Abstract
We integrated ionomic profiling of mouse liver with quantitative trait loci (QTL) analysis using a panel of recombinant inbred lines (RIL) resulting from a cross of C57BL/6J (B6) and DBA/2J (DBA) inbred mouse lines (BXD). Following acid digestion, the levels of 13 elements (Na, Mg, P, K, Ca, Mn, Fe, Co, Cu, Zn, Se, Mo, and Cd) were determined by ICP‐MS in 400 samples from 27 RIL. Bayesian mapping using gender and analytical run as covariates and incorporating two stages of marker selection based on probabilities amongst prior distributions was used to identify QTL. 37 QTL were located and 12 strong peaks with a Bayes Factor (BF) >10 affected liver Fe (3 QTL), Mg (1), P (1), Mn (2), Cu (2), Mo (1), and Cd (2). Few of these loci contained genes known to regulate the mineral metabolism, demonstrating the value of this approach for gene discovery. The peaks controlling liver iron level on Chr 16, 17 and 18 each contain >100 candidate genes. The Chr 16 QTL peak (BF>4.5e+15) included the transferrin receptor (Tfrc) gene and polymorphisms between B6 and DBA mice were found within the 3′ UTR that normally regulates mRNA stability. However, transcript‐level QTL analysis revealed no difference in Tfrc mRNA levels between the BXD lines and suggests a Tfrc‐independent mechanism. Our data highlight the potential of coupling ionomics and forward genetics to identify natural genetic variants controlling mineral metabolism.
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