Higher-order epistasis shapes natural variation in germ stem cell niche activity

To study how natural allelic variation explains quantitative developmental system variation, we characterized natural differences in germ stem cell niche activity, measured as progenitor zone (PZ) size, between two Caenorhabditis elegans isolates. Linkage mapping yielded candidate loci on chromosomes II and V, and we found that the isolate with a smaller PZ size harbours a 148 bp promoter deletion in the Notch ligand, lag-2/Delta, a central signal promoting germ stem cell fate. As predicted, introducing this deletion into the isolate with a large PZ resulted in a smaller PZ size. Unexpectedly, restoring the deleted ancestral sequence in the isolate with a smaller PZ did not increase-but instead further reduced-PZ size. These seemingly contradictory phenotypic effects are explained by epistatic interactions between the lag-2/Delta promoter, the chromosome II locus, and additional background loci. These results provide first insights into the quantitative genetic architecture regulating an animal stem cell system. Stem cell niches regulate proliferation of stem cells, but variation in this control across natural populations has not been explored. Here they combine quantitative genetics and gene editing to show that natural variation in C. elegans germ stem cell niche activity is shaped by complex gene-gene interactions.

Automated summary

This study characterizes natural differences in germ stem cell niche activity between two Caenorhabditis elegans isolates and identifies a promoter deletion in the Notch ligand, lag-2/Delta, which is associated with the size of the progenitor zone. The phenotypic effects of this deletion are further influenced by epistatic interactions between the lag-2/Delta promoter, a locus on chromosome II, and additional background loci. These findings provide insights into the quantitative genetic architecture of an animal stem cell system.