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Sunday, September 16, 2007
I finally had a chance recently to read the Venter genome paper, purportedly a landmark in personalized medicine. The short version of my thoughts: there's a long way to go.
Most of the paper is a straightforward list of the characteristics of Venter's genome-- it's different than the reference genome in a number of places, has some insertions, some deletions, and some inversions, all duly noted. And if the people quoted in the New York Times are to be believed, the quality of this new human genome assembly is quite high, better than the current reference sequence, which is a major contribution in and of itself.
The authors emphasize two things in this paper-- the attempt to separate Venter's chromosomes into haplotypes-- a paternal and maternal chromosome-- and the role of genome sequencing in associations studies. And I agree: sequencing, it is likely, will be the tool of choice for both of these applications in the future (as opposed to haplotype reconstruction from population data and SNP genotyping arrays). However, this paper makes it clear the technology simply isn't there yet. In a comparison of SNPs typed by sequencing with those typed with a SNP array, they find a whopping 9% error rate (SNP arrays now have error rates on the order of 0.1%, for comparison). Most of the miscalled positions are heterozygous, meaning that rare SNPs are likely to be missed. For a platform that seeks to remedy the bias towards common SNPs in current technologies, this is not good enough.
In terms of haplotype reconstruction, the authors make a number of dubious claims about the importance of their advances. It is not true, as stated in the introduction, that genome-wide association studies rely on phased haplotypes for analysis. In fact, most of the ones I have seen do nothing more than simply count up genotypes at each SNP in cases and controls and perform a chi-squared test. In most cases, haplotype-level analysis is simply not done. This may change in the future, of course, but it's difficult to see how what they've done (note they aren't even able to make ideal haplotype inference with the data) is that exciting. Again, though, advances here could end up being very important in the field.
Finally, the "personalized medicine" portion of the paper is weak. This is largely due to the fact that not much is known about the genetics of medically-relevant traits, but the authors simply provide a list of alleles known to play a role in phenotypes, and Venter's genotype at that position. There's not much more that can be done at this point, but still, it's not particularly of interest (unless you want confirmation that Venter indeed has blue eyes, as predicted by his OCA2 genotype).
All this said, this paper is indeed a first blind stab towards personalized medicine, and I'm glad someone is putting all this information out there. A number of people have raised ethical concerns about research like this (John Quackenbush, for example, a highly respected and respectable genomicist, has seemingly created a website explicitly for airing his views on Venter's ethics). In all seriousness, they suggest that someone should need approval from an Institutional Review Board to make public their own genome. While I'm sure IRBs would love to have the power to control information like that (see IRB Watch for various examples of the "mission creep" of IRBs), it's simply absurd, and the suggestion says more about people's distaste for Venter than anything else (when you can't criticize someone on scientific grounds, bust out the ethics card).
I look forward to having more people make their genomes public-- only with more information can better diagnostics be made.
Labels: Genetics
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