From Microcephaly to Genome Stability, Inflammation and Growth Regulation
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
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.
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.
Technical Summary
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.
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.
Organisations
- University of Edinburgh (Lead Research Organisation)
- Francis Crick Institute (Collaboration)
- Mount Sinai Hospital (Canada) (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- Radboud University Nijmegen Medical Center (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- Alfred I. duPont Hospital for Children (Collaboration)
- University of Bonn (Collaboration)
People |
ORCID iD |
Andrew Jackson (Principal Investigator) |
Publications
Bellelli R
(2018)
Pole Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis
in Molecular Cell
Benitez-Guijarro M
(2018)
RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition.
in The EMBO journal
Burrage LC
(2019)
Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.
in American journal of human genetics
Duker A
(2021)
Microcephalic Osteodysplastic Primordial Dwarfism Type II
in GeneReviews
Farach LS
(2018)
The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.
in American journal of medical genetics. Part A
Ferreira C
(2020)
Growth in individuals with Saul-Wilson syndrome
in American Journal of Medical Genetics Part A
Ferreira CR
(2018)
A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.
in American journal of human genetics
Ferreira CR
(2020)
Defining the clinical phenotype of Saul-Wilson syndrome.
in Genetics in medicine : official journal of the American College of Medical Genetics
Giordano AMS
(2022)
DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.
in The Journal of experimental medicine
Grange LJ
(2022)
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
in Nature communications
Handley MT
(2019)
ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.
in PLoS genetics
Haworth S
(2019)
Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.
in Nature communications
Heyn P
(2019)
Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.
in Nature genetics
Knapp KM
(2020)
Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome.
in Journal of medical genetics
Logan CV
(2018)
DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.
in American journal of human genetics
Martin CA
(2018)
Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.
in American journal of human genetics
Parry DA
(2020)
PRIM1 deficiency causes a distinctive primordial dwarfism syndrome.
in Genes & development
Parry DA
(2021)
Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy.
in Genetics in medicine : official journal of the American College of Medical Genetics
Reijns M
(2022)
Signatures of TOP1 transcription-associated mutagenesis in cancer and germline
in Nature
Reijns MAM
(2020)
A sensitive and affordable multiplex RT-qPCR assay for SARS-CoV-2 detection.
in PLoS biology
Tamayo-Orrego L
(2021)
Author Correction: Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma.
in Nature cancer
Tamayo-Orrego L
(2020)
Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma.
in Nature cancer
Tarnauskaite Ž
(2019)
Biallelic variants in DNA2 cause microcephalic primordial dwarfism.
in Human mutation
Uggenti C
(2020)
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
in Nature genetics
Vaisman A
(2021)
Novel Escherichia coli active site dnaE alleles with altered base and sugar selectivity.
in Molecular microbiology
Zimmermann M
(2018)
CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.
in Nature
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £662,000 | ||
MC_UU_00007/2 | Transfer | MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £3,730,000 |
MC_UU_00007/3 | Transfer | MC_UU_00007/2 | 31/03/2018 | 30/05/2022 | £3,053,000 |
MC_UU_00007/4 | Transfer | MC_UU_00007/3 | 31/03/2018 | 30/03/2023 | £1,772,000 |
MC_UU_00007/5 | Transfer | MC_UU_00007/4 | 31/03/2018 | 30/03/2023 | £4,524,000 |
MC_UU_00007/6 | Transfer | MC_UU_00007/5 | 31/03/2018 | 30/03/2023 | £2,878,000 |
MC_UU_00007/7 | Transfer | MC_UU_00007/6 | 31/03/2018 | 30/03/2023 | £2,829,000 |
MC_UU_00007/8 | Transfer | MC_UU_00007/7 | 31/03/2018 | 31/12/2022 | £4,072,000 |
MC_UU_00007/9 | Transfer | MC_UU_00007/8 | 31/03/2018 | 30/03/2023 | £3,137,000 |
MC_UU_00007/10 | Transfer | MC_UU_00007/9 | 31/03/2018 | 30/03/2023 | £6,948,000 |
MC_UU_00007/11 | Transfer | MC_UU_00007/10 | 31/03/2018 | 30/03/2023 | £2,421,000 |
MC_UU_00007/12 | Transfer | MC_UU_00007/11 | 31/03/2018 | 30/03/2023 | £1,205,000 |
MC_UU_00007/13 | Transfer | MC_UU_00007/12 | 31/03/2018 | 30/03/2023 | £1,174,000 |
MC_UU_00007/14 | Transfer | MC_UU_00007/13 | 31/03/2018 | 30/03/2023 | £1,838,000 |
MC_UU_00007/15 | Transfer | MC_UU_00007/14 | 31/03/2018 | 30/03/2023 | £2,551,000 |
MC_UU_00007/16 | Transfer | MC_UU_00007/15 | 31/03/2018 | 30/03/2023 | £1,496,000 |
MC_UU_00007/17 | Transfer | MC_UU_00007/16 | 31/03/2018 | 30/03/2023 | £1,886,000 |
Description | CSO Testing Oversight Group (Covid19) |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Setting up an efficient and effective method of delivery of diagnostic testing for Covid19 was essential in 2020. Testing for Covid19 resulted in improvements in public well-being by reducing infection rates, thereby reducing morbidity. |
Description | NHS Joint Covid19 Diagnostic Testing group |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Setting up an efficient and effective method of delivery of diagnostic testing for Covid19 was essential in 2020. Testing for Covid19 resulted in improvements in public well-being by reducing infection rates, thereby reducing morbidity. |
Description | EMBO LTF |
Amount | £61,200 (GBP) |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 01/2020 |
End | 01/2022 |
Description | Birmingham-Stewart |
Organisation | University of Birmingham |
Department | Institute of Cancer and Genomic Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | reagents, cell lines, antibodies, constructs, technical knowledge, intellectual input |
Collaborator Contribution | reagents, cell lines, antibodies, constructs, technical knowledge, intellectual input |
Impact | Output publications: PMID: 25728776, 26595769, 28191891 and 30773277. |
Start Year | 2013 |
Description | Boulton -CRICK |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | identification of mutations in gene, clinical characterisation and obtaining primary cell lines |
Collaborator Contribution | characterisation of cell lines for gene involved in DNA replication |
Impact | Output publication: PMID 30503519 |
Start Year | 2017 |
Description | Crow-Edinburgh |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | reagents, cell lines, antibodies, constructs, technical knowledge, intellectual input |
Collaborator Contribution | reagents, cell lines, antibodies, constructs, technical knowledge, intellectual input |
Impact | Output publication: PMID: 33230297 |
Start Year | 2018 |
Description | MOPD II |
Organisation | Alfred I. duPont Hospital for Children |
Country | United States |
Sector | Hospitals |
PI Contribution | contribution of clinical and molecular data |
Collaborator Contribution | contribution of clinical samples and data |
Impact | 21358632, 21358633, 22821869, 22333897, 23023959, 26595769, 28191891, 29265708, 30290151, 30503519, 31045292, 31949312, 32652690 |
Start Year | 2008 |
Description | MOPD II |
Organisation | University of Bonn |
Department | Molecular Genetics |
Country | Germany |
Sector | Academic/University |
PI Contribution | contribution of clinical and molecular data |
Collaborator Contribution | contribution of clinical samples and data |
Impact | 21358632, 21358633, 22821869, 22333897, 23023959, 26595769, 28191891, 29265708, 30290151, 30503519, 31045292, 31949312, 32652690 |
Start Year | 2008 |
Description | Meier Gorlin |
Organisation | Radboud University Nijmegen Medical Center |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | contribution of clinical and molecular data to study |
Collaborator Contribution | contribution of clinical and molecular data to study |
Impact | 23023959 22333897 21358632 |
Start Year | 2010 |
Description | parp-duorcher |
Organisation | Mount Sinai Hospital (Canada) |
Department | Lunenfeld-Tanenbaum Research Institute |
Country | Canada |
Sector | Hospitals |
PI Contribution | collaboration - provision of RNaseH2 reagents for project. |
Collaborator Contribution | collaboration - provision of reagents for project. expertise on crispr screens |
Impact | Output publication: PMID 29973717 |
Start Year | 2016 |
Title | Covid19 qPCR assay |
Description | During the start of the Covid19 pandemic, there was a need for sensitive, specific and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. We therefore developed a multiplex assay using well-established SARS-CoV-2 targets alongside a human cellular control (RPP30) and a viral spike-in control (Phocine Herpes Virus 1 [PhHV-1]), which monitor sample quality and nucleic acid extraction efficiency, respectively. We established that this test performs as well as widely used commercial assays, but at substantially reduced cost. We established a robust RT-qPCR assay at approximately 10% of the cost of equivalent commercial assays, which could benefit low-resource environments and make high-volume testing affordable. This work was published in a peer reviewed journal and the assay was widely used in Ghana for diagnostic testing of the population. This work was funded by the MRC. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Wide-scale adoption |
Year Development Stage Completed | 2020 |
Development Status | Closed |
Impact | This work was published in a peer reviewed journal (https://doi.org/10.1371/journal.pbio.3001030). The assay is now widely used in Ghana for diagnostic testing of the population. |
URL | https://doi.org/10.1371/journal.pbio.3001030 |
Description | Interviews regarding Covid19 testing for Scottish TV news |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | TV interviews about Covid19 testing in Scotland was to increase public awareness of NHS testing and sparked lots of discussion during the pandemic. |
Year(s) Of Engagement Activity | 2020 |
Description | MRC parliamentary event with MSPs - PH |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Policymakers/politicians |
Results and Impact | At this MRC sponsored parliamentary event, the MRC HGU stand was about the journey from developmental disorder patient to gene discovery to diagnosis. Patricia Heyn talked to MSPs about her experience researching the molecular side of gene discovery. |
Year(s) Of Engagement Activity | 2019 |
Description | Patient support group -Walking with Giants |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I attend the annual Walking with Giants Foundation support group meeting in Liverpool, which has a UKwide and international reach in its membership, with participants affected by extreme growth failure (often described in the media as 'the smallest people in the world'), sharing my clinical and research expertise on primordial dwarfism, and gaining insight into the needs and priorities of this patient group on which a major element of my research is based |
Year(s) Of Engagement Activity | 2018,2019 |