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October 20, 1998

Human or Chimp? 50 Genes Are the Key

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    Theologians may ponder the difference between God and the creature made in His image, but biologists have always asked a humbler question: How do humans differ from other animals? A proposal now under active discussion promises to provide an answer of possibly disconcerting precision.

    The idea is to identify the genes that are special to humans by sequencing the genome, or full DNA, of the chimpanzee and comparing it with the human genome.

    Chromosome Cousins

    Chromosomes of humans, chimpanzees, gorillas and orangutans, stained to show bands of active genes.

    Because chimpanzees are so closely related to humans, those genes that work differently in people than in chimpanzees could be all that is needed to convert a default-mode great ape into a human.

    The number of such genes may be only a few hundred, out of the 100,000 genes that humans and chimps are thought to possess, with just 50 genes accounting for the cognitive differences, according to scientists at GenoPlex, a company in Denver that is exploring chimp genes for medical reasons.

    Others, while welcoming pursuit of the new knowledge, foresee certain hazards that might accompany it, like the temptation to engineer more human humans through enhanced versions of the specially human genes, as well as the ethical problems inherent in trying to test the role of these genes by inserting them into chimpanzees.

    Most human genes have an ancestry that goes back to the earliest animals and are shared in common with other species. Creatures as distant from humans as the fruit fly or roundworm have genes whose DNA sequence is recognizably similar to their human counterparts, as if they were variant spellings of the same word.

    The Federal human genome project, which aims to decode the three billion units of human DNA by 2003, will lay the basis for understanding the human genetic programming as a whole but is not intended to ferret out the genes unique to humans.

    The idea of doing this by means of the chimp genome was first proposed a year ago by two biologists who study evolution at the DNA level, Edwin McConkey of the University of Colorado at Boulder and Morris Goodman of Wayne State University in Detroit. Their proposal was further explored at a meeting this month at the Field Museum of Natural History in Chicago.

    So far the leading supporter of chimp genome research in the United States has been GenoPlex, a company founded by two University of Colorado biologists, James M. Sikela and Thomas E. Johnson. The company has already identified a gene that may contribute toward chimpanzees' greater resistance to AIDS.

    DNA, the chemical tape that embodies the genetic programming, changes very slowly. Chimpanzees and humans are thought to have taken different evolutionary paths only five million years ago, a mere eye blink in evolutionary time. Because the two species shared an ancestor so recently, their DNA is on average 98.4 percent identical.

    It is a serious puzzle for biologists to explain how two such similar genetic programs generate such different animals. Dr. David L. Nelson, a biologist at the Baylor College of Medicine, said that some of the anatomical differences between chimps and humans might arise from very small changes in the genes that regulate fetal development.

    The human brain is about twice the size of the chimpanzee brain, but a genetic program that allowed time for the brain cells in the developing fetus to go through just one more doubling would account for the difference, Nelson said. The human face is tucked underneath the brain case instead of projecting beyond it as in the chimp, but this could be arranged just by arresting the forward movement of the face during fetal development.

    Still, there are many other human-chimp differences that have to be generated by the almost identical genetic programs. Dr. Nelson thinks some of the differences might be explained by a phenomenon that lies beyond the mere sequence of DNA.

    With a colleague, Elizabeth Nickerson, he has been studying a curious rearrangement in chimpanzee chromosomes, the bundles in which DNA molecules are packaged. Compared with humans, chimps have five chromosomes in which a central segment has been flipped. Genes on the flipped portion of the chromosomes would find themselves in a different environment and might be more or less active than before, Dr. Nelson said. Even a small difference in the activity of a high-level regulatory gene could produce significant effects in the developing animal.

    The genes that make humans more than just another great ape are unlikely to be totally novel genes, experts say, but rather ones that acquired a new role compared with their counterparts in the chimps.

    These genes would have been under strong evolutionary pressure, a force that can often be detected through a quirk in the genetic code, the system through which sets of three DNA units, or nucleotides, specify the 20 amino acid building blocks of proteins. The code is somewhat ambiguous in that in some cases one nucleotide can change or mutate to another without changing the specified amino acid. These changes are silent, meaning that they make no difference to the organism and are almost neutral in terms of its survival prospects.

    Nucleotide mutations that do change the specified amino acid are usually harmful, and thus are less common than the silent mutations. On the rare occasions when these consequential mutations are beneficial, they are quickly favored by natural selection and outnumber the silent mutations.

    Sikela hopes to identify the few hundred genes that are special to humans by pinpointing genes that have been under strong selective pressure. His plan is to compare the DNA sequence of human genes and their chimp counterparts, and look for genes in which consequential changes outweigh the silent ones.

    Many changes that seem distinctively human, like larger brain size, are in fact evolutionary trends that began far earlier in the primate line. Goodman thinks it will be necessary to sequence the genomes of a series of primate species in order to clarify these trends. To explore each of the major branch points leading to humans over the last 60 million years, he would like someone to sequence lemurs, bush babies, pottos, tarsiers, capuchin monkeys, rhesus monkeys, gibbons, orangutans, gorillas, chimps and bonobos.

    Dr. Francis Collins, director of the human genome project at the National Institutes of Health, said that having the chimp genome in hand would be extremely useful and that he would consider financing pilot projects to sequence the chimp genome, not from scratch but through its differences with human DNA.

    Discovery of the genes that are special to humans might not be without hazard.

    "The more we learn about the genes that are crucial for our uniquely human characteristics, the greater the temptation to produce humans that have optimal combinations of these genes, or even enhanced genes," McConkey said.

    Another problem is that biologists might wish to test the supposed role of the uniquely human genes by inserting them into chimpanzees. "I don't know whether society will ever be comfortable with such a drastic thing as adding a human gene to an ape," McConkey said.

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