Many others have abundantly commented on the publication of Craig Venter’s genome this week in PLOS Biology (Levy et al, 2007). The sequence of his full diploid genome (HuRef) reveals that the degree of genetic variability between maternal and paternal chromosomes is much higher (0.5%) than expected. Part of this variability is due to insertion/deletions (indels represent only 22% of variant events but amount to up to 75% of the variant nucleotides), alterations that are typically missed by SNP genotyping (SNPs represent 78% of the variants). Copy number variations (62, amounting to 10Mb) are also reported, albeit not determined by sequencing but via microarray genomic hybridization. With regard to variability in gene exons, the analysis shows that at least 44% of the genes are in the heterozygous state.
Beside its scientific content, the psychological impact of this study is considerable. The small interactive “toy” map (see illustration, modified from Levy et al, 2007) published on the PLOS Biology website is a particularly strong symbol: the entire genome of an individual human being displayed on a single page! The fact that a genome is a beautiful linear structure and can be displayed in such a simple and compact way, on a single poster, inevitably triggers the reflex to zoom in, focus on a favorite gene and speculate on the resulting phenotype. This almost unavoidable fascination for a linear interpretation of a linear structure (one gene maps to one disease) is illustrated by the many comments on Craig Venter’s “”http://www.cnn.com/2007/HEALTH/09/04/dna.venter/index.html">genetic destiny", “”http://www.nature.com/news/2007/070903/full/449006a.html">wet earwax", predispositions (or lack thereof) to “”http://www.nytimes.com/2007/09/04/science/04vent.html">alcoholism, coronary artery disease, obesity, Alzheimer’s disease, antisocial behavior and conduct disorder" and last but not least, to his blue eyes. Even if Venter himself makes it clear that it “is an impressive array of large sets of genes together with environmental conditions that will determine life outcomes” (Anderson Cooper Blog), it remains that it is very hard to visualize this reality in an intuitive way. The PLoS poster shows a linear map, not an intricate probabilistic network of any sort. The educational efforts required to change in the general public the easy linear representation into a more “integrative” view is certainly going to be a major but decisive challenge, if, with the advent of personal genomics, individuals will be expected to exert more control and responsibility over their own health. Will Systems Biology manage to enter in our daily lives?
Of course, this would imply deciphering the multigenic basis of complex human traits in the first place. But it is precisely this lack of current knowledge on the genotype-phenotype relationship which represents one the strongest scientific incentives to sequence many more individual human genomes and correlate them with the respective medical, physiological and environmental parameters. In this regard, the availability of much cheaper and more efficient sequencing technologies (eg. enabling sequencing, within 10 days, of 100 human genomes at 98% completion, 10-5 accuracy and for $10’000 per genome, as challenged by the Archon X prize foundation, or allowing sequencing 1% of the genome for $1000 as in George Church’s Personal Exome Project) may well represent an even more revolutionary advance than the first individual human genome published this week. As George Church wrote in his Editorial (The Personal Genome Project, Church (2005), Molecular Systems Biology 2005.0030),
Ready access to highly integrated and comprehensive human genome and phenome data sets is extremely important and increasingly feasible technically […] As DNA is only a small part of destiny, personal genomics might fruitfully de-emphasize ‘prediction’ and focus on augmenting systems biology interpretations and prioritizations of actual day-to-day measurements of our physiological states.