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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.)


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