Science And The Citizen.docx

SCIENCE AND THE CITIZEN How Many Genes and Y Gene mappers nd plenty, even in junk chromosomes When the idea of mapping and sequencing all the genes that make up a human being was rst proposed, it seemed an undertaking tantamount to putting a man on the moon. The massive international eort was expected by some to continue for 15 years or more. But after only two years, the Human Genome Project is proceeding more rapidly than most biologists had dared predict. We are two or three years ahead of schedule, says Daniel Cohen of the Center for the Study of Human Polymorphism (CEPH) in Paris. I believe it will be possible to have a very good map of the genome by the end of 1993. Probably the sequence of the genome will be nished by the end of the century. Sketchy though they are, the latest genetic road maps are already obliging geneticists to reappraise their theories about the functions of some human chromosomes. Meanwhile parallel work on simpler organisms, such as the much studied roundworm Caenorhabditis elegans, is revealing that they have unexpectedly large numbers of genes. As a result, some investigators are speculating that the human genome may turn out to be far larger than the 100,000 or so genes it is believed to contain. Norton D. Zinder of the Rockefeller University, a former co-leader of the project who now advises the National Institutes of Health on its eort, believes many of the recent discoveries could not have been made without a comprehensive gene-sequencing eort. There are real data coming in, and it proves that we are going in the direction we should be, he says. The genome project involves developing three increasingly detailed maps of the DNA in cells. The rst is a genetic linkage map, which shows the relative distances between markers on a chromosome. The second is a physical map, which locates similar genetic landmarks but species the actual number of nucleotide bases, or DNA subunits, between them. The ultimate map is the ordered sequence of bases in a chromosome that describes the genes and the proteins they make. DRAWINGAMAP of the Y chromosome was the task undertaken by Adrienne Hilton and her molecular geneticist colleagues at the Whitehead Institute at M.I.T. In early October, through a colossal combined eort by the NIH and CEPH, genetic linkage maps for 23 of the 24 types of human chromosomes were compiled and published. Simultaneously, physical maps for two of the chromosomes were released: chromosome 21, which was mapped by Cohen and his colleagues, and the Y chromosomefor which there was not a linkage mapby David C. Page, Simon Foote, Douglas Vollrath and Adrienne Hilton of the Whitehead Institute at the Massachusetts Institute of Technology. Cohen and Page both used essentially the same techniques to map the chromosomes. Through a process called sequence-tagged site mapping, they established the order of small marker sequences on the chromosomes. They then chopped the chromosomes into pieces of DNA about a million bases long and spliced the pieces into yeast DNAto produce articial chromosomes, which could be measured

conveniently. By looking for the markers on the articial chromosomes, the researchers deduced how to t them together, like pieces of a puzzle. Some segments of the human chromosomes are missing from these maps, but they are not believed to contain any genes. Because chromosome 21 has been associated with Downs syndrome, some forms of Alzheimers disease and other disorders, the clearer picture of its genetic contents is expected to have great medical relevance. In the short run, however, the Y chromosome may benet most from the new map because it is the least typical of the human chromosomes and in many ways the least understood. Were trying to make this chromosome respectable, Page says. The Y chromosome, according to Page, has often been regarded as basically a junkyard containing no more than a few genes related to spermatogenesis and other functions peculiar to males. Many people refer to the Y as a maleness chromosome, he says. I think that is much too narrow a cubbyhole to t this chromosome into. One piece of evidence on his side is the discovery by his mapping team that 25 percent of the studied Y regions are homologous, or highly similar, to parts of the X chromosome. On the X, several genes essential to both sexes are found in these areas. Other studies have also found similarities in gene sequence on the two chromosomes. Im sure thats just the tip of the iceberg, Page adds enthusiastically. One important implication of those similarities is that a classic tenet of geneticsthat males have only one copy of all the genes on the Xis wrong. Consequently, Page argues, the work on the Y chromosome sequence forces us to rethink not only the functions of the Y but also of the X. How important the genes on the Y chromosome are remains to be seen, but Page contends that history is on the side of people predicting an ever widening array of functions for this chromosome. The final stage of the project, sequencing the individual genes, has not yet begun. But related eorts in other species are well under way. In the spring of 1992 Robert Waterston of the Washington University School of Medicine and John Sulston of the Medical Research Council in Cambridge, England, and their colleagues published the sequence of more than 120,000 bases in the DNA of C. elegans. That represented only a tenth of a percent of the total genome, but the pace of sequencing is accelerating: Waterston reports that they have now sequenced about one million bases and expect to nish another two million bases within a year. Meanwhile a European consortium of 145 scientists has been sequencing chromosomes of the common yeast Saccharomyces cerevisiae. Last May the group published the complete sequence of chromosome III. According to Stephen G. Oliver of the University of Manchester Institute for Science and Technology, who served as DNA coordinator on the project, yeast chromosome XI is now about two thirds nished, and chromosome II is about half done; extensive work has also been done on chromosomes I and VI.

Endangered Genes an you name the male and female leads of the Human Genome Project? They star in Gray’s Anatomy and have white skin, urban homes and composite ancestry. Still can’t place them? They are John and Jane Doe. So much for ethnic diversity. The ethnocentric bias of the genome project has riled an international group of anthropologists who hope a more extensive catalogue of human genes will allow them to reconstruct human evolution. For the past two years, they have been planning a parallel initiative called the Human Genome Diversity Project. Their goal is to sample the genes of aboriginal peoples before these peoples die out or assimilate. A quick survey of the most endangered groups should take about five years and cost about $23 million, says Luigi L. Cavalli-Sforza of Stanford University. Those who map the genes of John and Jane Doe will never miss that paltry sum, although they may gain a substantial return on the investment. If the sample turns up genetic adaptations to disease, for example, workers may use the knowledge to develop new therapies. The project began two years ago, when five geneticists published a manifesto challenging the ethnocentricity of the genome project in the journal Genomics. Others quickly jumped on the bandwagon because two of the authors commanded such respect in the field’s main camps: those who study populations and those who study individual gene lineages. The first approach was championed by Cavalli-Sforza, the second by the late Allan C. Wilson of the University of California at Berkeley. Proponents of the two approaches worked out their differences at a workshop held last summer at Stanford. Cavalli-Sforza argued for intensive sampling, the only way to get the statistical depth he needs to look at gene frequencies in different populations. But to obtain enough specimens in each sample, Cavalli-Sforza conceded, he would have to make do with relatively few samples. He therefore wanted to study ethnic groups whose linguistic distinctiveness suggests they are of ancient descent. Wilson’s disciples favored a more extensive survey. Because they study the lineages of individual genes, they could broaden the coverage at the expense of sample size. In their most controversial work, they surveyed a few hundred individuals to build a genealogy tracing all humans to an African matriarch who lived some 200,000 years ago. The two schools clashed on a practical matter as well. Cavalli-Sforza’s group wanted to preserve specimens by immortalizing cells, a procedure that requires rushing fresh blood to the laboratory before the white cells die. Wilson wanted to facilitate a broad survey by letting ethnographers put the blood on ice, so that they could go on collecting for weeks. They could then deposit their trove in repositories from which future generations could draw repeatedly, using the new techniques of DNA amplification. The workshop compromised: ethnographers would concentrate on distinct ethnic groups, as Cavalli-Sforza wanted, but they would spread their resources over a greater number of groups, as Wilson’s team wanted. They also agreed to immortalize only a fraction of the specimens. They projected a sample of about 400 groups. A second workshop chose the groups at Pennsylvania State University over the Halloween weekend. Anthropologists, linguists and geneticists divided into teams specializing in each region save Europe, which has its own project under way. Eyes glazed as specialists struggled to fill out forms assigning priorities to tribes and pointing out problems ethnographers might face. Watch out for guerrillas and coca smugglers, said the South America group. Survey the hundreds of Polynesian populations at a few central labor exchanges, suggested the Pacific group. Refuse to report HIV-positive cases to governments on grounds of medical confidentiality, counseled the Africa group. All were

concerned about the language they—and reporters—might use to describe their work. “You can talk of ‘tribes’ in Africa but not in this country,” said one participant. Others worried that labeling a group as “endangered” would offend the majority group in their country. The third workshop, to be held in Washington early this year, and the fourth, to be held in Sardinia next fall, will discuss the logistics of reaching all points on the globe, the techniques for collecting and analyzing materials and the ethical problems in exploiting native peoples for their genes. Some groups find anthropomorphic sampling so repugnant that they refuse access to the dead as well as to the living. —Philip E. Ross