Patterns of geographic variation in communication systems can provide insight into the processes that drive phenotypic evolution.Although work in birds, anurans, and insects demonstrates that acoustic signals are sensitive to diverse selective and stochastic forces, processes that shape variation in mammalian vocalizations are poorly understood. We quantified geographic variation in the advertisement songs of sister species of singing mice, montane rodents with a unique mode of vocal communication. We tested three hypotheses to explain spatial variation in the song of the lower altitude species, Scotinomys teguina: selection for species recognition in sympatry with congener, S. xerampelinus, acoustic adaptation to different environments, and stochastic divergence. Mice were sampled at seven sites in Costa Rica and Panamá; genetic distances were estimated from mitochondrial control region sequences, between-site differences in acoustic environment were estimated from climatic data. Acoustic, genetic and geographic distances were all highly correlated in S. teguina, suggesting that population differentiation in song is largely shaped by genetic drift. Contrasts between interspecific genetic-acoustic distances were significantly greater than expectations derived from intraspecific contrasts, indicating accelerated evolution of species-specific song. We propose that, although much intraspecific acoustic variation is effectively neutral, selection has been important in shaping species differences in song. K E Y W O R D S :Acoustic adaptation, bird song, character displacement, ecological selection, mammal, speciation.Understanding the origins of phenotypic diversity is a fundamental goal of evolutionary biology; few phenotypes are as diverse as signals used in intraspecific communication (Endler 1992;Bradbury and Vehrencamp 1998). Acoustic signals make particularly good models for signal evolution because variation is readily quantifiable, and population and species differences can accrue over short evolutionary timescales with significant impact

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Alcohol Use Disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health1. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components2. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Background Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. Methods A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males (M)/14 females (F)) admitted to an alcohol detoxification program, was stratified into two groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/L, 7M/8F) and Group 2 (ALT ≥ 40 U/L, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia and inflammation were examined at baseline, day 8 and day 15 of the admission. The drinking history was also evaluated. Results Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide (LPS) levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. Conclusions The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with two weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program.