A
Sequence for All Mankind
The human genome
sequence has an enormous symbolic
significance, and its publication in the
Feburary 16 issue of Science and in this
week's Nature is likely to be greeted with
the same feeling of awe that accompanied
the landing of the first human in space,
on the moon and the detonation of the
first atomic bomb.
The reason for this is that these
breakthroughs change how we think about
ourselves. How ? The availability of a
reference human DNA sequence is a
milestone toward understanding how humans
have evolved, because it opens the door to
large-scale comparative studies. The major
impact of such studies will be to reveal
just how similar humans are to each other
and to other species. The first
comparisons are between the human genome
and distantly related genomes such as
those of yeast, flies, worms, and mice.
However, the most obvious challenge to the
notion of human uniqueness is likely to
come from comparisons of genomes of
closely related species. We already know
that the overall DNA sequence similarity
between humans and chimpanzees is about
99%. The close similarity of our genome to
those of other organisms will make the
unity of life more obvious to
everyone.
A 2.91-billion base pair (bp) consensus
sequence of the euchromatic portion of the
human genome is reported in Science
magazine. The sequence was generated by
the whole-genome shotgun sequencing method
over a period of 9 months from 27,271,853
high-quality sequence reads (5.11-fold
coverage of the genome) from both ends of
plasmid clones made from the DNA of five
individuals. Two assembly strategies were
used to combine sequence data from the
privately and publicly funded effort.
More than 90% of the genome is in scaffold
assemblies of 100,000 bp or more, and 25%
of the genome is in scaffolds of 10
million bp or larger. Analysis of the
genome sequence revealed 26,588
protein-encoding transcripts for which
there was strong corroborating evidence
and an additional ~12,000 computationally
derived genes with mouse matches or other
weak supporting evidence. Comparative
genomic analysis indicates vertebrate
expansions of genes associated with
neuronal function, with tissue-specific
developmental regulation, and with the
hemostasis and immune systems.
Although the researchers have identified
and mapped more than 3 million single
nucleotide polymorphisms, this by no means
implies that the task of finding and
cataloging SNPs is complete. SNP studies
will establish the range of haplotypes
present in subjects of different
ethnogeographic origins, providing
insights into population history and
migration patterns. Although such studies
have suggested that modern human lineages
derive from Africa, many important
questions regarding human origins remain
unanswered, and more analyses using
detailed SNP maps will be needed to settle
these controversies.
The next steps are to define the
complexity that ensues when this
relatively modest set of about 30,000
genes is expressed. The sequence provides
the framework upon which all the genetics,
biochemistry, physiology, and ultimately
phenotype depend. It provides in essence
the boundaries for scientific inquiry. The
sequence, however, is only the first level
of understanding of the genome. All genes
and their control elements must be
identified; their functions, in concert as
well as in isolation, defined; their
sequence variation worldwide described;
and the relation between genome variation
and specific phenotypic characteristics
determined.
Another paramount challenge awaits: public
discussion of this information and its
potential for improvement of personal
health. There are two fallacies to be
avoided: determinism, the idea that all
characteristics of the person are
"hard-wired" by the genome; and
reductionism, the view that with complete
knowledge of the human genome sequence, it
is only a matter of time before our
understanding of gene functions and
interactions will provide a complete
causal description of human variability.
The real challenge of human biology,
beyond the task of finding out how genes
orchestrate the construction and
maintenance of the miraculous mechanism of
our bodies, will lie ahead as we seek to
explain how our minds have come to
organize thoughts sufficiently well to
investigate our own existence.
(Excerpts taken from the Human Genome
Sequence article in Science
magazine.)