Our lab uses statistical methodology to describe and model genetic data, by identifying and making use of structure within the data. This pinpoints genomic regions that may harbor disease-causing mutations, as well as provide insight into disease pathogenesis. We implement these models through software development and bespoke data analyses, primarily in the R programming language.
We work on many disease identification projects concurrently, some of which can be readily solved with existing methods and analytic pipelines. Others may prove more challenging, potentially taking years of development and analysis before a breakthrough is achieved. We seek to identify when and where new technologies can be implemented to achieve breakthroughs in studies that have remained unsolved thus far.
Australia, Monash University, BSc (Hons), 1992
Australia, Monash University, PhD, 1997
2021 National Health and Medical Research Council Investigator Grant
2020 Fellow of the Australian Academy of Health and Medical Sciences (FAHMS)
2015 Ross Crozier Medal, Genetics Society of Australasia
2010 and 2016 National Health and Medical Research Council Senior Research Fellowship
2010 Australian Research Council Future Fellowship
2009 Moran Medal, Australian Academy of Science
2022-2023 Michael J Fox Foundation APP021399, Bahlo M, Bennett M, Wang L, Dewson G, Watson R, Cooper A. “Investigating the role of repeat expansions and mitochondrial dysfunction in Parkinson’s disease”.
2021-2025 NHMRC Investigator Grant APP1195236, Bahlo M. “Gene discovery and functional insights for neurological and retinal disorders“.
2020-2024 NHMRC Synergy Grant APP1181010, Guymer R, Bahlo M, Fletcher E, Ansell B, Pebay A, Fletcher E, Wu Z. “A Pathway to translation: uncovering novel causes, genetic associations and potential intervention strategies for age related macular degeneration”.
2019-2023 NHMRC Project Grant APP1160893 Bahlo M, Morgan A, Fisher S, Reilly S, Jackson V. “Finding the first genetic loci for stuttering”.
2021-Present Australian Academy of Health and Medical Sciences Australian Learned Academies Data Internetworking Network (ALADIN) Project Steering Committee (Member)
2021-Present Australian Academy of Health and Medical Sciences Reports Committee (Member)
2020-Present American Epilepsy Society Basic Sciences Committee (Member)
2019-Present Clinical Genomics Advisory Committee, Kinghorn Sequencing Center, Sydney (Chair)
2019-Present Gen V Scientific Advisory Committee, Murdoch Children’s Research Institute (Member)
2018-Present Viertel Foundation Medical Advisory Board (Member)
Oliver KL, Scheffer IE, Bennett MF, Grinton BE, Bahlo M, Berkovic SF. Genes4Epilepsy: An epilepsy gene resource. Epilepsia. 2023 Feb 21. Epub ahead of print. PMID: 36808730.
Grinton BE, Robertson E, Fearnley LG, Scheffer IE, Marson AG, O’Brien TJ, Pickrell WO, Rees MI, Sisodiya SM, Balding DJ, Bennett MF, Bahlo M, Berkovic SF, Oliver KL. A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure. Am J Hum Genet. 2022 Nov 3;109(11):2080-2087. PMID: 36288729.
Lotta LA, Pietzner M, Stewart ID, Wittemans LBL, Li C, Bonelli R, Raffler J, Biggs EK, Oliver-Williams C, Auyeung VPW, Luan J, Wheeler E, Paige E, Surendran P, Michelotti GA, Scott RA, Burgess S, Zuber V, Sanderson E, Koulman A, Imamura F, Forouhi NG, Khaw KT; MacTel Consortium, Griffin JL, Wood AM, Kastenmüller G, Danesh J, Butterworth AS, Gribble FM, Reimann F, Bahlo M, Fauman E, Wareham NJ, Langenberg C. A cross-platform approach identifies genetic regulators of human metabolism and health. Nat Genet. 2021 Jan;53(1):54-64. PMID 33414548
Bonelli, R., Jackson, V.E., Prasad, A. et al. Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder. Commun Biol 4, 274 (2021). https://doi.org/10.1038/s42003-021-01788-w
Bonelli R, Ansell BRE, Lotta L, Scerri T, Clemons TE, Leung I, MacTel Consortium, Peto T, Bird AC, Sallo FB, Langenberg C, Bahlo M. Genetic Disruption of Serine Biosynthesis is a Key Driver of Macular Telangiectasia Type 2 Etiology and Progression. Genome Med. 2021 Mar 9;13(1):39. doi: 10.1186/s13073-021-00848-4. PMID: 33750426.
Scerri TS, Quaglieri A, Cai C, Zernant J, Matsunami N, Baird L, Scheppke L, Bonelli R, Yannuzzi LA, Friedlander M; MacTel Project Consortium, Egan CA, Fruttiger M, Leppert M, Allikmets R, Bahlo M. Genome-wide analyses identify common variants associated with macular telangiectasia type 2. Nat Genet. 2017 Apr;49(4):559-567. Epub 2017 Feb 27. PMID: 28250457
Repeat Expansion Methods Development and Discoveries
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet. 2023 Jan 5;110(1):105-119. doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768
Bennett MF, Oliver KL, Regan BM, Bellows ST, Schneider AL, Rafehi H, Sikta N, Crompton DE, Coleman M, Hildebrand MS, Corbett MA, Kroes T, Gecz J, Scheffer IE, Berkovic SF, Bahlo M. Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families. Eur J Hum Genet. 2020 Jul;28(7):973-978. PMID: 32203200
Rafehi H, Szmulewicz DJ, Pope K, Wallis M, Christodoulou J, White SM, Delatycki MB, Lockhart PJ, Bahlo M. Rapid Diagnosis of Spinocerebellar Ataxia 36 in a three-Generation Family Using Short-Read Whole-Genome Sequencing Data. Mov Disord. 2020 May 14. PMID: 32407596
Corbett MA, Kroes T, Veneziano L, Bennett MF, Florian R, Schneider AL, Coppola A, Licchetta L, Franceschetti S, Suppa A, Wenger A, Mei D, Pendziwiat M, Kaya S, Delledonne M, Straussberg R, Xumerle L, Regan B, Crompton D, van Rootselaar AF, Correll A, Catford R, Bisulli F, Chakraborty S, Baldassari S, Tinuper P, Barton K, Carswell S, Smith M, Berardelli A, Carroll R, Gardner A, Friend KL, Blatt I, Iacomino M, Di Bonaventura C, Striano S, Buratti J, Keren B, Nava C, Forlani S, Rudolf G, Hirsch E, Leguern E, Labauge P, Balestrini S, Sander JW, Afawi Z, Helbig I, Ishiura H, Tsuji S, Sisodiya SM, Casari G, Sadleir LG, van Coller R, Tijssen MAJ, Klein KM, van den Maagdenberg AMJM, Zara F, Guerrini R, Berkovic SF, Pippucci T, Canafoglia L, Bahlo M, Striano P, Scheffer IE, Brancati F, Depienne C, Gecz J. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun. 2019 Oct 29;10(1):4920. PMID 31664034
Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, Gillies G, Diakumis P, Dolzhenko E, Eberle MA, Barcina MG, Breen DP, Chancellor AM, Cremer PD, Delatycki MB, Fogel BL, Hackett A, Halmagyi GM, Kapetanovic S, Lang A, Mossman S, Mu W, Patrikios P, Perlman SL, Rosemergy I, Storey E, Watson SRD, Wilson MA, Zee DS, Valle D, Amor DJ, Bahlo M, Lockhart PJ. Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. Am J Hum Genet. 2019 Jul 3;105(1):151-165. PMID: 31230722
Dolzhenko E, Bennett MF, Richmond PA, Trost B, Chen S, van Vugt JJFA, Nguyen C, Narzisi G, Gainullin VG, Gross AM, Lajoie BR, Taft RJ, Wasserman WW, Scherer SW, Veldink JH, Bentley DR, Yuen RKC, Bahlo M, Eberle MA. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 2020 Apr 28;21(1):102. PMID: 32345345
Tankard RM, Bennett MF, Degorski P, Delatycki MB, Lockhart PJ, Bahlo M. Detecting Expansions of Tandem Repeats in Cohorts Sequenced with Short-Read Sequencing Data. Am J Hum Genet. 2018 Dec 6;103(6):858-873. PMID: 30503517
Kaspi, A., Hildebrand, M.S., Jackson, V.E. et al. Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01764-8
Boyce, JO, Jackson, VE, van Reyk, O, Parker, R, Vogel, AP, Eising, E, et al. Self-reported impact of developmental stuttering across the lifespan. Dev Med Child Neurol. 2022; 64: 1297– 1306. https://doi.org/10.1111/dmcn.15211
Hildebrand MS, Jackson VE, Scerri TS, Van Reyk O, Coleman M, Braden RO, Turner S, Rigbye KA, Boys A, Barton S, Webster R, Fahey M, Saunders K, Parry-Fielder B, Paxton G, Hayman M, Coman D, Goel H, Baxter A, Ma A, Davis N, Reilly S, Delatycki M, Liégeois FJ, Connelly A, Gecz J, Fisher SE, Amor DJ, Scheffer IE, Bahlo M, Morgan AT. Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. Neurology. 2020 May 19;94(20):e2148-e2167. PMID: 32345733
Identity by descent methods
Henden L, Lee S, Mueller I, Barry A, Bahlo M. Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens. PLoS Genet. 2018 May 23;14(5):e1007279. PMID: 29791438
Collaborations within WEHI
Cavan Bennett, Victoria E Jackson, Anne Pettikiriarachchi, Thomas Hayman, Ute Schaeper, Gemma L Moir-Meyer, Katherine Louise Fielding, Ricardo Ataide, Danielle Clucas, Andrew James Baldi, Alexandra L Garnham, Connie SN Li-Wai-Suen, Stephen John Loughran, E Joanna Baxter, Anthony R Green, Warren S Alexander, Melanie Bahlo, Kate Burbury, Ashley P Ng, Sant-Rayn Pasricha; Iron homeostasis governs erythroid phenotype in Polycythemia Vera. Blood 2023; blood.2022016779. doi: https://doi.org/10.1182/blood.2022016779
One in five Australian children start school with a speech or language disorder. While some children will grow out of it, many others will go on to have persistent speech difficulties. Such disorders can have a profound effect on an individual’s social and mental wellbeing. Speech disorders are thought to be caused by a combination of genetic, neurological and environmental factors. Understanding more about the genetic causes of speech disorders may improve developments in treatment and help us to identify individuals most at risk of these disorders.
In this project, we take several approaches to investigate the genetics underlying speech problems.
Through whole exome and whole genome sequencing (WES/WGS) of families, we have identified causal variants responsible for rare forms of familial speech disorders. We are working to assemble an international cohort of people who stutter, with which we shall undertake a genome-wide association study (GWAS) to identify common genetic variation, influencing risk of stuttering in the general population.
Team members: Vicki Jackson (current). Antony Kaspi, Grace Jackel (past).
This matrix shows pairwise Spearman Correlations between genes, based on samples from the BrainSpan Atlas of the Developing Human Brain. Pairs of genes which are positively correlated (ie co-expressed) are shown in blue; pairs of genes that are negatively correlated are shown in red. Gene co-expression of candidate genes with known speech disorder genes increases burden of evidence for these genes and is performed using methods previously developed by the Bahlo lab (Oliver et al, PLOS ONE, 2014, Freytag et al, BMC Bioinformatics, 2015, Freytag et al, Genome Medicine, 2017).
Short tandem repeats are short repetitive elements of the genome, which can vary in length between individuals. Some repeats are unstable and can expand in length. Repeat expansions cause a number of neurological disorders, such as Huntington’s disease and spinocerebellar ataxias as well as other more common neurological disorders, such as epilepsy and motor neuron disease.
Identifying repeat expansions is difficult as their length can greatly exceeds the read lengths of short read sequencing. Standard clinical tests are specialised and expensive and not routinely performed for the majority of patients.
The Bahlo lab has developed new methods to identify repeat expansions in whole exome and whole genome sequencing data. We are interested in searching for known or novel repeat expansions associated with a variety of neurological disorders and indeed have discovered novel repeat expansions. Our work has also provided diagnosis for patients where it had previously not been possible to detect repeat expansions, even though they were the cause of their disorders.
Team members: Mark Bennett, Haloom Rafehi, Liam Fearnley, Erandee Robertson, Liam Scott (current). Rick Tankard (past).
The statistical methods we have developed can identify samples with repeat expansions using short read sequencing data.
Samples likely to be affected by the repeat expansion disorder have an increased number of repeated bases and appear shifted to the right which can be seen for the coloured samples in the figure above.
The Bahlo lab works on two retinal disorders: Macular Telangiectasia Type 2 (MacTel) and Age-related Macular Degeneration (AMD).
Using genome-wide association analysis (GWAS) methods for both diseases we discovered the first loci for MacTel in 2017. In recent years we have combined genomic data with metabolomic data as well as analysing and further combining extensive data generated by collaborators from the MacTel consortium.
In the past two years the Bahlo lab has started a collaboration to work on a subtype of AMD with poorer prognostic outcome. This will involve using GWAS and related methods to investigate the genetic basis of this AMD subtype.
Team members: Brendan Ansell, Sami Farashi, Vicki Jackson, Liam Scott (current). Roberto Bonelli, Aravind Manda (past).
This image displays more than 800 metabolites and their connections to each other as measured in a group of 50 MacTel patients. Connections are displayed as blue lines (positive connection) or red lines (negative connection).
We performed a stratified factorial analysis to explore and create potential clusters of metabolites (designated by different colours) which show evidence of an increased risk of developing MacTel disease. Metabolites that appear to be closer in this network should belong to the same cluster. The size of each dot indicates the relevance of each metabolite on the disease risk. Glycine and Serine identified in our genetic study as being very important in MacTel appear in this network as the two largest points of the blue cluster, confirming the importance of their role on the disease.
Genomic regions that are inherited from a common ancestor are said to be identical by descent (IBD). Identification of such regions has proven useful in human studies with application including discovery of familial relatedness, disease mapping and determining loci under selection.
The Bahlo lab has developed multiple implementations of IBD methods including:
The Bahlo lab has published many applications of IBD methods to refine the genomic location of disease-causing variants.
Team members: Erandee Robertson, Mark Bennett, Karen Oliver, Bronwyn Grinton (current). Lyndal Henden, Grace Jackel (past).
Each node represents a unique P. falciparum isolate, and a line is drawn between two isolates if they were inferred either partially or completely IBD over the gene Pfcrt. Isolates with a single infection, i.e. multiplicity of infection (MOI), of 1 are represented by circles while isolates with multiple infections (MOI > 1) are represented by squares. Here we see that many isolates from both Southeast Asia and Africa are IBD over Pfcrt, which is consistent with literature that suggests a haplotype conferring resistance to the antimalarial drug chloroquine has spread between Southeast Asia and Africa.
The Bahlo lab has been involved and also led several genome-wide association studies (GWAS) and has previously worked on X chromosome analysis methods, as well as demonstrating that saliva derived DNA achieves high quality data of an equivalent standard to that derived from blood samples.
We are continuing to perform GWAS studies in AMD, MacTel and stuttering, combining these basic analyses with techniques such as expression QTL and metabolomic QTL studies making use of modern analysis methods such as Mendelian Randomisation. The lab is also applying these methods to epilepsy through collaborations with the International League against Epilepsy (ILAE) consortium.
Team members: Karen Oliver, Vicki Jackson, Sami Farashi, Brendan Ansell, Liam Scott (current). Roberto Bonelli (past).
Dementia is a heterogeneous disorder with many different subtypes that are driven by dysregulation of biological pathways. Treatment selection for dementias is based on subtype, but accurate diagnosis in the clinical setting is very challenging early on in the disease when therapies have their greatest potential. Vast improvement in dementia diagnostics is required for truly targeted treatments.
We aim to supercharge dementia research by overlaying personalised genomics to WEHI’s current and future multi-disciplinary dementia projects.
Conducting whole genome sequencing on patients and analysing the data will help tease apart this heterogenous patient cohort, providing greater understanding of dementia sub-types and facilitate more suitable selection of clinical trials and therapies. It will also reveal if women are genetically pre-disposed to developing dementia.
Furthermore, working closely with the experts above and combining their projects’ data with the genomics information will generate an enormous, complex, and critical data set on dementia. This invaluable resource will fast track our biomarker development and diagnostic tests, advance our understanding of the disease to help identify potential targets for therapeutic development, and likely aid prognosis.
This four-year project launched with a $1million flagship grant from the Alfred Felton Bequest will involve conducting whole genome sequencing on 500 Victorian patients (recruited via Royal Melbourne Hospital, the Alfred Hospital, and others), then performing comprehensive data analysis on those results, as well as other WEHI dementia projects, to facilitate precision dementia research.
Team members: Longfei Wang, Jiru Han, Mark Bennett, Haloom Rafehi (current).