THE MICROBIOME AS A MEDIATOR OF HOST-GENOME-DETERMINED LACTATION OUTCOMES

Objective 1: Select inbred mouse strains with phenotypic extremes in milk production will be used to: a) identify genomic variants along with intestinal and mammary-expressed genes that differentiate low and high milk production, and b) determine the extent to which genome-driven differences in milk production and mammary gene expression are directly mediated through host-dependent differences in the intestinal and/or mammary tissue microbiome. Subobjective 1A: Sequence the genomes of additional unsequenced strains from our original milk yield cohort and then use this completed lactation phenome genotype data to identify strain-specific private alleles and predict the functional consequences of these variants on genes with the potential to regulate traits defined in the lactation phenome dataset. Subobjective 1B: Combine the lactation phenome dataset with the expanded common variant data from sub objective 1A to conduct an enhanced joint-GWAS of SNP, INDEL, and SV, and to subsequently predict the functional consequences of the newly identified variants to lactation. Subobjective 1C: Using a complete 3x3 diallele cross of QSi3, QSi5, and PL/J determine the contribution of strain-dosage, heterosis, parent-of-origin, and epistasis to milk production and composition, and mammary gland development during early lactation, and identify mammary epithelial cell and intestinal eGenes on the basis of allelic imbalance. Subobjective 1D: Integrate the set of eGenes discovered in 1C with the set of private and common variants discovered 1A and1B and employ network modeling to predict and test those variant-eGene pairs that are most likely to cause the variation in the lactation phenome traits. Subobjective 1E: Analyze the fecal microbiota along with prolactin and oxytocin in samples obtained from the diallel conducted under sub-objective 1C to determine the contribution of strain-dosage, heterosis, parent-of-origin, and epistasis to the diversity and richness of the intestinal microbiota, to the abundance of specific taxa, and to neuroendocrine function in mouse strains with a genetic propensity for high or low milk yield.