The genetic architecture of crop domestication is generally characterized by three trends: relatively few genomic regions with major QTL effects are involved, QTL are often clustered, and alleles derived from the crop do not always contribute to the crop phenotype. We have investigated the genetic architecture of lettuce using a recombinant inbred line population from a cross between a crop Lactuca sativa (‘Salinas’) and its wild relative L. serriola. Few genomic regions with major QTL, plus various intermediate QTL, largely control the transition from wild to cultivated Crisphead lettuce. Allelic effects of all major QTL were in the expected direction, but there were intermediate QTL where the crop contributed to the wild phenotype and vice versa. We found two main regions with clusters of QTL, one on linkage group 3, where the crop allele induced lower seed output, another on linkage group 7, where the crop allele caused a delay in flowering time. Potentially, knowledge of genetic changes due to the domestication could be relevant for the chance that a transgene inserted in a crop genome will spread to wild relatives due to hitchhiking effects. If a transgene would be inserted in one of these regions, background selection on the crop alleles may lead to a reduced fitness of hybrids with the transgene. QTL research on the effects of domestication genes can thus indicate regions in the crop genome that are less likely to introgress, although these still need to be verified under field conditions.