Hollox, Edward John; (2000) Molecular and population genetic analyses of variation within and surrounding the human lactase gene. Doctoral thesis (Ph.D), UCL (University College London).

Text Molecular_and_population_genet.pdf Download (19MB)

Abstract

This thesis describes an investigation of the variation within and around the human gene coding for the enzyme lactase-phlorizin hydrolase. The two major aims were to analyse sequence variation within and adjacent to the gene to study the extent and nature of diversity within and between populations, and to provide insight into the developmental and molecular bases of the lactase persistence polymorphism. The cis-acting effect of lactase persistence was confirmed using a panel of 15 children and quantification of lactase mRNA from intestinal biopsies which showed variable and progressive downregulation of the lactase gene. In order to extend sequence analysis a fosmid and cosmid contig was constructed across the lactase gene. Intron 1 was sequenced, and part of this sequence together with 1.8kb upstream and 2kb downstream of the gene was analysed in a panel of adult individuals of known lactase persistence status. The upstream region was analysed in six other species and is conserved in between humans, pigs and primates. Electromobility shift assays were done on a conserved region containing several human variants to analyse protein-binding activity of that region. Fluorescence in situ hybridisation analyses of clones from a PAC contig was used to confirm the physical map of a ~500kb region containing the lactase gene. 11 polymorphic sites were used to construct haplotypes in 596 individuals from 12 populations, and association with lactase persistence/non-persistence tested in cohorts of Finnish and Yakut individuals. A global picture of linkage disequilibrium and haplotype variation was formed which showed four common haplotypes in all non-African populations. Analysis of two sub-Saharan African populations showed these four haplotypes together with many more other haplotypes. This supports the 'Out of Africa' theory for the origin of modern humans.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as XMLCSVJSON

Archive Staff Only

View Item