The Case Against Gene Sequencing

T he debate over complete sequencing of the human genome continues at a fever pitch. Indeed, this sequencing has become the biologists’ cause celebre for the waning years of this decade. While many have spoken forcefully in favor of this sequencing, the voices of opposition, at least in public, have been more muted. Many think it foolhardy and retrogressive to argue against a project that promises to yield a mountain of new data. With the U.S. Department of Energy and the National Institutes of Health now fighting turf battles for various pieces of the action, the decision to go ahead seems already a fait accompli, as inevitable as taxes on April 15, death, and all the rest of life’s certainties. The project currently is encumbered by numerous technical and logistical problems, but these likely will be overcome in short order. Once they are and the torrent of data pours out, what will all this net us? Or, more to the point, what are the limitations on the bounty yielded by this vast $2-$3 billion project? After all, even its most enthusiastic proponents can attach only a finite amount of utility to the data that will emerge. The human genome contains 3 billion bases of information. The proposed sequencing project would determine the presence of the nucleotides A, C, G or T in each one of these 3 billion positions in the genome. Scattered among this enormous complexity are the functional segments, the genes. We are not certain how many genes there are; estimates range from 20,000 to 100,000. A single gene may comprise a DNA segment from several thousand to several hundred thousand bases. This organizational plan is repeated in identical fashion in the genomes of all other placental mammals from mice through whales. The limited data that we currently possess suggest that 90 to 95 percent of the base sequences in our DNA are biologically meaningless, having no ability to encode proteins or regulate gene expression. Of course, just because we can’t assign meaning to these sequences in 1987 doesn’t exclude our achieving great insights in 1997. But the more we learn about human DNA sequences and those of other mammals, the less convincing is the case that amid this 90-95 percent of the genome we will find sequences that explain interesting aspects of our biology. Much of this material seems to represent evolutionary detritus, dead ends, side alleys and parasitic sequences that are extrinsic .to the functioning of our genes. If your life depended on finding meaning in most of these sequences, you would be rather nervous right now. It is quite possible, if not highly likely, that the great bulk of data flowing out of this project will be relegated to some computer tape, of little or no interest to anyone. Even within a DNA segment that is functionally defined as a gene, the amount of ostensibly meaningful genetic information often encompasses only a minor proportion of the DNA. This fraction includes regulatory sequences and protein-encoding sequences. Most of the rest is taken up by introns. If you delete most of the introns of a gene by appropriate manipulation, more often than not it functions perfectly well. I once was involved in isolating a gene of 45,000 bases, only 600-800 of which seemed to have any interesting biological functions. More recently, I have been associated with a gene of about 200,000 bases in size, only 3,000-4,000 of which seem to be associated with interesting functions. If someone were to walk into my laboratory tomorrow and offer me the entire 200,000 base sequence of this gene (one associated with the disease retinoblastoma), I would respond with a blank stare and some disbelief. I cannot imagine what help this would prove in solving the important problems surrounding the function of this gene and its encoded protein. Many will laugh at my myopia—we shall see who has the last laugh! Seen from my perspective, a gene appears as a small archipelago of information islands scattered amidst a vast sea of drivel. One thorny problem for those who will interpret gemone sequences coming out of the planned project stems from the fact that is is often bard to know when one has left the vast ocean (introns) and emerged dryshod onto land (information-encoding sequences, including exons). Indeed, it often is hard to know when one has come across the string of islands that in ensemble constitutes a functional gene. This rather grim situation may change over the next few years. We may develop algorithms for sensing unambiguously any encounter with meaningful information present in this sea of nonsense. But certainly, those who would have us spend billions on sequencing have no clear view of when and if this development will occur. It is fair to say that most of the stumbling blocks currently in our way in the difficult problems of human biology will not be pushed aside by the sequencing juggernaut. We still will have great difficulties associating specific genes with specific biological traits, normal or pathological. Gene mapping (as opposed to sequencing) will ameliorate this somewhat, but sequencing will have only a marginal effect. Once we succeed in linking a gene with a biological trait, we will want to know the sequence of its encoded protein. But because of the vagaries of split genes, we will continue to rely largely on cDNA versions of genes for this information, not on the chromosomal versions sequenced by the multinational collaborative now being assembled. And when we determine the sequence of an encoded protein, we will still be confronted with the biggest puzzle of all: how does this protein function to affect cell and organismic physiology? In general, the base sequence data will provide almost no insight into this critical question. There are those who fear that this sequencing will lay bare the few remaining mysteries about humanity, its unique mind and spirit. They worry that we will uncover things we were not meant to know. For my part, the sequencers are welcome to all they can learn. Those who fret about the sanctity of the human genome needn’t worry—we may understand less about ourselves at the end of this project than when we began. Weinberg is a member of the Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge MA 02142

The Case Against Gene Sequencing

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