CHARACTERIZING ADAPTIVE NON-CODING CHANGES IN THE REGULATION OF HUMAN GENE EXPRESSION

Differential patterns of gene expression contribute to phenotypic differences between species. Understanding evolutionary changes in gene regulatory elements can help explain traits that separate humans from closely related species. Here, in two separate studies, we investigate gene expression and gene regulatory differences between humans our closest living evolutionary relatives, chimpanzees, in the context of uniquely human traits: increased susceptibility to epithelial cancers and neural developmental and functional processes that underlie our increased cognitive capacity. Using genomic methods to study gene expression and open chromatin, we compare human and chimpanzee responses to a serum challenge, an assay that that mimics patterns of gene expression that occur during cancer progression, and in another approach, we investigate the functional consequences of evolutionary changes in non-coding regulatory elements in neural progenitor cells and neurons. These studies identify recently evolved changes in physiological stress responses in humans, and patterns of adaptive changes in regulatory elements around highly conserved developmental pathways. Together, using these comparative genomic studies in relevant physiological contexts, we can thus further define the molecular basis for uniquely human phenotypes

Tempo and mode of gene expression evolution in the brain across primates

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien and Higham, 2019; Powell et al., 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-seq data from four brain regions in an unprecedented eighteen species. Here, we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our samples that represent a 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size. Our study extensively broadens the phylogenetic context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for the study of genetic regulation of brain evolution

Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide’s antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors’ hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1’s bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested