Skip Top Navigation

National Institute on Aging
National Institutes of Health
NIA Home
Research Programs

Photo of Andrew Singleton, Ph.D. Andrew B. Singleton, Ph.D., Senior Investigator
Chief, Molecular Genetics Section
Laboratory of Neurogenetics

Biography: Dr. Andrew Singleton is a human geneticist whose research interests focus on the genetics of neurological disease. Dr. Singleton received his B.Sc. (Hons) degree from the University of Sunderland, UK and his Ph.D. from the University of Newcastle upon Tyne, UK where he studied genetic causes and contributors to dementia. Dr. Singleton performed his postdoctoral training at the Mayo Clinic in Jacksonville, Florida, studying the genetic basis of neurological diseases such as dystonia, ataxia, essential tremor, dysautonomia, stroke and Parkinson's disease. In 2001 he joined the NIA as an Investigator within the newly created Laboratory of Neurogenetics. Dr. Singleton's group investigates the genetic and cellular mechanisms underlying simple-Mendelian and complex neurological diseases.
Overview: In recent years, an extremely successful approach to understanding disease has arisen from the study of rare familial forms of disorders related to more common "sporadic" disease. This is a research paradigm that was successful in Alzheimer's disease (AD). The identification of the APP, PS-1 and PS-2 mutations as causal of rare forms of early-onset familial AD led to a huge increase in our knowledge of the pathogenic mechanisms underlying the common late-onset form of AD. We are applying this approach to a number of disorders. Lubag or X-linked recessive dystonia parkinsonism (XDP) is a rare inherited movement disorder; however, given the clinical phenotype associated with this disorder, delineation of the disease process in XDP will be informative for Parkinson's disease, dystonia and related movement disorders. We are currently involved in a positional cloning project aimed at identifying this gene defect.
Our group, in collaboration with that of Dr. Gwinn-Hardy's of NINDS, employs two clinical research coordinators who recruit and expand families. In addition to XDP, we have actively recruited >300 families with a history of various neurological diseases, including but not limited to parkinsonism, dystonia, stroke, diffuse Lewy body disease, ataxia, essential tremor and hyperhidrosis. Once again the aim of this family collection is to aid in the identification of genes important in the pathogenesis of disease.
With the beginning of the new millennium, we are entering the post genome era. Now the vast majority of human genes have been sequenced and their sequences will be available on the web. In the last 10 years, the application of molecular genetics has led to the unraveling of the etiologies of many of the single gene disorders that lead to neurodegenerative disease, but has barely begun to allow the dissection of the more complex genetics of most neurodegenerative disease which do not show simple patterns of inheritance. The only genes that have been unambiguously identified as risk factors for non-mendelian disorders are the prion gene in iatrogenic and idiopathic Creuzfeldt Jakob disease (Collinge et al. 1991: Palmer et al. 1991), the apolipoprotein E gene in Alzheimer's disease (Corder et al. 1993) and the tau gene in progressive supranuclear palsy (Baker et al. 1999): in the cases of both the prion and tau genes, there were good genetic or pathologic reasons for suspecting their involvement in disease etiology (Hsiao et al. 1989, Flament et al. 1991); thus, apolipoprotein E is the only neurodegenerative risk-factor gene found, in part, through positional genetic analysis (Pericak-Vance et al. 1990).
It is to be expected that over the next decade, the application of molecular genetic techniques will promote dissection of the etiologies of non-mendelian neurodegenerative diseases in general; however, the problems of identifying risk factor loci for diseases with complex modes of inheritance and in particular oligogenic (10 genes) and polygenic (>10 genes) disease are formidable. Given the huge socio-economic impact of some of the disorders of this nature such as Parkinson's disease and Alzheimer's disease, it is of paramount importance to design a viable strategy for the delineation of genetic predisposition in complex traits.
We are tackling the problems of complex disease in a number of ways. First, we are studying rare familial forms of disease and then extrapolating the function of genes involved to related conditions (as outlined above). One of the methodologies we are using to reach this goal is expression analysis using microarray technology. In collaboration with Dr. Mark Cookson, we are analyzing the effects of TorsinA, known to be mutated in certain forms of idiopathic torsion dystonia, on the genomic expression pattern within neuronal cells. The idea of this approach is really two-fold; first, to give us an idea of pathologically relevant interactions/pathways and second, to provide us with candidate genes for other positional cloning efforts. A second technique that is aimed at simplifying complex traits and identifying genetic linkage is the use of population isolates to simplify complex traits. A similar paradigm has been used by DeCode Genetics, Inc. in Iceland to examine a number of diseases. Other methodologies currently in use in the general genetic community include sib-pair analysis, candidate gene association studies, whole genome association studies and linkage disequilibrium mapping. We employ some aspect of all of these techniques in our sample series and it seems clear that rather than using one approach, a complimentary battery of techniques is likely to yield success. Furthermore, as the contribution of an individual genetic defect to disease decreases, geneticists will have to rely increasingly on biology rather than statistics to prove pathogenicity.
Help Downloading Files on This Page
Skip Navigational Links
NIA Home  IRP Home     What's New     Contact Us     Accessibility     Disclaimer     Privacy     Site Map     NIA Home         
NIH logo-link to NIH Home Page DHHS logo-link to DHHS Web Site USA.Gov logo-link to USA.Gov Web Site
Updated: Wednesday July 28, 2010