The chimpanzee genome, which has existed in draft form since the beginning of this year, is poised to reveal new insights into human health and history, according to Svante Paabo. The renowned molecular anthropologist from the University of Leipzig spoke at a plenary session of the annual meeting of HUGO (the Human Genome Organization), which began in Berlin this week.
Paabo and colleagues bring molecular genetic techniques to bear on questions of human evolution. Few advances in that regard are more important than the imminent completion and publication of the chimpanzee genome sequence.
Chimpanzees are our closest relative in evolution, having diverged about 5 million years ago. The genomes of the two species are 98.8 percent identical at the DNA level – a trivial difference in some respects, although Paabo pointed out that this equates to some 40 million variants in total across the genome, not including numerous rearrangements and insertions and deletions.
A fraction of these variations may hold the key to understanding some of the key evolutionary differences that distinguish humans and chimps – areas such as cognition, language, aging, as well as diseases such as Alzheimer’s, schizophrenia, autism, and susceptibility to infectious diseases (AIDS, malaria), as well as cancer.
As these are likely to be polygenic conditions, however, Paabo cautioned that such insights will only emerge with additional genome resources – including the availability of another non-primate genome, the Rhesus macaque – in conjunction with parallel approaches, including studies of the proteome, transcriptome, and the “phenome.” To improve the phenotypic characterization of non-human primates, Paabo’s institute in Leipzig is building a multidisciplinary team to bolster research in primate physiology and social behavior, fields he says have been sorely neglected in the past. “We need to understand the phenotypic differences between chimps and humans,” says Paabo.
Early Insights
Paabo illustrated two examples of early insights into the biology of humanness that preliminary analysis of the chimp sequence has entailed.
First was the field of smell, which is governed by a family of about 1,000 odorant receptors (ORs) in the nose. These ORs transmit nerve signals to the brain that result in the sense of smell. In humans, however, more than half of these receptors are pseudogenes – genes that have withered via mutation and are no longer functional. This contrasts with mice, which have very few pseudogenes. Chimpanzees lie in the middle, having about 30 percent pseudogenes in the OR family. Thus humans are steadily losing functional OR genes – even to the present day. However, there is also evidence for positive selection in at least a subset of OR genes, suggesting that some OR genes may acquire new functions over time.
A second area highlighted by Paabo is the transcriptome. In studies performed using Affymetrix chips, surveys of different regions of the brain have consistently revealed 5-6 percent differences in gene expression. Overall, about 10 percent of the human/chimp genome shows significant difference of expression in some area of the brain. But are these differences functionally significant? To put it another way, are they the result of Darwinian selection or the neutral theory of evolution?
Paabo listed three predictions that would be expected if the sum changes were neutral, rather than the result of selection. However, studies on expression differences between species do not reject any of these predictions, suggesting that the changes seen for the majority of these genes do not appear to have widespread functional significance.
Two other speakers also discussed the pros of comparative genomics. Jenny Marshall-Graves (Australian National University, Canberra) spoke passionately of the virtues of the kangaroo and its “eight gorgeous chromosomes.” Marsupials diverged from eutherian mammals (including humans and primates) about 180 million years ago, and represent the first steps of mammalian evolution. The kangaroo embryo is born about the size of a pea, and is little more than “a mouth, a gut, and a pair of hands to get up to the mother’s pouch,” providing an exciting model for the study of early development. Graves said that a promising candidate gene for pouch development has been identified on the X chromosome. “Maybe we can give pouches to other animals – even humans!” she quipped.
Evan Eichler (Case Western University) highlighted the significance of segmental duplications in the human genome, either on the same chromosome (intrachromosomal) or between chromosomes (interchromosomal). About 150 million bases – the equivalent of a single chromosome – consist of duplicated regions of DNA. Rearrangement of these regions can increase susceptibility to diseases, including cancer.