A breakdown of self-incompatibility (SI) followed by a shift to selfing is commonly observed in the evolution of flowering plants. Both are expected to reduce the levels of heterozygosity and genetic diversity. However, breakdown of SI should most strongly affect the region of the SI locus (S-locus) because of the relaxation of balancing selection that operates on a functional S-locus, and a potential selective sweep. In contrast, a transition to selfing should affect the whole genome. We set out to disentangle the effects of breakdown of SI and transition to selfing on the level and distribution of genetic diversity in North American populations of Arabidopsis lyrata. Specifically, we compared sequence diversity of loci linked and unlinked to the S-locus for populations ranging from complete selfing to fully outcrossing. Regardless of linkage to the S-locus, heterozygosity and genetic diversity increased with population outcrossing rate. High heterozygosity of self-compatible individuals in outcrossing populations suggests that SI is not the only factor preventing the evolution of self-fertilization in those populations. There was a strong loss of diversity in selfing populations, which was more pronounced at the S-locus. In addition, selfing populations showed an accumulation of derived mutations at the S-locus. Our results provide evidence that beyond the genome-wide consequences of the population bottleneck associated with the shift to selfing, the S-locus of A. lyrata shows a specific signal either reflecting the relaxation of balancing selection or positive selection.