HUGO President Reports from the HUGO Symposium on Genomics and Ethics, Law and Society 2009

November 2, 2009 · Posted in HUGO Events

This post was contributed by HUGO President Prof. Edison T. Liu.

The opening talks at the HUGO conference on Genomics and Ethics, Law, and Society in Geneva, Switzerland led to lively discussions from the floor of the stately International Conference Center.

In the morning session, the focus was on the technologies. Dr. Ala Awan from the WHO reminded the audience of the new focus on health outcomes in governments worldwide including those who previously considered to be third world. This is in recognition of the increase in the burden of chronic illnesses as nations advance economically.

Both Edison Liu (Singapore) and Mark McCarthy (Oxford) described the new sequencing strategies and the seven orders of magnitude increase in throughput and decrease in cost of sequencing in the last 15-20 years. But the excitement was the outcome of sequencing many genomes or partial genomes of hundreds to thousands of individuals. Over three million SNPs are found in individuals, many that are new resulting in up to 20,000 amino acid substitutions. When complete genome sequences were compared, only ~700,000 are shared amongst 5 individual genomes, whilst the remaining are either unique to the individual or shared with only one or two other. 300,000 heterozygous and >500,000 homozygous indels (as compared to the reference genome). There is plenty of genomic variation in human beings.

In every genome there were a significant number of alleles associated with disease with each person studied. Craig Venter’s sequence revealed that he is heterozygous for the KL gene associated with lower risk coronary heart disease, homozygous 5A/5A in MMP3 associated with higher risk acute MI, hemizygous for APOEe4 associated with increased risk for Alzheimers, and possessed a variant in complement factor H linked to increased risk for macular degeneration. It looks like everyone has disease associated alleles in their genome leading to the observation that we are all genetically prone to disease.

A word of caution is that examination of James Watson’s genome suggested that he was homozygous for mutations associated with two monogenetic disorders: mutations in the ERCC6 (associated with Cockaynes syndrome) and in the Myosin VIIA gene (associated with Usher’s syndrome). (NEJM 359:2192-2193, 2008) Both should have resulted in significant and (in the case of Cockayne’s syndrome) severe phenotypes, but of course, the elderly Nobel Laureate appears quite intact. This observation raised the concern of sequencing standards and premature use of sequence data to make future health projections.

Ed Liu described a “genomic emergency” when the Genome Institute of Singapore was called on to help resolve the SARS crisis in 2003, and more recently in responding to the H1N1 flu epidemic. The SARS crisis, which killed 33 people in Singapore caused a 3% fall in the nation’s GDP. In both situations, sequence data on the viruses affecting patients was used to craft medical ad epidemiological responses and policies.

Mark McCarthy described his work on Type II diabetes (T2D) and showed the 37 alleles that have been associated with disease risk. The common features of these alleles are that the individual effect on the disease is in the range of 1.05 to 1.25, that these variants are often not even additive, and that perhaps only 10% of the disease risk can be explained by these genetics. His hope is that the identification of rare variants with high penetrance will explain the remaining 90% of genetic risk. This can only be done by sequencing to uncover rare variants.

A consortium made of Oxford, Broad Institute, and Michigan will be doing limited sequencing on 1500 T2D cases and 1500 controls in a search for these rare variants. Noting that simply knowing body mass index and family history is more predictive than the assessment of the 37 risk alleles in predicting risk for T2D, he cautioned that we should not place so much emphasis genetic predictors. However, each gene uncovered by GWAS may be reasonable and effective targets for therapeutic intervention.

Charles Auffray (Villejuif, France) described the challenges of data sharing and patenting genes and genomic information. He highlighted that the next frontier for genomic analysis in disease is in systems biology and systems reconstruction of disease alleles.