From Microcephaly to Genome Stability, Inflammation and Growth Regulation

This research programme identifies new genes for inherited disorders affecting the human brain. We also study how these genes function using cells and model organisms.
Aicardi-Goutières syndrome is a genetic condition in which faults in genes encoding enzymes called nucleases, mimic viral infection of the brain. These nucleases may normally clean up naturally produced ‘waste’ DNA and RNA, with failure of this process leading to the body mounting an immune reaction against itself. This immune response mechanism is relevant to common autoimmune diseases such as lupus and so we are studying these enzymes to understand their normal roles in cells and to establish what happens when these enzymes fail.
Secondly, we are identifying genes that cause extreme growth failure of the brain and body. Individuals with primordial dwarfism are often described as the 'smallest people in the world'. These genes are components of the core cell machinery which controls cell duplication and mutations likely result in fewer cells being made, leading to a smaller person. Identifying these genes will help diagnosis and management of these rare conditions. It may also help us better understand how the body regulates growth, perhaps shedding light into why humans are bigger than mice and how our brains evolved to be so large.

This program investigates the molecular mechanisms underlying Mendelian developmental disorders associated with neuroinflammation and microcephaly (microcephalic dwarfism).
The autoinflammatory disorder Aicardi-Goutières syndrome (AGS) is a genetic mimic of congenital viral infections. We have established Ribonuclease H2, encoded by three of the AGS genes, as a key genome surveillance enzyme essential for development. We demonstrated its substrate, genome-embedded ribonucleotides (rNs), to be the most common aberrant nucleotides in the mammalian genome, occurring at over 1,000,000 sites in each replicating cell, greatly exceeding the sum total of base lesions removed by Nucleotide Excision Repair (NER), Base Excision Repair (BER) and Mis-Match Repair (MMR) pathways. We have since harnessed such genome-embedded rNs as a tool to track replicative polymerases, demonstrating that lagging-strand replication elevates mutation rates at protein binding sites in eukaryotic genomes. Furthermore, we have also established that the cytosolic dsDNA sensor cGAS is activated in RNase H2 deficient cells, linking genome instability with inflammation.
We have discovered nine novel disease genes for microcephalic dwarfism in the last five years, identifying previously unrecognised genome stability proteins and the first condensinopathy genes. We have established systems to functionally characterise the encoded proteins using primary human cells, isogenic mES cell systems, zebrafish and mouse models and we have contributed to the development of cerebral organoids to model human brain development and microcephaly. Our work has provided new insights into the disease mechanisms of these disorders of extreme brain size and growth reduction, establishing them to be the consequence of impaired cellular proliferation during development.