In contrast, genuine phenotypic resilience is likely to result from functional overlap and compensation among paralogs and other members of complex molecular networks. Even after stringently filtering both sequence data and gene models, it is clear that many strong sequence variants are successfully buffered at intermediate levels373839. For example, a splice site mutation in Cyp2c39 (Supplementary Table 5) inactivates this P450 enzyme but has no detectable impact on higher order phenotypes—a compelling negative result. An obvious explanation is overlap with other members of the Cyp2c cluster. The strongest exemplar of paralog buffering in our study is the mutation in Actc1, which causes compensatory upregulation of the expression of both Acta1 and Acta2 (Fig. 7). In retrospect, this buffering of genetic variation is not surprising. A large fraction of knockout mutations in mice and other well-typed species are viable and many of these do not have any known functional consequences4041.
