Genome map guides
new era of discovery

It is a remarkable achievement that extends far beyond the technology and human resources that went into the 13-year project. It is the "Brooklyn Bridge" that connects the biological sciences with the physical sciences, a link that scientists have sought since Darwin wrote of his goal to search for the "rules of life" 165 years ago.

The genome is the sum of all genetic information of an organism. It is the organism's complete set of DNA, containing all of the instructions to construct, differentiate, duplicate, maintain, direct, and regulate the activities of cells.

The information and chemical functions work the same way and use the same components in all living systems, branding us direct chemical relatives of all life on earth. We share bits of DNA with every cell that has ever lived, from the simplest amoeba to other complex and highly evolved mammals and birds, yet each species possesses a unique genome.

Only about 2 percent of the human genome is actually genes. The remaining 98 percent performs other functions that include maintaining the structural integrity of chromosomes and regulating where, when, and in what quantity proteins are made. Many of the specific functions are mysteries, but with the genome sequencing now complete, understanding progresses quickly.

Some of the discoveries are quite surprising, and suggest that now that real work has just begun.

The sequence of nucleotides alone says nothing about where on the sequence individual genes are located nor does it reveal the meaning of the parts of the sequence that are not genes.

Understanding what kind of information other than the classical genetic traits the genome holds has become the holy grail of molecular biology.

Contained within each and every human cell (except mature red blood cells) are the instructions for assembling, regulating, and maintaining a complete human. This includes the timing and processes of cell division and differentiation, but also production of the 90,000 proteins that serve a variety of functions: structural components such as skin and cell walls; control and regulatory functions in the form of hormones and enzymes; other specialized cells such as neurons and nucleic acids.

Genes get all the attention, but proteins control most life functions and make up the majority of cellular structures.

The collection of all proteins in a cell is called its proteome, which, unlike the relatively unchanging genome, is dynamic. The proteome changes from minute to minute in response to tens of thousands of signals that come from both inside and outside the cell.

Somehow the genome stores all of this information along with the instructions for making copies of itself by cell division and creating a unique new genome through sexual reproduction.

Before the Human Genome Project began, scientists predicted that there might be as many as 300,000 genes in the genome under the "one gene one protein" assumption.

Considering our complexity, one would think that we would have more genes than the 19,500 of a small, thousand-cell roundworm or the 40,000 of corn.

As the human genome sequence emerged, the estimates got smaller and smaller. When the first draft of the sequence was published in 2001, the number of genes was estimated at an embarrassingly small 30,000 to 35,000 protein-coding genes.

With the completion of the sequencing in 2003, the revised estimate is now fewer than 25,000, begging the question of how the number of genes can be only one-fourth of the number of proteins.

Now it appears that the more complex the organism the more versatile and creative is its use of the genes through a mechanism called "alternative splicing."

When the time comes for a gene to "express" itself by carrying out its instructions, the helical DNA ladder "unzips" so that a single-stranded copy of its sequence can be assembled from RNA, like a wax impression of a key.

Some of the RNA molecules do not manufacture proteins but instead perform housekeeping and regulatory functions within the cell. Those that do encode a protein go through an editing process that is not unlike what a film editor does when scenes are deleted from a movie.

Each primary RNA transcript is like an instruction manual that contains groups of meaningless pages at apparently random intervals. These are called "introns," and must be "snipped" out of the sequence so that the meaningful chapters, called "exons," can be connected to form a final version of the instructions.

From this edited messenger RNA (mRNA) a particular protein is chemically assembled by collecting amino acids that match the sequence of nucleotides in the mRNA molecule.

It has been known for 25 years that the cellular editing machinery (which itself consists of proteins encoded within the genome) can exclude some exons and leave in some introns, or pieces of them, in the final mRNA by a process of alternative-splicing.

Alternative splicing significantly increases the versatility of the gene by allowing a single gene to encode more than one protein, depending on whether a given intron or exon is skipped, included, spliced in, or snipped out.

As continuing research reveals details of the workings of this molecular machinery, the intricacies of an exquisite system emerge that may also contain the key to understanding how small differences between genomes can produce large-scale differences between organisms.

Chimpanzees and humans share 99 percent of their genomes, including a special class of short, mobile, alternatively spliced exons called Alus that occur only in primates. Their function seems to be to generate copies of themselves and reinsert them back into the genome at random positions.

Once in the genome, an Alu has the potential to create a new species-specific protein. This genetic "invention" may have driven the divergence of primates from other mammals, ultimately giving rise to the combination of intelligence, symbolic reasoning and linguistic abilities, and fine motor control that distinguishes us from all other species.

These are exciting times in molecular biology, equivalent to the rapid discoveries in motion and gravitation in the 17th century, in chemistry in the 18th, electricity and magnetism in the 19th and in quantum mechanics in the 20th.