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Title: In silico mapping of quantitative trait loci (QTL) regulating the milk ionome in mice identifies a milk iron locus on chromosome 1

Author
item HADSELL, DARRYL - Baylor College Of Medicine
item HADSELL, LOUISE - Baylor College Of Medicine
item RIJNKELS, MONIQUE - Texas A&M University
item CARCAMO-BAHENA, YARELI - Baylor College Of Medicine
item WEI, JERRY - Royal Prince Alfred Hospital
item WILLIAMSON, PETER - University Of Sydney
item Grusak, Michael

Submitted to: Mammalian Genome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/17/2018
Publication Date: 8/2/2018
Publication URL: http://handle.nal.usda.gov/10113/6152384
Citation: Hadsell, D.L., Hadsell, L.A., Rijnkels, M., Carcamo-Bahena, Y., Wei, J., Williamson, P., Grusak, M.A. 2018. In silico mapping of quantitative trait loci (QTL) regulating the milk ionome in mice identifies a milk iron locus on chromosome 1. Mammalian Genome. http://doi.org/10.1007/s00335-018-9762-7.
DOI: https://doi.org/10.1007/s00335-018-9762-7

Interpretive Summary: Although breast milk is an important source of key nutrients for the breastfeeding infant, the concentrations of certain minerals in breast milk such as iron, zinc, phosphorus and others can be inadequate under certain conditions. The work described in this paper used a gene mapping technique known as genome-wide association to identify regions in the mouse genome that could control the concentrations of minerals in milk. These genomic regions, also known as loci, were found for calcium, magnesium, phosphorus, potassium, sulfur, zinc and iron. Further analysis of a locus found on mouse chromosome 1 supported the conclusion that there are several genes in this region that can control milk iron concentrations. Iron deficiency is considered a worldwide health issue. A better understanding of the biology of iron secretion could lead to new strategies to increase the concentrations of this mineral in milk.

Technical Abstract: The breast-feeding neonate depends on mother's milk for both macronutrients and micro-nutrients including minerals. The goals of the present study were to document the effects of genetic background in mice on milk concentrations of select minerals and to use genome-wide association analysis (GWAS) to identify QTL regulating milk mineral concentrations. Milk samples from lactating mice in each of 31 different inbred strains of the mouse diversity panel (MDP) were analyzed by inductively coupled plasma–optical emission spectroscopy (ICP-OES) to determine the concentrations of calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), sodium (Na), phosphorus (P), sulfur (S), and and zinc (Zn). GWAS analysis identified a single pleiotropic milk mineral concentration QTL (Mmcq) on chromosome 3 for Ca, Mg, and P. For the remaining minerals, six QTL were detected for Fe, four for K, three for Zn and one for S. Intersecting the Mmcq with published chromatin immunoprecipitation sequence (ChIP-Seq) data identified 15 out of 4,633 High-Linkage disequilibrium (LD) single nucleotide polymorphisms (SNP) that resided in signal transducer and activation of transcription 5 (STAT5) binding regions. A milk Fe-associated locus (Mmcq9) on chromosome 1 contained a SNP that localized to a STAT5 binding region and intersected with a HOMER motif predicted to bind the transcriptional regulator E74-Like ETS Transcription Factor 5 (ELF5). This locus also contained the genes for solute carrier family (Slc) members Slc9a2, Slc9a4, Slc39a10 and Slc40a1. Expression analysis of these transporters supports the conclusion that Slc9a2 and Slc40a1 within the mammary gland could mediate the effect of Mmcq9 on milk Fe concentration.