Pieces of the puzzle: expressed sequence tags and the catalog of human genes

Imagine trying to solve a jigsaw puzzle without having all of the pieces. This is exactly the dilemma faced by researchers in the field of molecular medicine when attempting to understand how human genes and their protein products interact with one another to lead to normal biological functions, how these functions can break down in various disease states, and how normal functions can be restored through molecular intervention. This description of the Puzzle of Life is not meant to deny the importance of environmental and other epigenetic factors, but is simply meant to define the boundaries of a puzzle whose solution is easily within our grasp. To further our basic understanding of human biology and the genetics of inherited diseases, it would be immensely valuable to compile a complete catalog of human gene sequences and to make this information available over the Internet to scientists around the world. Over the past few years huge amounts of data relevant to this puzzle have become available, but solving the puzzle remains a bioinformatics challenge. Before setting out to solve the Puzzle of Life, it would be useful to have a rough sense of how many pieces it contains. In other words, how many human genes are there? Based on indirect evidence, estimates ranging from approximately 64,000 [1] to 80,000 [2] genes have been advanced. Complete genomic sequencing has been used to generate gene catalogs for several organisms with relatively small genomes [3]. However, sequencing the human genome is a much more daunting task due to its immense size (about 3 billion bases). The United States Genome Project began in 1990 with the ambitious goal of sequencing the human genome within 15 years (i.e., by the year 2005) [4]. Unfortunately, only about 2% of the total bases make up the protein-coding portions of our genes; the remaining 98% is of unknown function and often referred to as “junk DNA.” Thus, sequencing the genome may not be the most efficient way to generate a catalog of human genes. A number of investigators have advocated large-scale sequencing of the transcription products of genes, in the form of complimentary DNA (cDNA) clones, as a prelude to sequencing of the entire human genome. As Brenner [5] put it, “If something like 98% of the genome is junk, then the best strategy would be to find the important 2%, and sequence it first.” An abundance of puzzle pieces