From a genetic standpoint, humans are overwhelmingly similar. If you compare the DNA of two randomly chosen people, you’ll find that it is 99.9% identical. The variability in the remaining 0.1% is why we have differences in eye color, height, and the ability to digest milk into adulthood. This 0.1% is also why we have different predispositions to certain diseases.
Most diseases common in the population today – such as most forms of diabetes and heart disease – are considered complex diseases. Most forms of pancreatitis are also considered complex. Complex diseases are caused by a combination of genetic variants across many locations in the genome – the 0.1% – and environmental factors. Environmental factors can include risks like smoking tobacco, drinking alcohol, having a poor diet, or a having a sedentary lifestyle.
Many of the genetic “risk variants” that predispose to these diseases tend to be common in the population. But why would genetic variants that are harmful and increase risk for disease be so widespread? The answer lies in our genetic history.
Why some genetic risk variants are common
Most genetic risk variants that predispose to complex diseases are thought to have risen to their present high frequency in the population by chance. These were at one point in human history neutral, representing harmless interpersonal variation, similar to eye color. But today – due to our longer lives, our modern lifestyles, or environmental influences – these variants are now harmful.
At the same time, there is increasing evidence that many risk variants were – paradoxically – previously helpful. Over the course of thousands of years, groups of people around the world were faced with different conditions. They encountered a variety of infectious diseases, climates, animals, and food sources. These circumstances shaped their genomes. Genetic variants that helped people survive infectious diseases, thrive at high altitudes, and overcome other challenges ultimately grew to be more common in the population.
However, due to the many recent changes in our environment, such as the agricultural and industrial revolutions, and our modern lifestyle, these formerly beneficial variants ultimately became a disadvantage.
For example, many genetic variants that helped our ancestors survive, such as those that promote conservation of energy, are today somewhat of a liability given the more ready access to hyperpalatable foods in the industrialized world. Instead of helping us survive in times of famine, these variants now predispose to obesity. Similarly, some of the genetic susceptibility variants for dyslipidemias, or abnormal amounts of fats in the blood, are thought to be related to biological processes that once helped people adapt to temperature or climactic extremes.
This may also be true for some (but not all) variants that cause Mendelian diseases, or diseases caused by variants in a single gene. For example, having harmful genetic variants in both copies of the CFTR gene causes the genetic condition cystic fibrosis and can predispose to pancreatitis. Yet variants that cause this condition are common in the population – about one in 35 Americans is a carrier of a CFTR variant. Carriers of a single variant are not affected with cystic fibrosis themselves, but have a 1 in 4 chance of having a child with cystic fibrosis if their partner is also a carrier. Having a single variant can also increase risk for a variety of traits and conditions, such as pancreatitis, diabetes and short stature, especially in the presence of additional genetic or environmental risks. Why would these variants be so common if they could possibly be harmful, especially when inherited in combination with other variants or environmental factors? Scientists theorize that these CFTR variants were, in fact, beneficial when present in just one copy in certain geographical regions. It is thought that these variants became widespread in certain areas because they conferred a survival advantage during outbreaks of cholera by making the cholera-caused diarrhea less severe.
Each of us has the genetic history of our ancestors and their migrations written in our genes, with a combination of neutral, harmful, and helpful genetic variants. Although we do not yet understand the role most pancreatitis risk variants played in human history, over time we may learn whether they may have been beneficial or neutral – or harmful all along. This perspective may, in turn, shed additional light on what aspects of modern life may have caused these variants to switch to being harmful – and give us additional insights into how to address them.
Chen R, Corona E, Sikora M, et al. Type 2 diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases. PLoS Genet. 2012;8(4):e1002621.
Dudley JT, Kim Y, Liu L, et al. Human genomic disease variants: a neutral evolutionary explanation. Genome Res. 2012;22(8):1383-94.
Hancock AM, Witonsky DB, Gordon AS, Eshel G, Pritchard JK, Coop G, et al. Adaptations to climate in candidate genes for common metabolic disorders. PLoS Genet. 2008;4:e32.
Hinds DA, Stuve LL, Nilsen GB, et al. Whole-genome patterns of common DNA variation in three human populations. Science. 2005;307(5712):1072-9.
Mersha TB, Abebe T. Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities. Hum Genomics. 2015;9:1.
Miller AC, Comellas AP, Hornick DB, et al. Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions. Proc Natl Acad Sci USA. 2020;117(3):1621-1627.
Quintana-murci L. Understanding rare and common diseases in the context of human evolution. Genome Biol. 2016;17(1):225.
Withrock IC, Anderson SJ, Jefferson MA, et al. Genetic diseases conferring resistance to infectious diseases. Genes Dis. 2015;2(3):247-254.