title: Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease.
abstract: A single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in the Saitohin (STH) gene and was initially found to be over-represented in the homozygous state in subjects with late-onset Alzheimer's disease (AD). More extensive studies provide limited support for the association with AD, but confirm an association of the Q allele with progressive supranuclear palsy and argyrophilic grain disease. A homologous sequence was found in the appropriate location of the rat and mouse tau genes, but there was no open reading frame allowing STH expression in these species, suggesting relatively recent evolution of this gene. In some non-human primates, the STH gene was identified, and this was found to differ from the human gene at two of 128 amino acids. All primates in which the STH gene was identified were homozygous for the R allele of STH, suggesting this is the ancestral allele. This observation was surprising, in that the Q allele is more common in human populations, and raises the possibility that natural selection has operated to favor individuals carrying this allele. The STH polymorphism is part of the tau gene haplotype, of which two major variants exist in human populations, the Q being part of the H1 haplotype and the R part of the H2 haplotype. More detailed studies confirm the H2 haplotype to be the ancestral tau gene. This situation is reminiscent of the evolution of the apolipoprotein (ApoE) gene, another locus that is potentially important for the risk of development of AD.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA. cgconrad@partners.org
authors.forename: Chris
authors.initials: C
authors.lastname: Conrad
authors.forename: Cintia
authors.initials: C
authors.lastname: Vianna
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Estifanos
authors.initials: E
authors.lastname: Ghebremedhin
authors.forename: Jack
authors.initials: J
authors.lastname: Lenz
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D003704:Dementia / Q000235:genetics; D019143:Evolution, Molecular; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011323:Primates; D051381:Rats; D012016:Reference Values; D016415:Sequence Alignment; D017421:Sequence Analysis; D024801:Tauopathies / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C458340:STH protein, human; D016875:tau Proteins