Rethinking Genetic Determinism
With only 30,000 genes, what is it that makes humans human?
By Paul H. Silverman

For more than 50 years scientists have operated under a set of seemingly
incontrovertible assumptions about genes, gene expression, and the
consequences thereof. Their mantra: One gene yields one protein; genes beget
messenger RNA, which in turn begets protein; and most critically, the gene
is deterministic in gene expression and can therefore predict disease
propensities.

Yet during the last five years, data have revealed inadequacies in this
theory. Unsettling results from the Human Genome Project (HGP) in particular
have thrown the deficiencies into sharp relief. Some genes encode more than
one protein; others don't encode proteins at all. These findings help refine
evolutionary theory by explaining an explosion of diversity from relatively
little starting material. We therefore need to rethink our long-held
beliefs: A reevaluation of the genetic determinism doctrine, coupled with a
new systems biology mentality, could help consolidate and clarify
genome-scale data, enabling us finally to reap the rewards of the genome
sequencing projects.

UNEXPECTED RESULTS In the mid- and late 1980s, our testimony before the
congressional committees controlling HGP purse strings relied upon our old
assumptions.1 In describing the genome's potential medical value, we
elevated the status of the gene in human development and by extension, human
health. At the same time, the deterministic nature of the gene entered the
social consciousness with talk of "designer" babies and DNA police that
could detect future criminals.

Armed with DNA determinism, scientific entrepreneurs convinced venture
capitalists and the lay public to invest in multi-billion-dollar enterprises
whose aim was to identify the anticipated 100,000-plus genes in the human
genome, patent the nucleotide sequences, and then lease or sell that
information to pharmaceutical companies for use in drug discovery. Prominent
among these were two Rockville, Md.-based companies, Celera, under the
leadership of J. Craig Venter, and Human Genome Sciences, led by William
Haseltine.

But when the first draft of the human genome sequence was published in the
spring of 2001, the unexpectedly low gene count (less than 30,000) elicited
a hasty reevaluation of this business model. On a genetic level, humans, it
seems, are not all that different from flies and worms.

Or maybe they are, if we can assume that genes are not strictly
deterministic. As Venter et al. reported in their genome manuscript: "A
single gene may give rise to multiple transcripts, and thus multiple
distinct proteins with multiple functions by means of alternative splicing
and alternative transcription initiation and termination sites."2

The industry shakeup was predictable. Celera, Human Genome Sciences, and
most of the other genomic sequencing firms refocused their business plans
and downsized. Venter resigned as president of Celera, and Haseltine has
indicated his intention to do the same.

Read the rest at The Scientist
http://www.the-scientist.com/yr2004/may/research3_040524.html

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