Mutations in human genetic disease

Аннотация

Just over 30 years ago, the first heritable human gene mutations were characterized at the DNA level: gross deletions of the human α-globin and β-globin gene clusters giving rise to α- and β-thalassaemia (1978) and a nonsense mutation in the human βglobin (HBB) gene causing β-thalassaemia (1979). With the number of known germline mutations in human nuclear genes either underlying or associated with inherited disease now exceeding 125,000 in ~5,000 different genes (Human Gene Mutation Database; http://www.hgmd.org; October 2012), the characterization of the spectrum of human germ-line mutations is proceeding apace. Such information is beginning to shed new light on longstanding questions such as the nature of disease predisposition, the determinants of the genotype-phenotype relationship, the molecular basis of reduced penetrance and the measurement of the human gene mutation rate, as well as posing profound questions pertaining to how we conceptualise genetic disease.