Root growth Control and Epistasis

Understanding how the genotype gives rise to phenotypes is one of the ultimate challenges of biology. Despite breathtaking progress in linking function to genetic information, most prominently in genome-wide association studies, current models involving individual genes are unable to account for much of the heritability of diseases, behaviors, and other phenotypes. Epistasis, the phenomenon that multiple genetic factors act as interdependent trait determinants, often conceals unambiguous assignment of heritability factors. In the past, various studies have shown that epistasis is an important determinant of complex traits. What is currently missing, however, is an efficient method to detect epistatically interacting genes. Moreover, studies exploring the molecular bases of epistasis have been often restricted to single cell systems, largely ignoring the complexities of epistastic interactions in multicellular systems. Combining genome-wide association mapping with gene network analysis, we identified a cluster of 3 leucine-rich-repeat receptor-like kinases and one protein kinase (further termed LRR-RLK cluster) for which we provide strong evidence for epistatic regulation of root growth. On the basis of this example for epistasis, we can now ask important questions such as: What is the extent of the epistatic interactions of these genes? How does this epistatic interaction regulate root growth rates? And how does this interaction work in the tissue context of the root? Here we propose to test the epistatic interaction of the 4 genes of the LRR-RLK cluster using all possible combinations of loss-of-function mutants, to elucidate their expression patterns on the RNA and protein level, to identify downstream target genes and pathways and finally to dissect the molecular basis for their epistastic interactions with regards to their downstream pathways and tissue context. The proposed approach is expected to extend the power of genome-wide association studies beyond the identification of single heritable traits and enables us to address complex genetic determination of traits. Furthermore, this project promises to shed light on how epistatic interactions can occur at the scale of tissues and cell types in multicellular organisms. Finally, we will learn how an ensemble of kinases tunes root growth rate.

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