Molecular Genetics of Lactase Persistence

This thesis is based on the following original articles, which are referred to in the text by their Roman numerals. In addition, some unpublished data are presented Assignment of the locus for congenital lactase deficiency to 2q21, in the vicinity of but separate from the lactase-phlorizin hydrolase gene. Identification of a variant associated with adult-type hypolactasia. Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. FinnDiane study group (2004) The genetic variant of lactase persistence C (-13910) T as a risk factor for type I and II diabetes in the Finnish population. * These authors contributed equally to this work The original publications have been reproduced with the permission of the copyright holders. 6 ABBREVIATIONS aa amino acids ASHG American Society of Human Genetics ATH adult-type hypolactasia BAC bacterial artificial chromosome BCM Baylor college of medicine BLAST basic local alignment search tool BMD bone mineral density bp base pair cDNA complementary DNA Cdx-2 caudal-related protein 2 CEPH Centre d´Etude polymorphisme Humain CLD congenital lactase deficiency cM centi Morgan cR centi Ray cSNP coding single nucleotide polymorphism DARS aspartyl-tRNA synthetase DDGE denaturing gradient gel electrophoresis DNA deoxyribonucleic acid dNTP deoxynucleosidetriphosphate E.C. Enzyme Commission Number EMBL European Molecular Biology Database ELSI the ethical, legal, and social issues of human genome project ER endoplasmic reticulum EST expressed sequence tag FDH Finnish disease heritage FISH fluorescence in situ hybridization FREACs Fork-Head related activators H Heterozygosity HGP Human genome project HNF1α Hepatic Nuclear Factor 1 α HOX11 Homeo box 11 kb kilobase KD kilodalton LD linkage disequilibrium LNP lactase non-persistence LOD logarithm of odds LP lactase persistence LPH lactase-phlorizin hydrolase LTT lactose tolerance test 7 LTTE lactose tolerance test with ethanol Mb megabase MCM6 minichromosome maintenance deficient 6 mRNA messenger RNA NCBI National Center for Biotechnology Information nt nucleotide OMIM Online Mendelian Inheritance in Man p short arm of chromosome PAC P1-artifical chromosome PCR polymerase chain reaction q long arm of chromosome RFLP restriction fragment length polymorphism RH radiation hybrid RNA ribonucleic acid RT reverse transcriptase RT-PCR reverse transcriptase polymerase chain reaction SNP single nucleotide polymorphism STR short tandem repeat tRNA transfer RNA UTR untranslated region YAC yeast artificial chromosome Θ recombination fraction λ proportion of excess of allele in chromosomes carrying the disease allele χ 2 chi-square test 8 SUMMARY Two types of lactase deficiency exist in human, congenital lactase deficiency and adult-type hypolactasia. Congenital lactase deficiency (CLD) is an …