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.

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).

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 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