Names of investigators
Jenefer M. Blackwell, Selma M.B. Jeronimo, Timo Lassmann, Denise Anderson, Dave Tang
Project description
Microcephaly is usually associated with Mendelian inheritance of rare genetic variants affecting developmental pathways. Clinical application of next generation sequencing has greatly improved ability to identify rare variants associated with developmental anomalies. We now know a lot about genes and mechanisms responsible for brain development, and where perturbations occur that cause congenital microcephaly and severe eye disorders. Our hypothesis is that congenital Zika virus infection dysregulates these genes early in the developing fetus, in a manner similar to what our data suggests is happening in other congenital infections like CMV (microcephaly) and toxoplasmosis (severe ocular disease; brain lesions). We can get a handle on this in two ways: (i) using next generation sequencing that captures regulatory and coding regions of all genes; and (ii) using DNA methylation arrays to determine whether congenital Zika infection has left its mark on the epigenome of infected babies. In this project we are looking for enrichment of rare genetic defects in microcephaly/eye disorder genes in Zika babies, and identifying the genes that are subject to changes due to epigenetic signatures left by the virus. This proposal is timely as Zika transmision, and associated microcephaly in babies, is now spreading outside of South America, and could be introduced into Australia. Determining developmental pathways perturbed during congenital Zika infection could identify key pathways for drug repurposing, while genetic screening could identify babies at increased risk in mothers infected during pregnancy. The results will have broader implications for other congenitally-acquired infections causing developmental anomalies in babies, including CMV and toxoplasmosis.
Funders of the project
Brazilian CNPq
Wesfarmers Centre Seed Funding
External collaborators
Professor Selma Jeronimo, Director, Institute of Tropical Medicine of Rio Grande do Norte, Universidade Federal do Rio Grande do Norte, Natal, Brazil.