Most people learned about genetics in middle or high school science.  The basis of what we were taught were the discoveries of a Modolvian-Silesian monk, Gregor Mendel, who demonstrated in the 1860s that the action of dominant and recessive genes underlies the scientific basis of heredity. Many diseases, including cystic fibrosis and colon cancer due to an inherited risk of colon polyps, follow this pattern.

However, for the past ninety years scientists have argued about how this “yes-no” model of genetics could explain the many aspects of life that appear to be more graduated or dimensional. Height is perhaps the clearest example. “Normal” adult height for women in the U.S. varies between approximately 4’11” and 5’8”, with the mean or average height being close to the middle, around 5’4”; for men it varies between 5’4” and 6’2” with a mean of 5’9”. Since height is one of the most heritable characteristics of humankind, how could genetics explain this bell-curve shaped distribution of height? And how about the many diseases that seem to run in families but not follow the pattern described by Mendel such as type 2 diabetes, Parkinson disease, and Alzheimer disease?

Scientists had hoped that one of the great triumphs of science, the sequencing of the human genome in 2001, would provide the answer by leading quickly to the discovery of abnormal genes in diseases long been known to run in families. Surprisingly, it has taken more than a decade for the fruits of that extraordinary effort to emerge. Why? Because most human traits and common diseases don’t follow the Mendelian pattern! Rather, they are associated with variations on many genes and each variation contributes a small amount, often around 1% of the genetic risk. Height, for example, seems to be influenced by more than 700 genes.

This is a revolutionary finding. It means that two people who have a disease that looks, even to experts, to be the same might have quite different genetic causes. What we still do not know is how the 50 or more genes that contribute to Type 2 diabetes, the 30 or more genes that are associated with developing Parkinson disease, and the 25 or more genes contributing to late-onset Alzheimer disease interact to cause illness. Are the effects of each genetic variant additive? Do some genes increase risk and others lower it? Are there specific combinations of genes that have a greater effect than others? And how many other genes are yet to be discovered that contribute significantly less than 1% of the risk?

The stakes are big. The answers to these questions will determine how disease risk will be determined for single individuals and should provide important information about disease causation. Hopefully, unearthing these genetic pathways will lead to the discovery of treatments, as they seem to be in cancer. It is unknown whether this means that many different therapies will be needed for what have appeared to be single diseases or, alternatively, whether a general shared mechanisms might link many disparate genes and require only a single or small number of treatments.

What is extraordinary is that one of the greatest scientific discoveries of all time, Mendelian genetics, would survive relatively intact for 150 years, only to be clarified by an extraordinary convergence of advances in molecular biology, computational mathematics, and automated (robotic) techniques at the turn of the 21st century.

ÓPeter Rabins 2016