Massively parallel experimental interrogation of natural variants in ancient signaling pathways reveals both purifying selection and local adaptation.

The nature of standing genetic variation remains a central debate in population genetics, with differing perspectives on whether common variants are mostly neutral or have functional effects. We address this question by directly mapping the fitness effects of over 9,000 natural variants in the Ras/PKA and TOR/Sch9 pathways-key regulators of cell proliferation in eukaryotes-across four conditions in . While many variants are neutral in our assay, on the order of 3,500 exhibited significant fitness effects.

A genome-to-proteome atlas charts natural variants controlling proteome diversity and forecasts their fitness effects.

Despite abundant genomic and phenotypic data across individuals and environments, the functional impact of most mutations on phenotype remains unclear. Here, we bridge this gap by linking genome to proteome in 800 meiotic progeny from an intercross between two closely related isolates adapted to distinct niches. Modest genetic distance between the parents generated remarkable proteomic diversity that was amplified in the progeny and captured by 6,476 genotype-protein associations, over 1,600 of which we resolved to single variants.

The Hsp90 Molecular Chaperone as a Global Modifier of the Genotype-Phenotype-Fitness Map: An Evolutionary Perspective.

Global modifier genes influence the mapping of genotypes onto phenotypes and fitness through their epistatic interactions with genetic variants on a massive scale. The first such factor to be identified, Hsp90, is a highly conserved molecular chaperone that plays a central role in protein homeostasis. Hsp90 is a "hub of hubs" that chaperones proteins engaged in many key cellular and developmental regulatory networks.

Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate.

Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate.