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PhD in Molecular Genetics, University of Melbourne (2016)
Department of Biological and Medical Sciences
Faculty of Health and Life Sciences
+ 44 (0)1865 483276
Headington Campus, Oxford
I am an early career researcher in the Newbury lab. I use a range of bioinformatic and molecular biology techniques to study how genetics influences human learning through extreme traits. My main interests are:
Speech Genetics (Robinson Crusoe Island)
Speech and language disorders are a common childhood developmental issue (7% of children) (Norbury et al. 2016) and result in an increased lifetime risk of mental health issues and poor life outcomes (Conti-Ramsden et al. 2008). Despite being so common, we understand little of the biology underpinning disorders of speech, however, it is becoming increasingly apparent that genetic risk, or susceptibility, plays an important role. The identification of genetic risk factors for speech and language disorder may also help explain why language ability is so often affected in related disorders such as autism spectrum disorder, developmental dyslexia, intellectual learning disability or ADHD.
Using recent advances in genetic technologies, I am investigating genetic contributions to speech and language disorders in the inhabitants of Robinson Crusoe Island (RCI), Chile. The island was colonised in the late 19th century, and is physically isolated, over 600km away, from the mainland. Most of the people who live there today are related to the original 62 founders. Two-thirds of Islander children have speech and language disorder, 10-fold higher than expected.
The Genetics of Face Recognition
We know there is something special about the way we interact with faces. From an early age, both animals and humans show a clear preference for faces over other visual stimuli - new born babies will actively choose to look at images of faces (Goren et al 1975), and can identify their mother over other females after only two days (Bushnell 1989). The ability to discriminate between faces allows us to establish individual identity and plays an important role in human bonding and social exchange. The lack of ability to recognise peers by their faces often leads to struggles with social isolation and mental health issues. It is a fundamental and vital part of human behaviour, one which develops so early in our development, that we almost take it for granted. Despite it being pivotal to our success as a social species, we understand little of how the brain recognises faces, or which neuro-molecular pathways are involved in this essential process.
Super recognisers can recognise faces they have only glimpsed before. Most people can recognise about 20% of the faces they see, whereas a super recogniser can remember up to 95%. This super ability is thought to occur in less than 1% of the population.
Face recognition plays an important role in the Metropolitan Police who use super recognisers to identify suspects from CCTV footage. Following the 2011 London riots, a single super recogniser identified 190 suspects from grainy images and footage, in stark comparison with the Met’s state-of-the-art computer software that only successfully identified one.
In collaboration with Dr Josh Davis (University of Greenwich), we are studying the genetics of individuals with extreme face recognition ability - super recognisers.
If you think you might be a super recogniser, click here to take the test http://superrecognisers.com/
2017 - Oxford Brookes University Santander Research Scholarship Award Scheme - £1500
2011-2015 - Dora Lush Biomedical Post Graduate Research Scholarship, National Health and Medical Research Council - AU$78,750
2011 - 2015 - Australian Mitochondrial Disease Foundation scholarship top-up award - AU$15,750
2011-2014 - Australian Mitochondrial Disease Foundation student travel award - AU$9000
The ability to finely control our movement is key to the achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to our early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown.
Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature.
Here we present the first genome-wide association study (GWAS) to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children (MABC), providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N=4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance however 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNP, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20 and ADAM21.
Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Studies examining genetic conditions common in Latin America are highly underrepresented in the scientific literature. Understanding of the population structure is limited, particularly Chile, in part due to the lack of available population specific data. An important first-step in elucidating disease mechanisms in Latin America countries is to understand the genetic structure of isolated populations. Robinson Crusoe Island (RCI) is a small land mass off the coast of Chile. The current population of over 900 inhabitants are primarily descended from a small number of founders who colonized the island in the late 1800s. Extensive genealogical records can trace the ancestry of almost the entire population. We perform a comprehensive genetic analysis to investigate the ancestry of the island population, examining ancestral mitochondrial and Y chromosome haplogroups, as well as autosomal admixture. Mitochondrial and Y chromosome haplogroups indicated a substantial European genetic contribution to the current RCI population. Analysis of the mitochondrial haplogroups found in the present-day population revealed that 79.1% of islanders carried European haplogroups, compared to 60.0% of the mainland Chilean controls from Santiago. Both groups showed a substantially lower contribution of indigenous haplogroups than expected. Analysis of the Y chromosome haplogroups also showed predominantly European haplogroups detected in 92.3% of male islanders and 86.7% of mainland Chilean controls. Using the near-complete genealogical data collected from the RCI population, we successfully inferred the ancestral haplogroups of 16/23 founder individuals, revealing genetic ancestry from Northern and Southern Europe. As mitochondrial and Y investigations only provide information for direct maternal and paternal lineages, we expanded this to investigate genetic admixture using the autosomes. Admixture analysis identified substantial indigenous genetic admixture in the RCI population (46.9%), higher than that found in the Santiago mainland Chilean controls (43.4%), but lower than a more representative Chilean population (Chile_GRU) (49.1%). Our study revealed the Robinson Crusoe Island population show a substantial genetic contribution for indigenous Chileans, similar to the level reported in mainland Chileans. However, direct maternal and paternal haplogroup analysis revealed strong European genetic contributions consistent with the history of the Island.
Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)—stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss‐of‐function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within‐group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.
Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the membrane insertion of subunits, attachment of co-factors, and stabilization of assembly intermediates. The major fraction of complexes I, III and IV are present together in large molecular structures known as respiratory chain supercomplexes. A number of assembly factors have been proposed as required for supercomplex assembly, including the hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines and extensive steady state, translation and affinity enrichment proteomics techniques we show that loss of HIGD2A leads to defects in the de novo biogenesis of mtDNA-encoded COX3, subsequent accumulation of complex IV intermediates and turnover of COX3 partner proteins. Deletion of HIGD2A also leads to defective complex IV activity. The impact of HIGD2A loss on complex IV was not altered by growth under hypoxic conditions, consistent with its role being in basal complex IV assembly. While in the absence of HIGD2A we show that mitochondria do contain an altered supercomplex assembly, we demonstrate it to harbor a crippled complex IV lacking COX3. Our results redefine HIGD2A as a classical assembly factor required for building the COX3 module of complex IV.
Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems.
Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis.
Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. We go on to test whether the overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage.
In the absence of explanatory rare variants, we further investigate these candidate genes within a complex model of inheritance, where inheriting a small number of moderate impact common variants may increase susceptibility of developing TEL. We examine if any variants segregate with affection status or with founder-brother-related status, and therefore may increase risk of developing a language disorder. Finally, we perform a pooled, gene-based tests to evaluate relationships between combined variation across candidate genes and TEL affection status.
Here we report a comprehensive examination of genes directly implicated in language-related mechanisms to identify ‘low hanging fruit’ of causative monogenic Mendelian variants, and complex association model of increased susceptibility in developmental language disorder found on Robinson Crusoe Island.
This chapter focuses on the understanding of the role of genetics in language and explores how genetics contribute to language, and shows how new genetic techniques can offer inroads into the molecular basis of language acquisition. It discusses some of the key findings of gene x environment studies and provides a snapshot of the understanding in the field, considering some of the limitations of the type of study design. The chapter describes the field of play in the genetics of language acquisition and explains the heritability of language and the role of family and twin studies in the understanding of language. It also explores the inheritance mechanisms that are implicated in language development. The chapter considers how modern DNA sequencing approaches are revolutionizing the field of language genetics. Heritability studies have provided many key insights into the genetics of both language acquisition and language disorders. Insights into mechanisms can also come from the opposite end of the language ability spectrum.
Developmental Language Disorders
Next generation sequencing