Enormous interest is being generated by a new open access article in PLoS Biology: Identifying genetic variants that affect viability in large cohorts, by Mostafavi, H., Berisa, T., Day, F. R., Perry, J. R. B., Przeworski, M., & Pickrell, J. K.  The press release from Columbia was titled “Large-scale Study of Genetic Data Shows Humans Still Evolving.” New Scientist covered it as “Our genomes reveal modern-day evolution.” At The Atlantic the headline was “Huge DNA Databases Reveal the Recent Evolution of Humans.”  What does the article really show?  

Author summary:  Our global understanding of adaptation in humans is limited to indirect statistical inferences from patterns of genetic variation, which are sensitive to past selection pressures. We introduced a method that allowed us to directly observe ongoing selection in humans by identifying genetic variants that affect survival to a given age (i.e., viability selection). We applied our approach to the GERA cohort and parents of the UK Biobank participants. We found viability effects of variants near the APOE and CHRNA3 genes, which are associated with the risk of Alzheimer disease and smoking behavior, respectively. We also tested for the joint effect of sets of genetic variants that influence quantitative traits. We uncovered an association between longer life span and genetic variants that delay puberty timing and age at first birth. We also detected detrimental effects of higher genetically predicted cholesterol levels, body mass index, risk of coronary artery disease (CAD), and risk of asthma on survival. Some of the observed effects differ between males and females, most notably those at the CHRNA3 gene and variants associated with risk of CAD and cholesterol levels. Beyond this application, our analysis shows how large biomedical data sets can be used to study natural selection in humans.

The method is creative.The authors looked at genetic data from more than 60,000+ people in the Kaiser Permanente  system and 150,000+ people in  the U.K. Biobank and asked if certain genetic variations were less common in older people, implying that people with those variations died young. The astounding result is that only two variations popped out. One is APOE ε4, long recognized as a cause of heart disease and Alzheimer’s disease in modern populations.  The other is a variation in CHRNA3 that is associated in higher smoking rates in smokers. 

  • We know that about 25% of the variation in human lifespan results from genetic variations (Brooks-Wilson, 2013) so there should be genetic variations to be found. Why didn’t they show up?
  • Despite having hundreds of thousands of subjects, the study was able to detect only effects from variations present in over 10% of the population. To achieve genome wide significance requires a p<10−8   Perhaps  many more alleles are waiting to be identified;the authors understandably would now like to look at samples of many hundreds of thousands of people. 
  • Both identified alleles may qualify as “genetic quirks” that may cause harm only when interacting with modern environments.  
  • The authors suggest that perhaps all other common variations have been purged by natural selection, perhaps via benefits to kin from long-lived post-reproductive adults. Kin selection is powerful, but is is plausible that it would eliminate all but two common alleles that reduce fitness up at age 75? This is a better starting point than assuming that genetic drift accounts for most disease, however, it seems unlikely. 
  • Environments are so vastly different now from those of our ancestors that many previously neutral variations should now influence age at death. 
  • Mention was made about antagonistic pleiotropy and its role in aging however  genes that are not polymorphic would not have any variation to find. 
Brooks-Wilson, A. R. (2013). Genetics of healthy aging and longevity. Human Genetics, 132(12), 1323–1338. https://doi.org/10.1007/s00439-013-1342-z

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