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Dealing with Uncertain Significance of the Genome

“Risky Business”

Most of us are wired to be risk averse. Yet, I have been giving serious contemplation to the “risky business” of having my whole genome be sequenced as a preventative medicine approach to my healthcare.

What will happen if go there?

I find myself staring into the murky abyss from the edge of the data cliff. A creepy feeling urges in my belly from the depths of my ski-bum days… Should I….


Photocredit: Bradly J. Boner for Jackson Hole Magazine

Upon landing, I will need “spoon-my-tracks” to get the data to be interpretable and informative as possible.

Photocredit: James Fagedes at Foothill freak

Mental Health

There is plenty of reason to be cautious. A recent publication by the Hasting Center report urges a high level of caution (Johnston 2018).  Although we can be somewhat dismissive of their dismissiveness –  the cost of whole genome sequencing is dramatically dropping and phenotyping technology is rapidly improving – one observation is likely to hold true for a while:

“Given the psychosocial costs of predicting one’s own or one’s child’s future life plans based on uncertain [Genomic] testing results, we think the hope and optimism deserve to be tempered.”

So it is clear there will be quite a bit of uncertainty when one opens the Pandora’s box of the genome, but hope and optimism will remain. Whether there is clearly actionable results, or frustrating uncertainty, the knowledge gained means there are things to be done, platforms to build, and cures to be discovered.

Not If, but When

Caution keeps us safe. But safe for how long? By not “going there” we might be just deluding our selves from the inevitable.  At some point, we will have a deep understanding of the consequence of genome variation.  The first to fall into line will be variants delivering functional consequence on the monogenic side of the spectrum.  These will be the easiest to model and uncover biological consequence because the variant will have clear and sometimes deterministic output on life quality and healthspan. More challenging will be the variants whose effects predominate in polygenic contexts.  These are the more subtle “risk factor” effects where the other variants in one’s genome are the influencers that either enhance or suppress the capacity of the risk factor variant to manifest.  Adding to the challenge of understanding a risk factor is the influence of external factors, such as diet and exercise. Or the more internal factors such as genomic imprinting and gene methylation status.

Yet it is clear where we are heading. Much of the uncertainty will be resolved and we will soon be living in the genome-actionable era where medicine becomes highly personalized to the individual’s variant profile.  For a glimpse of what the future holds, and if you can make the time for an amazing Rob Reid interview of Dr. Robert Green from Harvard, put the headphones on for the following podcast:


1. Johnston J et al. Sequencing Newborns: A Call for Nuanced Use of Genomic Technologies. Hastings Cent Rep. 2018 Jul-Aug;48(2):S2-6. https://onlinelibrary.wiley.com/doi/full/10.1002/hast.874


About the Author: Chris Hopkins

x Dr. Hopkins pioneered the commercialization of C. elegans transgenics. As a scientist turned entrepreneur, he now pioneers the application of humanized animal models for clinical variant prototyping.
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