From Human Genome Research to Personalized Health Care: The Potential Is Widely Recognized, but Much More Knowledge Is Needed to Make the Science Clinically Useful
Omenn, Gilbert S., Issues in Science and Technology
"Big Science" in the life sciences was launched in 1986 with a bold plan to develop the technologies to determine the sequence of the 3 billion nucleotide base pairs (letters of DNA code) in the human genome. The Human Genome Project declared success by 2001 and has stimulated a wealth of related research. Analyses of the genomes of many organisms have yielded powerful evidence of sequences conserved during evolution. Analyses of microorganisms set the stage for pathogen/host interaction studies. Essentially all fields of life sciences research have been transformed by knowledge of protein-coding genes, recognition of genomic variation across individuals, findings of new mechanisms of regulation of gene expression, and patterns of proteins and metabolites in generating the features of living organisms. From the beginning, there have been high expectations that such knowledge would enhance clinical and public health practice through understanding of predispositions to disease, identification of molecular signatures and biomarkers for stratification of patients with different subtypes of a disease, earlier diagnoses, and discovery of molecular targets for therapeutic and preventive interventions.
There has been compelling evidence for at least 150 years that genetics plays a major role in many traits and diseases. Identical twins are much more likely to manifest similar traits and develop similar diseases than are fraternal twins (or regular siblings). Modern researchers first tested individual genes that seemed scientifically related to a particular disease. Now gene chips can probe 500,000 sequences throughout the genome for variation in single-nucleotide polymorphisms (SNPs) and segments of chromosomes. Genome-wide association studies have demonstrated genetic influence on height; glucose, cholesterol, and blood pressure levels; and risks for childhood-onset and adult-onset diabetes, macular degeneration of the retina, various cancers, coronary heart disease, mental illnesses, inflammatory bowel disease, and other diseases. Enthusiasm about these statistical associations stimulated the formation of companies to offer testing services with direct-to-consumer promotion. However, the market was leaping way ahead of the science.
Serious limitations in this approach have now been recognized. First, stringent statistical criteria are required to reduce the likelihood of false-positive associations, since such large numbers of genomic variants (SNPs) are tested. Second, very few of the highly associated genomic variants actually alter protein-coding gene sequences; this is no surprise, since our 20,000 protein-coding genes take up only 1.5% of the genome sequence. Tying genomic variants to nearby protein-coding genes is highly speculative, making predictions of the functional effects of the variation quite uncertain. Third, the 20 genomic variants associated with height together account for only 3% of the actual variation in height; similarly, 20 or more genomic variants associated with a risk of diabetes account for less than 10% of the risk. The results are not a sufficient basis for predictive medicine. Undeterred, geneticists are screening a far larger set of SNPs to identify more variants of small effect and are searching for less common variants that might have larger effects on disease risk. They are also using new sequencing methods that aim to find all variation, not just sample the SNP sites. The cost of SNP genotyping is now under $1,000 per person. The cost of sequencing, meanwhile, has dropped from the original investment of $3 billion to obtain the first sequence to an estimated $10,000 to sequence an individual with the latest technology, and may reach $1,000 in the next few years.
I believe that much of the unexplained variation in susceptibility will be explained by nongenetic environmental and behavioral risk factors that interact with genetic variation to mediate the risk and severity of disease. …