Joachim Wittbrodt - US grants

Abstract Environmental pollutants (contaminants) have a profound impact on human health leading to in utero congenital defects, early childhood development defects and the incidence and progression of chronic adult disease. As well as being a major contributor to health burden overall, the heterogeneous distribution of environmental contaminants leads to health disparities between different groups. However, environmental exposures have a variable impact on individuals, and a substantial part of that variation is due to genetic effects. By studying these ?Gene x Environment? (GxE) effects, one can both quantify phenotypic changes and importantly gain mechanistic, molecular understanding of the biological pathways involved in contaminant responses. This understanding in turn can inform both treatment and policy in environmental health. To make a step change in our understanding of GxE interactions, we have assembled an international, multi-disciplinary team to exploit a unique resource, the wild-derived inbred Kiyosu panel of medaka (Japanese rice-paddy) fish. This panel is formed from 111 inbred lines from a single population (captured near the town of Kiyosu), inbred to near-homozygosity and each genome sequenced. In this proposal, we seek to screen 10 environmental contaminants (chosen for their impact and chemical diversity) on multiple early developmental, high dimensional, quantitative measurements on heart physiology, heart development and skeletal development. The Kiyosu panel brings together the best features of both the Mouse Collaborative Cross (CC) and the Drosophila Reference Genome Panel. Similar to the CC, the Kiyosu panel is in a model vertebrate with a broad range of genetics capabilities. However, a critique of the CC is the relative lack of founding genetic diversity, and that the diversity of the founders is not representative of a wild population. Here the Kiyosu panel is similar to the DRGP being derived from a single diverse wild population and capturing the majority of its genetic diversity. Preliminary data demonstrate reproducible GxE effects of selected chemicals on heartbeat phenotypes in a subset of medaka lines, and careful statistical power analysis provides confidence that we can map individual loci using a directed F2 cross strategy. The high dimensional phenotypes can be exploited using modern, scalable multi-trait techniques. Having discovered individual GxE loci underlying differential contaminant response in this vertebrate, we will molecularly characterize the loci using in depth phenotyping, CRISPR genetic tools, and RNAseq. All data and results will be made openly available to the community, and the panel can be accessed via an open MTA. We will also integrate the information with other killifish environmental models (Fundulus heteroclitus), the Mouse (Collaborative Cross), and human (UK BioBank, ALSPAC) resources to exploit this information with the community and translate insights to a human context.