Weinstock, G. | Search bioRxiv

bioRxiv2018

Systems genetic discovery of host-microbiome interactions reveals mechanisms of microbial involvement in disease

The role of the microbiome in health and disease involves complex networks of host genetics, genomics, microbes and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in the laboratory mouse enables data-driven discovery of network components and mechanisms of host-microbial interactions underlying multiple disease phenotypes. To examine the interplay among the whole host genome, transcriptome and microbiome, we mapped quantitative trait loci and correlated the abundance of cecal mRNA, luminal microflora, physiology and behavior in incipient strains of the highly diverse Collaborative Cross mouse population. The relationships that are extracted can be tested experimentally to ascribe causality among host and microbe in behavior and physiology, providing insight into disease. Application of this strategy in the Collaborative Cross population revealed experimentally validated mechanisms of microbial involvement in models of autism, inflammatory bowel disease and sleep disorder.\n\neTOC BlurbHost genetic diversity provides a variable selection environment and physiological context for microbiota and their interaction with host physiology. Using a highly diverse mouse population Bubier et al. identified a variety of host, microbe and potentially disease interactions.\n\nHighlights* 18 significant species-specific QTL regulating microbial abundance were identified\n* Cis and trans eQTL for 1,600 cecal transcripts were mapped in the Collaborative Cross\n* Sleep phenotypes were highly correlated with the abundance of B.P. Odoribacter\n* Elimination of sleep-associated microbes restored normal sleep patterns in mice.

genetics↗

bioRxiv2016

Ancient hybridization and strong adaptation to viruses across African vervet monkey populations

Vervet monkeys (genus Chlorocebus, also known as African green monkeys), are highly abundant in savannahs and riverine forests throughout sub-Saharan Africa. They are amongst the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases1 and in vaccine research2-4. They are particularly interesting for HIV/AIDS research as they are the most abundant natural hosts of simian immunodeficiency virus (SIV), a close relative of HIV. Here we present the first genome-wide survey of polymorphism in vervets, using sequencing data from 163 individuals sampled from across Africa and the Caribbean islands where vervets were introduced during the colonial era. We find high diversity, within and between taxa, and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across vervet taxa yields gene enrichments much stronger than in similar studies on humans5. In particular, we report strong and highly polygenic selection signals affecting viral processes -- in line with recent evidence that proposes a driving role for viruses in protein evolution in mammals6. Furthermore, selection scores are highly elevated in genes whose human orthologs interact with HIV, and in genes that show a response to experimental SIV infection in vervet monkeys but not in rhesus macaques, suggesting that part of the signal reflects taxon-specific adaptation to SIV. Intriguingly, rather than affecting genes with antiviral and inflammatory-related functions7, selection in vervets appears to have primarily targeted genes involved in the transcriptional regulation of viruses, and in particular those that are harmful only under immunodeficiency, suggesting adaptation to living with SIV rather than defense against infection.

evolutionary biology↗