Dianne teaches genetics and genomics to undergraduates and post-graduates

Modules taught

P10112: Molecular Basis of Human Genetic Disease

P10114: Clinical Genetics and Diagnostics

P10199: MSc research project

U14520: Molecular Biology and Genetics

U14592: Molecular Medicine

U14675: Experimental Based Medicine and Diagnostics

U14699: Undergraduate research projects

Supervision

MSc Medical Genetics and Genomics programme

Research in my lab centres around genetic contributions to speech, language and Communication Disorders (SLCDs). A recent study found that, at school entry in the UK, approximately 10% of children are affected by speech, language or communication impairments (Norbury et al., 2016). As a group these children are less likely to meet educational targets (Norbury et al., 2015) and more likely to display symptoms of social, emotional and behavioural problems when compared to their peers (Norbury et al., 2016).

But yet, we do not know why some children have language difficulties or how these difficulties relate to other aspects of neurodevelopment and behaviour. In our lab, we are trying to identify genetic factors that might play a role in these disorders. We investigate this problem through a mixture of research questions and by studying individuals, families and populations.

This research is important because it will help us to understand why some children have language difficulties and what brain processes are important in language learning. It may allow us to identify new kinds of language disorders and will clarify the relationships between language impairment and other developmental disorders.

Research group membership

Hayley Mountford (post-doc) p0083144

Lidiya Nevedska (PhD student) 16034238

Nuala Simpson (post-doc) p0084691

Research grants and awards

Research Excellence (CRF) award – Functional characterisation of RIC3 in backwards speech. Aug 2016-Jan 2017

ESRC Newton Award - A language and reading intervention programme for Chile, piloted in the Robinson Crusoe population. Feb 2016 – Oct 2018

Research projects

Studies show that developmental language disorders run in families - a brother or sister of someone who has already been diagnosed will have an increased risk of developing the disorder themselves. There are two possible situations which may explain this observation: (1) something in the family environment causes the language disorder; or (2) Developmental language disorders are genetic and is therefore caused (at least in part) by the genes passed on from parents to children.

Although there is strong evidence for the role of a genetic component in language disorder, we do not know which genes contribute to this disorder or how the inheritance of language problems work. In most cases, it is likely that several genes combine to bring about a heightened risk of disorder. This is known as a complex genetic disorder. Working closely with other collaborators active in this field, we aim to identify specific genetic variants that cause this predisposition and to investigate the kinds of biological processes that they take part in.

The work in our lab is split into different project areas. You can find out more about each area on our research website.

Research impact

Our research impacts upon our understanding of the biological processes underlying speech and language development. This will be relevant to families of affected individuals and has impact upon research in psychology, neuroscience and education.

Journal articles

• De Barbieri Z, Fernandez MA, Newbury DF, Villanueva P, 'Family aggregation of Language Impairment in an Isolated Chilean Population from the Robinson Crusoe Island'
  International Journal of Language and Communication Disorders (2018)
  ISSN: 1368-2822 eISSN: 1368-2822
  Abstract Background: It has been reported that the inhabitants of the Chilean Robinson Crusoe Island have an increased frequency of Specific Language Impairment (SLI) or Developmental Language Disorder (DLD). Aims: In this paper, we aim to explore the familial aggregation of DLD in this community. Methods & procedures: We assessed the frequency of DLD amongst colonial children between the ages of 3 years and 8 years, 11 months (50 individuals from 45 nuclear families). Familial aggregation rates of language-disorder were calculated by assessing all available first-degree relatives (n= 107, 77 parents, 25 siblings, 5 half-siblings) of the probands. Outcomes & results: We found that 71% of the child population performed significantly below expected in measures of phonological production or expressive and receptive morphology. The majority of these children presented with severe expressive and/or receptive language difficulties. A quarter of language disordered probands primarily had phonological difficulties. Family members of affected probands, experienced a higher risk of language-disorder than those of typically-developing probands. This increased risk was apparent regardless of nonverbal IQ. Conclusions & implications: Our study substantiates the existence of a familial form of speech and language disorder on the Robinson Crusoe Island. Furthermore, we find that the familiality is stable regardless of non-verbal IQ, supporting the recent movement to reduce the importance of nonverbal IQ criterion in DLD diagnoses.Website
• Newbury DF, Simpson NH, Thompson PA, Bishop DVM, 'Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis'
  Wellcome Open Research 3 (10) (2018)
  ISSN: 2398-502X eISSN: 2398-502X
  Abstract Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed. Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.Website
• Mountford HS, Newbury DF, 'The Genomic Landscape of Language Disorders: Insights into Evolution'
  Journal of Language Evolution (2018)
  ISSN: 2058-4571 eISSN: 2058-4571
  Abstract Studies of severe, monogenic forms of language disorders have revealed important insights into the mechanisms that underpin language development and evolution. It is clear that monogenic mutations in genes such as FOXP2 and CNTNAP2 only account for a small proportion of language disorders seen in children, and the genetic basis of language in modern humans is highly complex and poorly understood. In this review, we examine why we understand so little of the genetic landscape of language disorders, and how the genetic background of an individual greatly affects the way in which a genetic change is expressed. We discuss how the underlying genetics of language disorders has informed our understanding of language evolution, and how recent advances may obtain a clearer picture of language capacity in ancient hominins. Website
• Grabitz CR, Button KS, Munafò MR, Newbury DF, Pernet CR, Thompson PA,Bishop DVM, 'Logical and methodological issues affecting genetic studies of humans reported in top neuroscience journals'
  Journal of Cognitive Neuroscience 30 (1) (2017) pp.25-41
  ISSN: 0898-929X eISSN: 0898-929X
  Abstract Genetics and neuroscience are two areas of science that pose particular methodological problems because they involve detecting weak signals (i.e., small effects) in noisy data. In recent years, increasing numbers of studies have attempted to bridge these disciplines by looking for genetic factors associated with individual differences in behaviour, cognition and brain structure or function. However, different methodological approaches to guarding against false positives have evolved in the two disciplines. To explore methodological issues affecting neurogenetic studies, we conducted an in-depth analysis of 30 consecutive articles in 12 top neuroscience journals that reported on genetic associations in non-clinical human samples. It was often difficult to estimate effect sizes in neuroimaging paradigms. Where effect sizes could be calculated, the studies reporting the largest effect sizes tended to have two features: (i) they had the smallest samples, and were generally underpowered to detect genetic effects; and (ii) they did not fully correct for multiple comparisons. Furthermore, only a minority of studies used statistical methods for multiple comparisons that took into account correlations between phenotypes or genotypes, and only nine studies included a replication sample, or explicitly set out to replicate a prior finding. Finally, presentation of methodological information was not standardized and was often distributed across Methods sections and Supplementary Material, making it challenging to assemble basic information from many studies. Space limits imposed by journals could mean that highly complex statistical methods were described in only a superficial fashion.  In sum, methods which have become standard in the genetics literature – stringent statistical standards, use of large samples and replication of findings – are not always adopted when behavioural, cognitive or neuroimaging phenotypes are used, leading to an increased risk of false positive findings. Studies need to correct not just for the number of phenotypes collected, but also for number of genotypes examined, genetic models tested and subsamples investigated. The field would benefit from more widespread use of methods that take into account correlations between the factors corrected for, such as spectral decomposition, or permutation approaches. Replication should become standard practice; this, together with the need for larger sample sizes, will entail greater emphasis on collaboration between research groups. We conclude with some specific suggestions for standardized reporting in this area.Website
• Chen XS, Reader RH, Hoischen A, Veltman JA, Simpson NH, Francks C, Newbury DF, Fisher SE, 'Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment'
  Scientific Reports 7 (2017)
  ISSN: 2045-2322 eISSN: 2045-2322
  Abstract A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including 36 microtubule transport and cytoskeletal regulation.Website
• Devanna P, Chen S, Ho J,Gajewski D, Smith SD, Gialluisi A, Francks C, Fisher SE, Newbury DF, Vernes SC, 'Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders'
  Molecular Psychiatry (2017)
  ISSN: 1359-4184 eISSN: 1359-4184
  Abstract Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome are likely to play an important role in these phenotypes. Herein we show the importance of 3’UTR non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from NGS data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant, and the affected gene (ARHGEF39), represent new putative risk factors for SLI. Furthermore, we identified 3’UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.Website
• Pettigrew KA, Frinton E, Nudel R, Chan MTM, Thompson P, Hayiou-Thomas ME, Talcott JB, Stein J, Monaco AP, Hulme C, Snowling MJ, Newbury DF, Paracchini S, 'Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes'
  Journal of Neurodevelopmental Disorders 8 (24) (2016) pp.1-8
  ISSN: 1866-1947 eISSN: 1866-1947
  Abstract Background: Specific Language Impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10% of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods: We used two independent family-based cohorts characterised with reading- and language-related traits:  a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. Results: We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions: A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits. Website
• Shore R, Covill L, Pettigrew KA, Brandler WM, Diaz R, Xu Y, Tello JA, Talcott JB, Newbury DF, Stein J, Monaco AP, Paracchini S., 'The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts'
  Human Molecular Genetics (2016)
  ISSN: 0964-6906 eISSN: 0964-6906
  Abstract We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10−8) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left–right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.Website
• Prekovic S, Đurđević DF, Csifcsák G, Šveljo O, Stojković O, Janković M, Koprivšek K, Covill LE, Lučić M, Van den Broeck T, Helsen C, Ceroni F, Claessens F, Newbury DF, 'Multidisciplinary investigation links backward-speech trait and working memory through genetic mutation.'
  Scientific Reports 6 (2016) pp.1-15
  ISSN: 2045-2322 eISSN: 2045-2322
  Abstract Case studies of unusual traits can provide unique snapshots of the effects of modified systems. In this study, we report on an individual from a Serbian family with the ability to rapidly, accurately and voluntarily speak backwards. We consider psychological, neural and genetic correlates of this trait to identify specific relevant neural mechanisms and new molecular pathways for working memory and speech-related tasks. EEG data suggest that the effect of word reversal precedes semantic integration of visually presented backward-words, and that event-related potentials above the frontal lobe are affected by both word reversal and the maintenance of backward-words in working memory. fMRI revealed that the left fusiform gyrus may facilitate the production of backward-speech. Exome sequencing identified three novel coding variants of potential significance in the RIC3, RIPK1 and ZBED5 genes. Taken together, our data suggest that, in this individual, the ability to speak backwards is afforded by an extraordinary working memory capacity. We hypothesise that this is served by cholinergic projections from the basal forebrain to the frontal cortex and supported by visual semantic loops within the left fusiform gyrus and that these neural processes may be mediated by a genetic mutation in RIC3; a chaperone for nicotinic acetylcholine receptors.Website

Pre-2016 publications - See research website.

Areas of expertise

Gene mapping (linkage, association, sequencing)

Speech and language disorders

Neurodevelopmental disorders

Membership of professional bodies

MRC College of Reviewers for the Newton Fund.

International Scientific Advisory board for the University of Connecticut

Scientific Advisor for the Press and Information Office at the University of Oxford.

Conferences

See presentations page on research website

Other experience

University Reseach Lecturer at Oxford University

MRC career Development Fellow

Junior Research Fellow, St Johns College

Tutorial Fellow, Somerville College

Other publicity

http://cell-cell-cell.com/

Further information

See http://www.well.ox.ac.uk/webcasts-podcasts for podcasts and interviews

@diannenewbury