(A) Based on a study of 1011 genomes it is known that 93% of the genetic variants in the yeast Saccharomyces cerevisiae are rare (that is, they have a frequency <1%; blue). Moreover, just over 508000 variants (31% of the total; dotted blue) were found in just 1 of the 1011 genomes studied. However, genome-wide association studies (GWAS) tend to focus on the 7% of genetic variants that are common (that is, have a frequency >1%; pink). (B) The frequency of a rare allele can be increased by crossing a yeast isolate carrying the rare variant with an isolate with the alternative (more common) variant. To obtain a variety of isolates with a specific rare allele in different genetic backgrounds, the isolate carrying the rare variant (allele A, dark red) can be crossed with several different isolates with the alternative allele (allele G, pink, yellow, blue, grey). As a result, allele A is more frequent in the experimental panel than in the parental isolates, making it suitable for GWAS analysis. Importantly, regardless of the frequency that any allele reaches in the experimental panel, the real natural frequency can be looked up in the collection of 1011 yeast genomes (panel A).