When the Human Genome Project was completed, in 2003, it opened the door to a radical new idea of health—that of personalized medicine, in which disease risk and appropriate treatment would be gleaned from one’s genetic makeup. As more people had their genomes sequenced; disease-related genes would start coming into view and while this is true in many ways; things also turned out to be much more complicated.
Sixteen years on; tens of thousands of people have had their genomes sequenced yet it remains a major challenge to infer future health from genome information. Part of the reason may be that genes interact with each other to modify trait inheritance in ways that aren’t totally clear; write Donnelly Centre researchers in an invited perspective for the leading biomedical journal Cell.
“All the genome sequencing data is highlighting the complexity of inheritance for the human genetics community;” says Brenda Andrews, University Professor and Director of U of T’s Donnelly Centre for Cellular and Biomolecular Research and a senior co-author; whose lab studies interactions between genes. “The simple idea of a single gene leading to a single disease is more likely to be an exception than a rule;” she says.
Thousands of mutations
Andrews and Charles Boone; who is also a senior co-author, are professors in U of T’s Donnelly Centre and the Department of Molecular Genetics; as well as Senior Fellows of the Genetic Networks program at the Canadian Institute for Advanced Research, which Boone co-directs.
Genome wide association studies, or GWAS; which scan the genomes of patient populations and compare them to healthy controls; have unearthed thousands of mutations, or genetic variants, that are more prevalent in disease. Most variants are found in common diseases that affect large swathes of the world’s population but their effects can be small and hard to see.
Instead of there being a single gene for heart disease or schizophrenia; for example; there may be many combinations of subtle genetic changes scatter across the genome that tune up or down a person’s susceptibility to these diseases. Vast genetic diversity in the human population further influences trait inheritance while environmental effects; such as diet and upbringing; further complicate matters.
In some cases, a single gene variant can be extremely potent and cause a disease, as seen in cystic fibrosis, hemophilia and other inherited disorders. But even two people with the same disease variant can experience a wildly different disease severity which, presently; cannot be gleaned from their genomes. Even more astonishing, sequencing studies have identified people who carry damaging mutations but remain perfectly healthy; presumably protected by other; as yet unknown gene variants within their genomes.