Richards, J. | Search bioRxiv

bioRxiv2018

Genome wide association study of body weight, body mass index, adiposity, and fasting glucose in 3,173 outbred rats

Objective Obesity is influenced by genetic and environmental factors. Despite success of human genome wide association studies (GWAS), the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify genetic loci underlying obesity and related morphometric and metabolic traits.Methods We measured obesity-relevant traits including body weight, body length, body mass index, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat GWAS to date. Genetic loci were identified using a linear mixed model that accounted for the complex family relationships of the HS and covariate to account for differences among the three phenotyping centers.Results We identified 32 independent loci, several of which contained only a single gene (e.g. Epha5, Nrg1 and Klhl14) or obvious candidate genes (Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and extensive pleiotropy at individual loci.Conclusions These studies demonstrate utility of HS rats for investigating the genetics of obesity related traits across institutions and identify several candidate genes for future functional testing.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2017

The rumen microbiome: an underexplored resource for novel antimicrobial discovery

Antimicrobial peptides (AMPs) are promising drug candidates to target multi-drug resistant bacteria. The rumen microbiome presents an underexplored resource for the discovery of novel microbial enzymes and metabolites, including AMPs. Using functional screening and computational approaches, we identified 181 potentially novel AMPs from a rumen bacterial metagenome. Here, we show that three of the selected AMPs (Lynronne-1, 2 and 3) were effective against numerous bacterial pathogens, including methicillin resistant Staphylococcus aureus (MRSA). No decrease in MRSA susceptibility was observed after 25 days of sub-lethal exposure to these AMPs. The AMPs bound preferentially to bacterial membrane lipids and induced membrane permeability leading to cytoplasmic leakage. Topical administration of Lynronne-1 (10% w/v) to a mouse model of MRSA wound infection elicited a significant reduction in bacterial counts, which was comparable to treatment with 2% mupirocin ointment. Our findings indicate that the rumen microbiome may provide viable alternative antimicrobials for future therapeutic application.

microbiology↗