Melanie Bahlo-Projects

Melanie Bahlo-Projects


Genetics of speech disorders

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 are seeking to identify 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 member: Vicki Jackson, Antony Kaspi, Grace Jackel 


Scientific diagram
Gene co-expression matrix for candidate genes for Childhood Apraxia of Speech (CAS).

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).


Detecting repeat expansions

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).


Chart showing repeat expansion disorder
Detecting repeat expansions 

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.


Retinal disorders

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, Aravind Manda, Vicki Jackson (current). Roberto Bonelli (past).

Scientific diagram
MacTel Metabolomic Network 

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.


Identity by descent methods and applications

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:

  1. IBD methods applicable to the X-chromosome, a special case
  2. 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, Grace Jackel (current). Lyndal Henden (past).


Scientific diagram
Relatedness network for pairs of P. falciparum isolates that are related over the chloroquine resistance transporter gene, Pfcrt.

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.


Infectious diseases

The Bahlo lab has a secondary interest in the population genetics and genomics of two infectious diseases that have a large contribution to the global burden of disease: malaria and tuberculosis.

We work with a range of sequencing data to characterise the strains present in various disease cohorts, examine the relationship between strains, and identify cases of mixed/polyclonal infection. To achieve this we employ methods such as identity by descent (IBD) analysis, phylogenetic inference and mixture modelling. This has led to the mapping of genomic loci under drug selection pressure and has allowed greater insights into relapse versus reinfection in recurrent infectious diseases, an important facet of the prevalence and spread of infectious diseases.

Team members: Jacob Munro, Jiru Han

Scientific diagram
Inferred phylogenetic tree of 5,000 Mycobacterium tuberculosis complex (MTBC) isolates.

This figure details the inferred genetic relationship between 5,000 MTBC isolates, with each leaf node representing an individual strain, and each internal node representing an inferred ancestral state. The branch length between nodes corresponds to the genetic distances between the nodes. Isolates presented in this figure were obtained from publically available sequence data on ENA, and the phylogenetic tree was produced with RAxML from an alignment of the core genome. The terminal branch leading up to each isolate node is coloured according to a widely used SNP barcode (Coll et al., 2014). Additionally, the major MBTC lineages are indicated with text labels (1-6, B).


Rare variant detection

The ability to whole exome and whole genome sequence human DNA has led to a rapid increase in the ability to determine the genetic causes of disease where single, highly penetrant, and consequently most often extremely rare or even novel, are the cause of the disease.

The Bahlo lab has a state of the art analysis pipeline for rare variant detection which incorporates the lab’s recent repeat expansion analysis methods.

The Bahlo lab also has interests in the analysis of rare variants from unusual DNA sources, such as brain or cell-free DNA. Somatic mutations are another area of special interest. The lab routinely collaborates with clinician scientists, in particular neurologists, to identify causal genetic mutations leveraging both family-based analysis, including identity-by-descent (IBD) methods, trio designs and for somatic mutations, germline/tissue pairwise analyses.

Team members: Longfei Wang, Antony Kaspi, Mark Bennett, Karen Oliver, Haloom Rafehi, Liam Scott, Jacob Munro

Genome-wide association study investigations

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 (current). Roberto Bonelli (past).