A population genomic study of domestic and wild yeasts, *Saccharomyces cerevisiae* and *S. paradoxus*, reveals significant genetic and phenotypic differences despite their ecological similarities. The study sequenced over 70 isolates of *S. cerevisiae* and its relative *S. paradoxus*, identifying 235,127 high-quality SNPs and 14,051 indels in *S. cerevisiae*, and 623,287 SNPs and 25,267 indels in *S. paradoxus*. The *S. cerevisiae* reference strain S288c differs from the reference genome by 498 SNPs. The study found that *S. paradoxus* populations are well-delineated geographically, while *S. cerevisiae* isolates show less differentiation and are comparable to a single *S. paradoxus* population. The population structure of *S. cerevisiae* consists of several geographically isolated lineages and many mosaics, suggesting human influence facilitated cross-breeding and new genetic combinations. *S. cerevisiae* has a long association with human activity, leading to the idea of domestication, while *S. paradoxus* is not associated with humans and is found globally. The study identified extensive variation in *S. paradoxus* populations across continents but limited variation in *S. cerevisiae* isolates. The population structure of *S. cerevisiae* is more complex, with five clean lineages and many mosaics. The study also found evidence of natural selection, with derived allele frequencies for nonsynonymous polymorphisms lower than synonymous ones. The analysis of SNPs and indels showed that many mutations may be deleterious. Phenotypic profiling revealed that *S. paradoxus* strains are more resistant to certain drugs than *S. cerevisiae* strains. The study also found that *S. cerevisiae* has higher phenotypic variance than *S. paradoxus*, suggesting it occupies a wider range of ecological niches. The study highlights the importance of population genomics in understanding genetic variation and adaptation in yeasts. The results suggest that human activity may have facilitated the domestication of *S. cerevisiae* by allowing cross-breeding and the production of new genetic combinations. The study also indicates that the domestication of *S. cerevisiae* may not be a single event but rather a process involving multiple lineages. The findings have implications for understanding the genetic basis of traits in yeasts and for future studies in evolutionary genetics.A population genomic study of domestic and wild yeasts, *Saccharomyces cerevisiae* and *S. paradoxus*, reveals significant genetic and phenotypic differences despite their ecological similarities. The study sequenced over 70 isolates of *S. cerevisiae* and its relative *S. paradoxus*, identifying 235,127 high-quality SNPs and 14,051 indels in *S. cerevisiae*, and 623,287 SNPs and 25,267 indels in *S. paradoxus*. The *S. cerevisiae* reference strain S288c differs from the reference genome by 498 SNPs. The study found that *S. paradoxus* populations are well-delineated geographically, while *S. cerevisiae* isolates show less differentiation and are comparable to a single *S. paradoxus* population. The population structure of *S. cerevisiae* consists of several geographically isolated lineages and many mosaics, suggesting human influence facilitated cross-breeding and new genetic combinations. *S. cerevisiae* has a long association with human activity, leading to the idea of domestication, while *S. paradoxus* is not associated with humans and is found globally. The study identified extensive variation in *S. paradoxus* populations across continents but limited variation in *S. cerevisiae* isolates. The population structure of *S. cerevisiae* is more complex, with five clean lineages and many mosaics. The study also found evidence of natural selection, with derived allele frequencies for nonsynonymous polymorphisms lower than synonymous ones. The analysis of SNPs and indels showed that many mutations may be deleterious. Phenotypic profiling revealed that *S. paradoxus* strains are more resistant to certain drugs than *S. cerevisiae* strains. The study also found that *S. cerevisiae* has higher phenotypic variance than *S. paradoxus*, suggesting it occupies a wider range of ecological niches. The study highlights the importance of population genomics in understanding genetic variation and adaptation in yeasts. The results suggest that human activity may have facilitated the domestication of *S. cerevisiae* by allowing cross-breeding and the production of new genetic combinations. The study also indicates that the domestication of *S. cerevisiae* may not be a single event but rather a process involving multiple lineages. The findings have implications for understanding the genetic basis of traits in yeasts and for future studies in evolutionary genetics.