Dr Mark Bailey

Dr Mark Bailey

Current research by my group focuses on three main areas:

  • Molecular genetics of disorders of the brain/sensory systems
  • Genetics of normal traits and their relation to complex disease risk
  • The role of meme-gene co-evolution and selection on ‘reputation’ in human brain evolution

Currently less active research interests include:

  • Molecular genetics of idiopathic epilepsy
  • Molecular biology of neuronal regeneration
  • Evolution of gene families involved in brain function and development

Molecular Genetics

We are studying a disorder of the brain, Rett syndrome, and a disorder of the inner ear, Ménière disease.

Rett Syndrome (RTT)

Rett Syndrome is a severe disorder of the brain that affects only girls, leaving them with severe dyspraxia, motor disabilities and possibly cognitive disabilities lifelong, as well as related health problems. It is caused in most cases by sporadic mutations in MECP2, a gene that encodes a protein that participates in epigenetic regulation of genome function and gene expression. My initial studies were in the molecular genetics of RTT and the relationship between genotype (what mutation is carried, and in what gene?) and phenotype (what are the clinical signs and natural history of the disorder in the individual patient?). More recently, I also participated in work to redefine the diagnostic criteria and terminology for RTT as part of the ‘RettSearch’ consortium. This work has been published in a number of papers – Xiang et al., 2000; Jian et al., 2005; Charman et al., 2005; Knudsen et al., 2006; Archer et al., 2007; Neul et al., 2010.

More recently, in collaboration with Dr Stuart Cobb here in Glasgow, we have become interested in the pathway from genotype to phenotype in RTT (how the downstream events in the causal pathway leading to the clinical disorder come to disrupt neuronal functioning and network behavior) and in prospects for novel therapeutic avenues in tackling this disorder. This stems from the seminal paper in 2007 from Prof. Adrian Bird and Dr Cobb, in which they showed that restoration of a normal Mecp2 gene to most brain cells in a mouse knockout (KO) model of RTT could ameliorate and reverse the phenotype. This suggests that RTT may be both reversible after onset and preventable prior to onset (with implications for whether RTT should be considered a neurodevelopmental disorder in the traditional sense). We have demonstrated a number of aspects of the Mecp2 KO mouse phenotype at molecular, cellular, physiological and whole animal phenotypic levels. We have preliminary data to show that almost all measureable aspects of the RTT-like phenotype in the KO mouse are likely to stem from effects of MeCP2 loss of function in the brain, rather than in the periphery (with a few exceptions).

We are also actively developing a gene therapy approach to tackling RTT. We have reviewed the prospects for development of novel therapeutic avenues in RTT from the viewpoint of its unexpected reversibility. We also demonstrated for the first time, in collaboration with Dr Steve Gray (Univ. of North Carolina), that a gene therapy approach, delivering an exogenously derived MECP2 gene via a viral vector, could lead to substantial amelioration of the phenotype in the KO mouse. We are currently funded to carry out projects aimed at optimising delivery vectors and routes – the longer-term objective is to translate this gene augmentation therapy approach for use in humans, and help prepare the ground for clinical trials in patients in due course. My own contribution to this research is reflected in a number of publications from our joint group – Weng et al., 2011; Gadalla et al., 2013; Gadalla et al., 2013; a number of additional papers are in prep.

Most recently, I initiated a project to examine prospects for using a genome editing approach to treat RTT. We are examining whether TALEN or CRISPR/Cas9 reagents can be employed in an approach that targets and repairs specific mutations causing RTT. In collaboration with Dr Adam West and Dr Katherine West, also here at the University of Glasgow, we are developing other novel approaches using genome editing to effect the restoration of functional MeCP2 expression within neurons.

A fuller account of the collaborative work we are doing on RTT here in Glasgow is given at the Cobb group website.

Ménière disease (MD)

Ménière disease affects about 1/2000 people, mostly sporadically, and generally manifests as disorienting and incapacitating episodes of vertigo, tinnitus and hearing loss. We are working with Mr Gavin Morrison, whose father, Andrew, collected a unique set of rarely identified, multiply-affected Ménière families. We have mapped a gene predisposing to familial MD in these families (in prep) and are currently trying to identify the genetic lesion underlying the disease. We are also planning, in collaboration with Jessica Tyrrell and a number of clinicians around the UK, a larger study aimed at identifying predisposing gene variants in patients with sporadic MD. Our published work so far has concentrated on the pattern of inheritance and clinical characteristics in the familial MD cases – Morrison et al., 2009.

Both these project areas will contribute to our understanding of important disorders at the molecular and genetic level, and to knowledge of the genetic disease burden in the UK population.

Genetics of normal traits and disease risk

Over several years now, I have collaborated with Dr Jason Gill (Institute of Cardiovascular & Medical Sciences, MVLS), and with Dr Yannis Pitsiladis (was in Institute of Cardiovascular & Medical Sciences, MVLS; now Univ. of Brighton) and Dr Richard Wilson (now retired, MVLS) to investigate the effect that genes have on body composition, on sporting performance phenotypes and on diabetes risk factor levels in the normal population. We have focused particularly on the interaction of such genes with environmental factors. We are interested particularly in the genes influencing adiposity/obesity and how their influence is modulated by dietary factors and exercise in children, adolescents and adults. Thus far, our analyses have helped to provide an understanding of the roles of such genes as FTO/IRX3, ACE, ADRB2 and ACTN3 in influencing adiposity and performance in the context of different environmental exposures, and further work is planned with other genes and other population samples.
In a study carried out in collaboration with Dr Gill, together with a former PhD student, Dr Carlos Celis Morales and colleagues in Chile, we found that people of different ethnic origins in Chile (the Mapuche, a native Chilean people, and Chileans of European origin) have different risk factor profiles in different environments and we observed profiles associated with type 2 diabetes risk to a much greater extent in Mapuche living a Westernised lifestyle, particularly in those doing less daily exercise. We have also shown that genetic variants with limited influence on diabetes risk factors in Europeans have a much greater influence in the Mapuche, again contingent on levels of daily exercise (in prep). This suggests that there are ethnic differences in the actions of some gene variants contributing to disease risk – we are going on to investigate the possible causes of such differences. Further information about research into lifestyle, obesity and cardio-metabolic disease at Glasgow can be found here.

My own contribution to this research is reflected in a number of publications from our groups – Moran et al., 2005/2006/2007; Lagou et al., 2007; Scott et al., 2010; Wilson et al., 2010; Koni et al., 2011; Celis Morales et al., 2011/2012/2013; Giangagna et al., 2013, Wang et al., 2013.


Meme-gene co-evolution and human brain evolution

I have an interest in the process by which the human brain came to be the way it is during the last phase of human evolution since approx. 1 Myr ago. The most striking changes during this period involved a massive increase in brain size and the evolution of language capabilities. My research question focuses round the reasons for these changes – why were a very large brain and language of use to early humans, or, rather, in service of what did these capacities evolve? A significant part of the answer may lie in the role played by memes in governing what was and was not useful in the social domain – via gossip, competition, performance, religious practices, etc., and the new facet of human existence that went with the communication facility provided by spoken language – reputation.

Other areas of research

Neuronal regeneration

In collaboration with Dr John Riddell, Institute of Neuroscience & Psychology, MVLS, we have investigated the molecular events underlying successful and failed, or blocked, regeneration of peripheral sensory neurons after injury using a transcriptomics (microarray) approach.

Genetics of idiopathic epilepsy

The term idiopathic epilepsy covers a number of different syndromes in which repeated, spontaneous seizures are exhibited. IE is complex and complicated - more than one gene can predispose to the same epilepsy subtype, and genes that predispose to more than one epilepsy subtype exist, leading to the clustering of complex mixtures of epilepsies within families. We have worked on the identification of genes that cause predisposition to various IE subtypes, either in families or sporadic cases, including idiopathic generalised epilepsy (IGE), juvenile myoclonic epilepsy (JME), generalised epilepsy with febrile seizures plus other seizures ('GEFS+') and 'unclassified' epilepsies. This work has involved collaborations with clinicians including Dr Sameer Zuberi (Royal Hospital for Sick Children, Glasgow) and Prof Martin Brodie and Dr Graeme Sills (Western Infirmary, Glasgow).

Evolution of gene families involved in brain function and development

We have studied the evolution of brain gene families, particularly the family that encodes the subunits of the type A receptor for the neurotransmitter, GABA (GABAA receptors), and what the phylogenomics of such families can tell us about the history of genome evolution in chordates - in particular whether there is evidence for a series of genome duplications early in chordate evolution that can help explain the dominance of this group and the extreme importance of the brain in vertebrates. This has involved gene cloning and bioinformatic/phylogenomic/phylogenetic approaches to investigate when any possible expansions in gene number occurred and their implications. There is also the hope that an understanding of the evolutionary relationships between gene family members will help us in the analysis and prediction of their functional attributes. This information might one day be used in the rational design of new drugs for conditions such as epilepsy, anxiety and many others.