ENHS Nature Trails March 2001 Article 2

Natural History and You - The President's Forum
by Nathan Tublitz

The Biological Big Bang: Sequencing the Human Genome

What is a scientific revolution? T.S. Kuhn defines a scientific revolution as a transforming paradigm shift, a cataclysmic re-evaluation of the established doctrine resulting in a new world view by the practitioners of that discipline. Galileo's heliocentric theory, Einstein's theory of relativity, and Pauling's explanation of chemical bonds profoundly and irreversibly altered the fields of astronomy, physics and chemistry, respectively. In biology, the two biggest revolutions have been Darwin's theory of evolution and Watson's and Crick's discovery of the structure of DNA. Both initially caused tremors of such magnitude that biology shook at its very foundation. However after the passage of the initial shock wave, the response quickly became a chorus of "bravos" as the fundamental importance of these discoveries was realized.

The sequencing of the human genome is no less an accomplishment. It is without a doubt the most important biological discovery of my lifetime, dazzling not only in its scope and implications but also as a tour de force accomplishment.

Humans contain 23 separate pairs of chromosomes, each of which consists primarily of DNA (deoxyribonucleic acid), a class of specialized chemicals with distinctive structures. DNA come in four flavors: adenine (A), guanine (G), cytosine (C), and thymine (T). These attach to each other forming a long, winding chain of individual DNA molecules. Each of our chromosomes is formed by entwining of two DNA chains into the famed double helix of Watson and Crick. Within each chromosome resides functional regions called genes, encoding the structures for the 1000s of proteins that regulate all aspects of our body's activities, from thinking to language to muscular movements.

The human genome - our 23 chromosomes - consist of 3.2 billion (!) DNA molecules. The very thought of deciphering the sequence of every A, C, G and T in our genome was thought impossible as recently as 20 years ago primarily due to the enormity of the task and the slowness of the DNA sequencing process. The tide began to turn in the mid 1980s with improvements in DNA sequencing technology and by the early 1990s it became a question of when rather than whether the sequencing would be accomplished. The pace of sequencing was abruptly increased when a private company enter the fray, turning the US government sponsored effort into a race between public and private concerns. Both groups announced their success last month through articles in scientific journals Science and Nature. It is interesting to note that only about 83% of the genome has been sequenced, including most of the regions thought to contain genes.

The first glimpse of the genome has already revealed many surprises. One surprise is how little of the human genome is actually taken up by genes. Only 1.1-1.4% actually codes for proteins, through an intermediate step called RNA (ribonucleic acid). Another 2% codes for RNA but is never converted into protein.. What about the remaining 96.6% of the human DNA? Much of this is so-called "junk" DNA, short and long repeated sequences long been thought to be functionless. However it appears that junk DNA might not be as worthless as first thought because the repeated sequences are non-randomly distributed in the genome, with some found in gene-rich regions and others found in gene-poor regions. Why do we have so many repeat sequences? The puffer fish, a bony fish known for its potent neurotoxin, has very few repeats in its genome and yet, that creature functions quite well. Maybe the "junk" regions are more than space fillers and not as useless as first thought.

Another major surprise comes from the analysis of the number of genes in the human genome. Both groups estimate that humans have about 30,000 genes (+/- ~5000). This is much less than previous estimates (the number still stated in most college biology textbooks is 100,000 genes). What makes this number remarkable is that we have only a few more genes than fruit flies (13,000), worms (19,000) or even a plant (25,000). Even more astonishing is that humans have only 300 genes not present in the mouse. But for an extra few genes, we may have all been born with long hairless tails.

How can we be different from mice, worms or even a plant yet have such a common genetic heritage? This question comes into sharp focus when faced with the realization that only 94 of the 1278 protein families (groups of proteins sharing similar structures and usually similar functions) are unique to vertebrates. That means humans share 93% of our protein heritage with the fruit fly or a slug. And if we are so closely related to those organisms, what makes you different from me? The answer probably lies in another remarkable finding from the genome work called single nucleotide polymorphisms or SNPs. Individual humans apparently differ from one another by about one DNA molecule per thousand or about 3.2 million different DNA building blocks in a complete human genome. These differences probably govern individual differences in capacities such as mathematical computation skills, athletic ability, social skills, and perhaps creativity.

The elucidation of the human genome sequence signals a fundamental, new era in biology with ramifications extending into all aspects of our lives. What does it mean to be human? Is it language? Consciousness? Our ability for high artistic achievement? Music? These questions, one thought impossible, can now begin to be unraveled. The real journey is just beginning. Hang on - the ride will be fantastic.

Nathan Tublitz
Professor of Biology
Institute of Neuroscience
University of Oregon
Eugene OR 97403
Phone: 1-541-346-4510 FAX: 1-541-346-4548

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