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Nearly all human traits are influenced by genetic variability [1, 2]. Genetic variants associated with diseases can also inform about disease aetiology, may have clinical applications and often become therapeutic targets [3]. Generally, the heritability of phenotypes, that is the impact of genetic variation versus the effect of environmental factors, covers a broad range from very small to large effects. A major focus of modern genetics is understanding the heritability of traits, and largescale genetic studies, including genome-wide association studies (GWASs), are a major tool to this end.

However, genetic association studies—including GWAS—can only detect associations if the underlying genes have functional genetic variants. Human genetic variability is limited, a snapshot of our current species. Here, we propose that the finite genetic variability of the human species means that we have only a small search space for …