interpreted as false negative results or inadequate phenome coverage, but we suspect that most commonly this reflects molecular resilience that buffers the phenotype from apparently strong homozygous mutations. For example, a tandem duplication in the cardiac actin gene (Actc1) reduces expression of mRNA by ∼50% in hearts of strains that inherit the D allele (Fig. 7a–c). This duplication upregulates expression of both skeletal muscle actin (Acta1) and smooth muscle actin (Acta2) by 30 and 50%, respectively (Fig. 7c). Since variation in both of these actin transcripts maps precisely to Actc1, it is clear that this compensation is ultimately caused by the duplication (Fig. 7d,e). The depletion of cardiac actin has already been shown to be associated with compensatory increase in skeletal and smooth muscle actins in the mouse heart27. Another study has shown that Actc1 can effectively replace Acta1 to produce adequate function in the mouse postnatal skeletal muscle28.
