Nearly all genetic variants that influence disease risk have human-specific origins; however, the systems they influence have ancient roots that often trace back to evolutionary events long before the origin of humans. Here, we review how advances in our understanding of the genetic architectures of diseases, recent human evolution and deep evolutionary history can help explain how and why humans in modern environments become ill.
Human populations exhibit differences in the prevalence of many common and rare genetic diseases. These differences are largely the result of the diverse environmental, cultural, demographic and genetic histories of modern human populations. Synthesizing our growing knowledge of evolutionary history with genetic medicine, while accounting for environmental and social factors, will help to achieve the promise of personalized genomics and realize the potential hidden in an individual’s DNA sequence to guide clinical decisions. In short, precision medicine is fundamentally evolutionary medicine, and integration of evolutionary perspectives into the clinic will support the realization of its full potential.
Genetic disease is a necessary product of evolution. Fundamental biological systems, such as DNA replication, transcription and translation, evolved very early in the history of life. Although these ancient evolutionary innovations gave rise to cellular life, they also created the potential for disease. Subsequent innovations along life’s long evolutionary history have similarly enabled both adaptation and the potential for dysfunction. Against this ancient background, young genetic variants specific to the human lineage interact with modern environments to produce human disease phenotypes. Consequently, the substrates for genetic disease in modern humans are often far older than the human lineage itself, but the genetic variants that cause them are usually unique to humans.
The advent of high-throughput genomic technologies has enabled the sequencing of the genomes of diverse species from across the tree of life. Analysis of these genomes has, in turn, revealed the striking conservation of many of the molecular pathways that underlie the function of biological systems that are essential for cellular life.
These breakthroughs have revealed the recent, often complicated, history of our species and how it influences the genetic architecture of disease. With the expansion of clinical whole-genome sequencing and personalized medicine, the influence of our evolutionary past and its implications for understanding human disease can no longer remain overlooked by medical practice; evolutionary perspectives must inform medicine.
Much like a family’s medical history over generations, the genome is fundamentally a historical record. Decoding the evolution of the human genome provides valuable context for interpreting and modelling disease. This context is not limited to recent human evolution but also includes more ancient events that span life’s history. In this Review, we trace the 4 billion-year interplay between evolution and disease by illustrating how innovations during the course of life’s history have established the potential for, and inevitability of, disease. Beginning with events in the very deep past, where most genes and pathways involved in human disease originate, we explain how ancient biological systems, recent genetic variants and dynamic environments interact to produce both adaptation and disease risk in human populations.
Given this scope, we cannot provide a comprehensive account of all evolutionary events relevant to human disease. Instead, our goal is to illustrate through examples the relevance of both deep and recent evolution to the study and treatment of genetic disease. Many of these key insights stem from recent discoveries, which have yet to be integrated into the broader canvas of evolutionary biomedicine
