Genetics & Genomics
Professor James Scott, Group Leader
Completed Research
Distinguished for discoveries in biology and medicine in the fields of cardiac and metabolic disease
We have received support from:
Structure and Function of Apolipoprotein B
Apolipoprotein B (apo B) is the main triglyceride and cholesterol transport protein in blood. We were the first to characterize apo B. It is one of nature’s largest proteins - prior to our studies the molecular size of apo B and the fact that there is one molecule apo B in LDL was not known (Knott TJ et al 1985 Science 230:37-43; Knott TJ et al 1986 Nature 323:734-738). Our observations paved the way for the measurement of apo B levels in blood, and this is one of the best clinical predictors of cardiovascular risk (Emerging Risk Factors Collaboration 2009 JAMA 302:1993-2000).
Genetic Variation Affecting Apolipoprotein B Metabolism
Mendelian genetics was used to investigate diseases of cholesterol transport, and apo B-containing lipoprotein assembly, secretion and metabolism. APO B, microsomal triglyceride transfer protein (MTP) and SAR1B genes (Figure 1) were discovered to be defective in hereditary hypobetalipoproteinaemia, abetalipoproteinaemia and chylomicron retention disease (Collins DR et al 1988 Nucl Acids Res 16: 8361-8375; Narcisi YM et al 1993 Human Genetics 92:312-313; Jones B et al 2003 Nat Genet 34:29-31). These observations provided insights into the structural evolution of apo B-containing lipoproteins (Figure 2), and provided potential targets for drug discovery, such as MTP inhibitors. (Shoulders CC et al 1994 Nature Struc Biol 1:285-286; Mann C et al 1999 Journal of Molecular Biology 285:391-408; Nicodeme E et al1999 J Biol Chem 274, 1986-1993; Read J et al 2000 J Biol Chem 275:30372-30377).
Generation of Apolipoprotein B Isoforms by RNA Editing
Two forms of apo B are produced. Full-size apo B (called apo B100 on the percentile system) is made solely in human liver, and the short form of apo B (apo B48) made solely in the intestine. We discovered that apo B48 mRNA is generated by a totally novel mechanism of RNA processing, which we called RNA editing, that deaminates apo B mRNA to convert a specific Glu codon to a stop translation codon. This represents a new tier in the regulation of gene expression, with major implications for intestinal lipid absorption and cholesterol metabolism (Powell LM et al 1987 Cell 50:831-840; Driscoll DM 1989 Cell 58:519-525; Navaratnam N et al 1995 Cell 81:187-195; Chester A et al 2003 EMBO 15:3971-3982). Subsequently nucleic acid editing by the same mechanism and family of enzymes has been implicated in antibody formation (Neuberger M, Scott J 2000 Science 289:1705-1706), protection against HIV (Chelico L et al 2010 JBC 285:16195-16205) and primordial germ cell reprogramming, which prevents transgenerational epigenetic inheritance (Popp L et al 2010 Nature 463:1101-1106).
Ongoing Research & Future Developments
Genetics and Genomics of Obesity, Insulin Resistance and Cardiovascular Disease
Obesity and insulin resistance genetics are the main focus of our recent and ongoing research. Pioneering genetic and functional genomics approaches led to the identification CD36 variants as a cause of hypertension and the metabolic syndrome (Aitman TJ et al 1997 Nat Genet 16:197-201; Aitman T et al 1999 Nat Genet 21:76-83; Aitman TJ et al 2000 Nature 405:1015-1016). We were also among the first to combine genetic, transcriptomic and metabonomic data, and demonstrate the role of intestinal microbes in metabolic disease (Dumas ME et al 2006 Proc Natl Acad Sci 103:12511-12516; Dumas ME et al 2007 Nat Genet 39:666-672). Bioinformatics and systems biology approaches have been used for disease mechanism discovery, and are an ongoing and integral part of our programme (Figure 4) (Li et al, in preparation). These studies have lead to the identification of new genes involved in appetite control and the metabolic-inflammation in adipose tissue that leads to insulin resistance. This is a major focus of our ongoing research.
We have performed ground-breaking genome-wide association studies on cohorts of subjects with the metabolic syndrome, type-2 diabetes and cardiovascular disease. This has lead to the identification of common genetic variants associated with dyslipidaemia, obesity, chronic renal disease and risk of sudden cardiac death (Figure 3) (Chambers JC et al 2008 Nat Genet 40:716-718; Kooner JS et al 2008 Nat Genet 40:149-151; Chambers JC et al 2010 Nat Genet 42(2):149-152; Chambers JC et al 2010 Nat Genet 42(5):373-375; Teslovich TM et al Nature in press 2010). This has been enabled by a large (35k) multi-ethnic cohort collection (Lolipop) (with particular focus on South Asians) assembled by our team for the purpose of epidemiological, biomarker and genetic studies. This is a major focus of our ongoing research, particularly in relation to whole genome resequencing.
Epigenetics and Epigenomics
An emerging new focus is the study of epigenetic processes leading to metabolic disease. Preliminary observations were presented to the House of Lords Science and Technology committee on Genomic Medicine 2009.
