Bahlo Lab

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:

• IBD methods applicable to the X-chromosome, a special case
• IBD methods to mixed samples, such as those seen in microorganisms that recombine and multiply infect humans, for example those that cause malaria

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).