With the completion of the first draft of the human genome sequence, the next major challenge is assigning function to genes. One approach is genome-wide random chemical mutagenesis, followed by screening for mutant phenotypes of interest and subsequent mapping and identification of the mutated genes in question. We (a consortium made up of GlaxoSmithKline, the MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Imperial College, London, and the Royal London Hospital) have used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for use as animal models of human disease and for gene function assignment (Nolan et al., 2000). As of 2003, 35,000 mice have been produced to date in a genome-wide screen for dominant mutations and screened using a variety of screening protocols. Nearly 200 mutants have been confirmed as heritable and added to the mouse mutant catalogue and, overall, we can extrapolate that we have recovered over 700 mutants from the screening programme. For further information on the project and details of the data, see http://www.mgu.har.mrc.ac.uk/mutabase.

Pregnant women undergo dynamic metabolic and immunologic changes to ensure provision of nutrients to, and prevent rejection of, the fetus. The mother increases glucose production, glucose intolerance and insulin resistance to support fetal-placental development and transitions from lipid storage to lipolysis to meet her own energy demands. Maternal immunoregulation prevents rejection of the fetal semi-allograft whilst maintaining protection against pathogens. Hypothesis Immunometabolic adaptation underpins maternal immune function changes in pregnancy. Aim To determine whether monocytes undergo metabolic adaptation in pregnancy and at which gestational stage this might occur. Results Peripheral blood monocytes of term pregnant (>37 weeks) and not pregnant women were compared using flow cytometry. Pregnant women had significantly more non-classical CD16+ monocytes, and CD16+ and CD16− subsets had more CD36 (fatty acid transporter; p = 0.0025) and less CD98 (amino acid transporter; p = 0.0043). Bioenergetic analysis of monocytes showed oxidative phosphorylation was significantly reduced in pregnant women; glycolysis was unchanged. Also, oxidative phosphorylation was reduced significantly in the mononuclear cells of women with gestational diabetes at 28 weeks compared to healthy pregnant women at the same gestational stage. Discussion Ongoing work includes analysis of mitochondrial health and measuring transcriptomics, biosynthetic lipids, cytokines, and enzyme responses. Results are vital to understanding immunological adaptation during pregnancy. This could provide insight into adverse pregnancy outcomes and women’s long-term health in relation to immune-mediated diseases.

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