Genetics Select

The complete human genome sequence presents researchers with unique opportunities not only for identifying the mechanisms underlying a battery of genetic diseases but also for revealing what makes us human. This issue's Genetics Select highlights recent developments in the field of human genetics that promise to direct future studies in the fields of comparative genomics and human disease research. Genomics-scale analyses are now used to study evolution, comparative genetics, and human disease. As such analyses become more common, proper annotation of protein-coding genes will be essential, and a tough challenge is making this determination on a genome-wide basis. It is not feasible to tackle this problem experimentally gene by gene, and assigning labels based on sequence conservation is difficult. In a new study, Clamp et al. (2007) address this challenge by establishing criteria to define protein-coding genes in the human genome, and they develop a computational protocol that enables them to rapidly classify human genes according to their genomic characteristics. Current catalogs consider the presence of open reading frames (ORFs) to be indicative of a protein-coding gene, even if the sequence is not conserved in other mammals. This mode of thinking predicts that human evolution necessitated the advent of new genes. Through a new method of genome analysis, Clamp et al. reject this practice, proposing that nonconserved, or orphan, ORFs might arise randomly during geno-mic evolution. Indeed, their analysis suggests that there might be only 168 human-specific protein-coding genes in the human genome. This new methodology trims the calculated number of human protein-coding genes from 24,500 to 20,500 and establishes criteria for future evaluation of putative human protein-coding genes. The authors suggest that areas of the genome that have not been adequately annotated, especially those regions encoding short polypeptides or containing non-coding genes, where marked changes might be more readily observed, are ripe areas for future study. Overall, the new work indicates surprisingly that relatively little genomic innovation might have occurred during human evolution. Importantly, the genomics algorithm used in this study should be readily applicable to other sequenced genomes. The differences between humans and chimpanzees, although visually striking, are relatively small on a genomic scale. Although chimpanzees are our closest relatives, we display many species-specific morphological, immunological, and behavioral differences. How are these differences established? Certainly some genes are expressed differentially, but in most cases, the same protein products are produced, leading to only slight alterations in cellular signaling …