As most of you know, we are all mutants. Each of us carries variations in our gene sequence that, collectively, mark us uniquely. What does it mean to have a mutation? The simple answer is that you have a genetic sequence that is different than the decided upon consensus or “wild-type” sequence.

Well, what decides the “wild-type” sequence? To put it simply, it is the sequence most typically seen to date. This is where we enter a paradox. Pending the source of the genetic information used to decide the “wild-type” sequence, we could potentially be using information that is relevant for one demographic, but not for another.

The realization of this paradox is not a new phenomenon. For instance, Maynard Olson concluded that a single wild-type genetic sequence is a mere illusion and a wild-type human simply does not exist (Olson, 2011). He also said, “…genetics is unlikely to revolutionize medicine until we develop a better understanding of normal phenotypic variation (Olson, 2011).”

If we look at the literature, it seems that these words fell onto deaf ears or were just placed on a side burner. Since 2005, the number of studies involving genome-wide association studies (GWAS) to look for genetic mutations (i.e., variations) that can indicate a person’s risk of disease has exploded (Gallagher & Chen-Plotkin, 2018). Many associations have been made about genetic changes and a variety of diseases, however, they are only correlative in most cases. Compared to the deluge of GWAS studies, little has been done to determine that the associations found are indeed causing the disease (Gallagher & Chen-Plotkin, 2018).

Even if a direct link has been found, it does not completely explain why people who harbor genetic mutations known to cause detrimental disease appear perfectly healthy. In looking at a population of ~500,000 individuals, a recent genomic analysis revealed that 13 individuals harbored mutations that normally give rise to severe Mendellian childhood diseases but these people show no physical manifestations of the diseases (Chen et al., 2016). While this might seem a rare event, it really is not. From analyzing the genomes of 1000 “healthy” people, one group estimated that an average individual may actually be harboring >400 genetic changes that can damage the person’s biological equilibrium and >2 known disease causing mutations (Xue et al., 2012).

With everyone potentially harboring so many genetic changes that could have profound consequences, how is it that the clear majority of the people on this planet are functioning, and even functioning well? As James Evan from the University of North Carolina said in an NPR article, “The good news is that most of those mutations do not overtly cause disease, and we appear to have all kinds of redundancy and backup mechanisms to take care of that (Stein, 2012).”

What should we take away from all of this with regards to our individual health? Well, this is another reminder that our genes really only convey a risk and not an imminent fate. This is particularly true when the link between a genetic change and physical outcome is only correlative and not yet directly linked. Until researchers sift through all the associations found through GWAS to identify the ones that actually cause problems (this might not even be possible for the vast majority of associations found), we need to focus on the phenotypes. This includes – perhaps primarily – the proteins encoded by the genes and how they respond to our environment. Focusing on how proteins respond to environmental cues may begin to reveal the buffering systems and lead us to a path of health enlightenment.

 

References

Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., . . . Friend, S. H. (2016). Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat Biotechnol, 34(5), 531-538. doi:10.1038/nbt.3514

Gallagher, M. D., & Chen-Plotkin, A. S. (2018). The Post-GWAS Era: From Association to Function. Am J Hum Genet, 102(5), 717-730. doi:10.1016/j.ajhg.2018.04.002

Olson, M. V. (2011). Genome-sequencing anniversary. What does a “normal” human genome look like? Science, 331(6019), 872. doi:10.1126/science.1203236

Stein, R. (2012, December 6) Perfection Is Skin Deep: Everyone Has Flawed Genes. NPR. (Retrieved on May 16, 2018 from https://www.npr.org/sections/health-shots/2012/12/06/166648187/perfection-is-skin-deep-everyone-has-flawed-genes).

Xue, Y., Chen, Y., Ayub, Q., Huang, N., Ball, E. V., Mort, M., . . . Genomes Project, C. (2012). Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am J Hum Genet, 91(6), 1022-1032. doi:10.1016/j.ajhg.2012.10.015