips strung along the human genome to find the 200,000 snips occurring within the coding regions that actually affect the individual.
Such a chip could, in effect, sequence a person's genome in minutes by identifying all significant differences from the consensus sequence. It would also provide a kind of fate map, enabling a physician to assess the genetic strength of a person's constitution, the diseases to which they were vulnerable and perhaps their likely longevity.
At present, of course, the 200,000 coding snips are far from being identified, let alone understood in terms of their medical significance. Still, the snip chip is already under way. In May, Lander and his colleagues described a chip that can analyze 500 snips simultaneously with reasonable accuracy, and a 2,000-snip chip is also in development.
Lander views his concept of a whole genome chip as more a diagnostic than a predictive tool. People can already forecast their medical fate pretty accurately by noting their parents' ages and causes of death, he said.
The snip chip "is a way of teasing apart the causes of disease rather than predicting the future," Dr. Lander said. "For every spot on the chip, you need information and understanding, and that will take a long time."
As that understanding is acquired, however, the chips seem likely to intensify the existing problems of human genetics, such as how to counsel patients and how to insure that the information is not used to their detriment.
"This is a very major ethical issue, and ELSI has already decided to make this its highest priority," Dr. Collins said, referring to the branch of the human genome project that studies its ethical and legal consequences. "This ability to collect very large amounts of variation on individuals will be quickly upon us. It will empower people to take advantage of preventive strategies, but it could also be a nightmare of discriminatory information that could be used against people."
Of course, the links between snips and disease may prove more elusive than expected. A recent analysis of a gene that regulates fat metabolism and is thought to play a role in heart disease turned up an unexpectedly complex pattern of snips among the three populations surveyed.
The pattern makes it less certain that association studies between snips and genes will pinpoint the genes involved in disease, said Dr. Andrew G. Clark of Pennsylvania State University, an author of the study.
In an article in the current issue of Genome Research, Dr. Kenneth M. Weiss, also of Penn State, warns of "unrealistic expectations of the questions that can be answered from genetic data."
Weiss notes that evolution acts on the phenotype, not the genotype, meaning on the organism that is produced from the genes, not the genes themselves. Although the genes carry a message as precise as the digital code of a computer program, the phenotype is tolerant of variation and survives with as wide a range of genetic instructions as possible.
Therefore, the link between genes and people may be somewhat fuzzier, Weiss suggests, than the crispness of a DNA sequence would suggest.

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