Mo Siddiq

Our research explores the tension between evolutionary constraint and innovation. How do core biological functions remain conserved while their underlying genetic determinants diversify, and how does this diversification shape genotype-phenotype relationships? Our projects, aimed at addressing these questions, broadly fall into two areas: 1) the origin, context-dependency, and diversification of “moonlighting” functions in proteins that retain their evolutionarily essential function(s) and 2) the diversification in the architecture of metabolic and regulatory pathways amidst conservation of overall activity. We combine population genetics, phylogenetics, and natural history to organize phenotypic variation and generate hypotheses about its genetic, molecular, and historical causes. We then test these hypotheses experimentally — manipulating regulatory and structural components of genes, as well as characterizing reconstructed ancestral genes alongside extant ones — to establish causal links across biological levels.

Our research foci seek to provide insight into why some genetic variants affecting core processes are intolerable while others are inconsequential or context-dependent. Ultimately, this work enables us to use the shared history of life to understand the molecular mechanisms relating genotype to phenotype — mechanisms whose flexibility evolution exploits and whose constraints disease violates.

Current Project Areas
Protein moonlighting: How do life's most conserved molecules evolve additional functions while retaining the ones that made them essential?
The enzymes that carry out glycolysis are among the most broadly conserved across life and epitomize “housekeeping” molecules. Yet, nearly all of them have been found to have additional biochemically distinct and important moonlighting functions. Using primarily Saccharomyces and Ascomycetes yeasts as our model, genetically tractable eukaryotes, we are investigating when different functions of glycolytic enzymes originated, how these functions coevolve across genomic and environmental contexts, and what the genetic mechanisms are that underlie their evolution.

Pathway drift: How do molecular systems that make life possible continuously change in architecture while meeting the demands of necessity
Mutations and stabilizing selection can cause biological systems to “drift” among functionally equivalent but genetically distinct configurations. We seek to understand the molecular causes of flexibilities and constraints shaping this drift. Currently, using the activity of different glycolytic steps as a model, we are investigating the molecular mechanisms through which promoter activity, protein catalytic efficiency, and paralog redundancy coevolve to enable metabolic drift, and how the resulting divergence in genetic architecture reshapes the mutational sensitivities of individual pathway genes. We are using a similar framework to study the evolution of transcriptional circuits, with a focus on coevolution between the protein-protein and protein-DNA interactions that collectively result in productive regulatory complexes. Together, these projects ask how conserved phenotypes emerge from different molecular causes and histories — and give us a lens for understanding why similar systems, faced with similar perturbations, produce different effects.