Epistatic interactions can make the outcomes of evolution unpredictable, but no comprehensive data are available on extent and temporal dynamics changes in effects mutations as protein sequences evolve. Here, we use phylogenetic deep mutational scanning to measure functional effect every possible amino acid mutation a series ancestral extant steroid receptor DNA binding domains. Across 700 million years evolution, epistatic caused most become decorrelated from their initial windows...

Heritable differences in gene expression are caused by mutations DNA sequences encoding cis-regulatory elements and trans-regulatory factors. These two classes of regulatory change differ their relative contributions to natural populations because the combined effects mutation selection. Here, we investigate how new create variation upon which selection acts quantifying frequencies hundreds cis- trans-acting altering activity TDH3 promoter yeast Saccharomyces cerevisiae absence We find that...

The roles of chance, contingency, and necessity in evolution are unresolved because they have never been assessed a single system or on timescales relevant to historical evolution. We combined ancestral protein reconstruction new continuous technology mutate select proteins the B-cell lymphoma-2 (BCL-2) family acquire protein–protein interaction specificities that occurred during animal By replicating evolutionary trajectories from multiple proteins, we found contingency generated over long...

How complicated is the genetic architecture of proteins - set causal effects by which sequence determines function? High-order epistatic interactions among residues are thought to be pervasive, making a protein's function difficult predict or understand from its sequence. Most studies, however, used methods that overestimate epistasis, because they analyze relative designated reference causing measurement noise and small local idiosyncrasies propagate into pervasive high-order have not...

Heritable changes in gene expression are important contributors to phenotypic differences within and between species caused by mutations cis-regulatory elements trans-regulatory factors. Although previous work has suggested that preferentially accumulate with time, technical restrictions closely related limited comparisons have made this observation difficult test. To address problem, we used allele-specific RNA-seq data from Saccharomyces hybrids expand both the evolutionary timescale...

Gene expression noise is an evolvable property of biological systems that describes differences in among genetically identical cells the same environment. Prior work has shown heritable and can be shaped by selection, but impact variation on organismal fitness proven difficult to measure. Here, we quantify effects altering for TDH3 gene Saccharomyces cerevisiae. We show increases deleterious or beneficial depending difference between average level a genotype maximizing fitness. also simple...

A protein’s genetic architecture – the set of causal rules by which its sequence produces functions also determines possible evolutionary trajectories. Prior research has proposed that proteins is very complex, with pervasive epistatic interactions constrain evolution and make function difficult to predict from sequence. Most this work analyzed only direct paths between two interest excluding vast majority genotypes trajectories considered a single protein function, leaving unaddressed...

The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding genetic basis of phenotypic variation natural populations limited by inefficient association mapping due to strong complex population structure. To overcome this challenge, we generated genome sequences 85 strains performed a comprehensive genomic survey total 190 diverse strains. We identified considerable structure among chromosomes 181 genes that are...

A protein's genetic architecture - the set of causal rules by which its sequence produces functions also determines possible evolutionary trajectories. Prior research has proposed that proteins is very complex, with pervasive epistatic interactions constrain evolution and make function difficult to predict from sequence. Most this work analyzed only direct paths between two interest excluding vast majority genotypes trajectories considered a single protein function, leaving unaddressed...

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA active against number of fungi, it has little activity Aspergillus fumigatus, an important human pathogen, and attempts to improve the this organism by structural modifications have date involved chemistries too complex for continued development. This report describes novel chemistry modification AbA. key step involves functionalization phenylalanine...

Significance From seasonal variation in the color of butterfly wings to trees bending toward light, organisms often change response their environment. These changes, known as phenotypic plasticity, can result from differences how genes are expressed among environments. Mutations causing environment-specific changes gene expression provide raw material for but frequency, effect size, and direction effects environments not well understood. This study shows that mutations promoter a yeast...

Heritable variation in gene expression is common within species. Much of this due to genetic differences outside the with altered and trans-acting. This trans-regulatory often polygenic, individual variants typically having small effects, making architecture evolution challenging study. Consequently, key questions about remain, including variability a species, how selection affects variation, are distributed throughout genome To address these questions, we isolated measured affecting TDH3...

Genetic variants identified by mapping are biased toward large phenotypic effects because of methodologic challenges for detecting genetic with small effects. Recently, bulk segregant analysis combined next-generation sequencing (BSA-seq) was shown to be a powerful and cost-effective way map effect in natural populations. Here, we examine the power BSA-seq efficiently mutations isolated from mutagenesis screen. Specifically, determined impact population size, intensity selection collect...

Heritable variation in a gene’s expression arises from mutations impacting cis - and trans -acting components of its regulatory network. Here, we investigate how -regulatory are distributed within the genome gene network by identifying characterizing 69 with effects on same focal Saccharomyces cerevisiae . Relative to 1766 without this gene, found that these were enriched coding sequences transcription factors previously predicted regulate gene. However, over 90% identified mapped other...

Abstract Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought evolve because they provide some functional advantage. In many cases, however, no specific advantage known and, quaternary structure varies among orthologs. This has led the proposition that self-assembly may instead vary neutrally within families. The extent such variation been...

ABSTRACT The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding genetic basis of natural phenotypic variation limited by inefficiency association mapping owing to strong complex population structure. To facilitate mapping, we analyzed 190 high-quality genomes diverse strains, including 85 newly sequenced ones, uncover yeast’s structure that varies substantially among genomic regions. We identified 181 genes...

The relationship between genetic code robustness and protein evolvability is unknown. A new study in PLOS Biology using silico rewiring of codes functional data identified a positive correlation that protein-specific.

ABSTRACT We recently reanalyzed 20 combinatorial mutagenesis datasets using a novel reference-free analysis (RFA) method and showed that high-order epistasis contributes negligibly to protein sequence-function relationships in every case. Dupic, Phillips, Desai (DPD) commented on preprint of our work. In published paper, we addressed all the major issues they raised, but respond directly them here. 1) DPD’s claim RFA is equivalent estimating reference-based (RBA) models by regression...

Abstract Gene expression noise is an evolvable property of biological systems that describes differences in gene among genetically identical cells the same environment. Prior work has shown heritable and can be shaped by natural selection, but impact variation on organismal fitness proven difficult to measure. Here, we quantify effects altering for TDH3 Saccharomyces cerevisiae . We show increases deleterious or beneficial depending difference between average level a genotype maximizing...

Abstract Heritable variation in gene expression is common within species. Much of this due to genetic changes at loci other than the affected and thus trans -acting. This -regulatory often polygenic, with individual variants typically having small effects, making architecture challenging study. Consequently, key questions about remain, including how selection affects are distributed throughout genome Here, we show that affecting TDH3 promoter activity among strains Saccharomyces cerevisiae ....