Genetics and genomics of human breast milk composition

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Project Summary Breastfeeding plays a critical role in infant and maternal health; however, the components of milk underlying the health effects of milk and consequences of variation in milk composition are not well understood. Except for a few milk components, the role of maternal genetics in milk composition is largely unknown, limiting the epidemiological tools available to tease apart the effects of variation in milk composition on infant and maternal health. Thus, enhancing our understanding of the genetic and genomic basis of variation in milk composition is critical for identifying the mechanisms linking breastfeeding to infant and maternal health outcomes. One such outcome is the infant gut microbiome, for which breastfeeding is a primary determinant, with implications for the nascent immune system and the child’s long-term metabolic health. This proposal contains a comprehensive analysis of the molecular and cellular composition of breast milk, the effect of maternal genetics on this composition, and the impact of host-microbiome interactions in milk on the infant gut microbiome. The results will provide foundational data for advancing milk research and help advance our knowledge of human nutrition during the critical first 1000 days of life. Three specific aims will address these priorities by (1) applying single cell RNA-seq to assess the cellular composition of milk at two time points in lactation, thus profiling changes in gene expression in the mammary gland across lactation and the maternal immune cells that provide critical immune support to the neonate; (2) identifying genetic variants associated with gene expression in milk (eQTLs) and cell type-eQTL interactions in milk; and (3) applying multi-omic data integration to milk gene expression, the milk microbiome, and infant gut microbiome to uncover the biological pathways underlying shared variation across these systems, and to assess the impact of maternal metabolic health on these pathways. Each Aim will leverage cutting edge genomics techniques never previously applied to human milk to expand our understanding of the genetic and genomic basis of milk composition. Research will take place at the University of Minnesota – Twin Cities, a major research institution, with state-of-the-art core facilities for genomics and clinical/translational research. The trainee will receive training in the biology of milk and lactation, computational biology, human subjects research, and responsible conduct of research from an interdisciplinary sponsorship team in the departments of Epidemiology & Community Health and Genetics, Cell Biology and Development. This training plan will result in the trainee acquiring the skills and a scientific foundation to launch her independent academic career.