Psychiatry in the Genomics Era "We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest."

what the timetable will be. In this commentary we argue that genomics may soon become an important aspect of psychiatry, and we consider what genomics can and cannot do for mental disorders. Let’s start with a few definitions. A gene is simply a sequence of DNA that provides a critical code for messenger RNA, which in turn is translated into protein. How is genomics different from genetics? Genomics and genetics both study the transmission of traits across generations (an interest of Darwin and Freud as well as Mendel). Genetics is the study of single genes and their effects. Genomics is the more ambitious study of all the genes in the genome, including their function, their interaction, and their role in a variety of common disorders that are not due to single genes (2). Advanced draft descriptions of the human genome have now been published (3, 4), and the complete sequence is soon expected in public databases. The number of genes is around 30,000, with these genes spaced unevenly across the 2.9 gigabases of DNA that constitute the human genome. While we note a growing tendency to refer to this period following the sequencing effort as the post-genomic era, we want to emphasize that, from a discovery perspective, we are just entering the genomic era. Certainly, there are many mysteries still to be explained. For instance, less than 2% of the DNA in the genome codes for proteins. The >98% that remains consists of vast repetitive stretches of DNA and other sequences that may have regulatory effects or may be a nonfunctional residual of evolution. While this >98% of the genome has been frequently disregarded as “junk DNA,” it almost certainly has important functions still to be discovered. As evidence, a recent comparison of the human and mouse genomes (5) revealed that the proteincoding regions account for less than half of the DNA that has been strongly conserved over the 70 million years since humans and rodents diverged. The conservation of millions of base pairs of DNA that do not code for protein suggests that these regions might be functional. It is certain that some of these conserved segments will be found to be involved in regulating gene expression by serving as target sites for protein factors that regulate transcription. Others may act by producing small RNA fragments that interfere with gene expression or may confer other biological functions not yet understood. The arrangement of genes across the genome is strikingly uneven. Some chromosomes (17, 19, and 22) are gene dense and some (13, 18, and 21) are sufficiently gene poor that trisomy (having a third copy) is nonlethal. We do not understand the importance, if any, of this variation in gene density across chromosomes, although it may have something to do with position in the interphase nucleus. The number of genes is itself a mystery, with humans having essentially the same number as mice (27,000–30,500) (5), less than twice the number of the nematode C. elegans (approx. 19,700) (6) and slightly more than twice the number of the fly Drosophila (approx. 13,600) (7). But the relatively low number of genes may be misleading, since the original dogma that each gene specifies only a single protein has now been supplanted by the observation that single genes routinely make multiple proteins through the mechanism of alternative splicing (8). By alternative arrangements of RNA follow