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.
Subject(s)
Alzheimer Disease/genetics , Evolution, Molecular , Haplotypes , Tauopathies/genetics , tau Proteins/genetics , Aged , Aged, 80 and over , Alleles , Amino Acid Sequence , Amino Acid Substitution/genetics , Animals , Base Sequence , Case-Control Studies , Dementia/genetics , Gene Frequency , Genotype , Humans , Mice , Middle Aged , Molecular Sequence Data , Open Reading Frames/genetics , Polymorphism, Single Nucleotide/genetics , Primates , Rats , Reference Values , Sequence Alignment , Sequence AnalysisABSTRACT
A previously undescribed gene, Saitohin (STH), has been discovered in the intron between exons 9 and 10 of the human tau gene. STH is an intronless gene that encodes a 128-aa protein with no clear homologs. The tissue expression of STH is similar to tau, a gene that is implicated in many neurodegenerative disorders. In humans, a single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in STH and was used in a case control study. The Q7R polymorphism appears to be over-represented in the homozygous state in late onset Alzheimer's disease subjects.