A chimpanzee genome project is a biomedical imperative.

Abstract

A near-complete sequence of the human genome is now available, and many efforts are currently focused on the next logical biomedically relevant target — the mouse genome. Given limited resources, which vertebrate genome(s) should be tackled after that? Reasonable candidates include other well-studied model organisms such as Rattus rattus (the rat), Xenopus laevis (the African clawed toad), and Danio rerio (the zebra fish). Over the last few years, some have been advocating a genomic approach toward understanding our closest evolutionary relatives, the great apes (McConkey and Goodman 1997; Paabo 1999; McConkey et al., 2000). Pan troglodytes (the chimpanzee) and Pan paniscus (the bonobo) share nearly 99% of human genomic sequences (see Box 1 for discussion) (King and Wilson 1975; Sibley and Ahlquist 1984; Caccone and Powell 1989; Ruvolo 1997; Goodman et al. 1998; Satta et al. 2000). Thus, it is cogently argued that knowing the complete genome of at least one of these species will give us a window into genes that contribute to humaness (the chimpanzee is the first choice, because we know more about this species than we do about the bonobo). The emergence of humans can be regarded as one of the major transitions in evolution (Szathmary and Smith 1995), and the complete explanation of this phenomenon ranks as one of the greatest unsolved mysteries of science. Taxpaying citizens might argue that, given limited resources, this lofty and anthropocentric pursuit should not take precedence over the pragmatic value of sequencing genomes of model organisms that have already been better studied by a variety of biomedical and genetic approaches. Moreover, it might be suggested that this is a matter for the National Science Foundation (NSF) to deal with, not the National Institutes of Health (NIH). Programs within the NSF are currently considering a Human Origins Initiative (Weiss and Yellen 2000). However, I would like to suggest that there is clear and compelling biomedical value to giving high priority to the complete sequencing of the chimpanzee genome and that of at least one Old World monkey. The experience of primate centers and zoos over the last century indicates that there are many interesting differences in disease frequency and severity between humans and great apes such as the chimpanzee. Whereas the evidence is sometimes fragmentary or inconclusive, the nature and significance of these medical conditions (including AIDS, Alzheimer’s disease (AD), cancer, malaria, and perimenopausal complications) are sufficient to draw attention to the issue. After all, extrapolating findings in physiology and pathology from mice, rats, toads, or fish to humans can be difficult, because of our significant physiological and genetic differences from these species. In contrast, the >99% identity of amino acid sequences of most chimpanzee and human proteins (see Box 1) predict a stronger likelihood of finding genetic explanations for any disease differences. Studies of the chimpanzee genome could be considered a logical extension of the current emphasis on exploiting sequence differences between various human groups to identify important disease susceptibility genes. For this and other reasons, the cost of a chimpanzee genome project should also be much less than for the original Human Genome Project. Also, as discussed below, the knowledge gained could be of much value in our efforts to conserve and care for the great apes themselves. Some pathological states in humans seem to represent the normal situation in chimpanzees, including craniosynostosis (closure of the skull sutures in the perinatal period) (Cohen 1991), general leukocytosis (a high white blood cell count) (Hodson et al. 1967; McClure et al. 1972) and extensive hypertrichosis (hairiness). Several other diseases or physiological states of humans appear to be rare or markedly attenuated in the chimpanzee (Scott 1992). Some of these diseases can be attributed to anatomic differences between the species, including protracted, painful, and dangerous childbirth (resulting from the larger head of the human fetus and the altered pelvis of the bipedal human female), neonatal cephalhematoma (the common subperiosteal blood clot of the new born human skull bones), wisdom tooth impaction (resulting from the reduced jaw size in humans and the lack of a post-molar gap), and various diseases attributed to gravity effects on bipedal humans (vertebral osteoarthritis, intervertebral disc protrusion, varicose veins, and hemorrhoids). There are also a few anatomically unique diseases of great apes that do not occur in humans, such as infection of the pharyngeal air sacs (an organ that is absent in humans) (Strobert and Swenson 1979). The rarity of certain other human conditions such as sexually transmitted diseases and severe hypercholesterolemia in great apes is possibly explained on a behavioral/ cultural basis, as they can be induced experimentally in the latter (Scott 1992). The higher frequency in humans of anatomical disorders of the central nervous system such as hydrocephalus is also inE-MAIL avarki@ucsd.edu; FAX (858) 534-5611. Insight/Outlook