RESUMO
Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.
Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 17 , Evolução Molecular , Polimorfismo Genético , Proteínas tau/genética , Animais , Sequência de Bases , Duplicação Gênica , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Pan troglodytes/genética , Filogenia , Pongo pygmaeus/genética , Análise de Sequência de DNARESUMO
BACKGROUND AND PURPOSE: Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene (IL1RN) and cerebrovascular disease. METHODS: An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race. RESULTS: After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11; P=0.03) for the white participants. The effect of allele 2 of IL1RN on stroke risk most closely fits a recessive genetic model (P=0.009). For the smaller sample of nonwhite participants, the results were not significant. CONCLUSIONS: Allele 2 of IL1RN, present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted.
Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Repetições Minissatélites/genética , Polimorfismo Genético/genética , Acidente Vascular Cerebral/genética , Idoso , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , América do Norte , Irmãos , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , População BrancaRESUMO
A segregating splice site mutation in the CHMP2B gene has been shown in the single Danish family which has been reported to show linkage between dementia and chromosome 3 markers. Despite extensive analysis, no other segregating mutations have been found in other kindreds, although some point variants have been found both in sporadic cases and in controls. We recently found a premature stop codon in a person without dementia and this led us to investigate whether the splice site mutation in the Danish kindred did not explain the disease, but rather was hitchhiking on the segregating disease haplotype. We determined to test this possibility by sequencing every other gene on the haplotype in a case from the kindred. We did not find any other unique variants. The implications of these findings for the likely mode of pathogenesis of frontal temporal dementia are discussed.
Assuntos
Cromossomos Humanos Par 3 , Demência/genética , Fases de Leitura Aberta/fisiologia , Sequência de Bases , Haplótipos , Humanos , Análise de Sequência/métodosRESUMO
We have assessed the pattern of the extended haplotype block over the tau gene which covers a region of approximately 2 Mb in different ethnicities. This analysis shows that the pattern of linkage disequilibrium over the tau region is shared by different ethnic groups indicating that haplotype structure in human is ancient. We discuss this observation in terms of the establishment of the haplotype structure and the possible impact of the tau haplotype on neurodegeneration in humans.
Assuntos
Etnicidade/genética , Haplótipos , Proteínas tau/genética , Frequência do Gene/genética , Humanos , Doenças Neurodegenerativas/etnologia , Doenças Neurodegenerativas/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Neurofibrillary tangles are found in many neurologic diseases. Here we review the unusual characteristics of the MAPT locus, which shows genetic association with many of these diseases and in Caucasian populations, is the largest stretch of linkage disequilibrium in the genome. We discuss the reason for this disequilibrium, its evolutionary history, and the role of genetic variability at MAPT in the etiology of tauopathies.
Assuntos
Doença de Alzheimer/genética , Inversão Cromossômica/genética , Mapeamento Cromossômico , Haplótipos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Proteínas do Tecido Nervoso/genética , Emaranhados Neurofibrilares/genética , Paralisia Supranuclear Progressiva/genética , Tauopatias/genética , Animais , DNA Complementar/genética , Progressão da Doença , Duplicação Gênica , Variação Genética/genética , Humanos , Desequilíbrio de Ligação , Pan troglodytes , Análise de Sequência de DNA , Especificidade da Espécie , Proteínas tauRESUMO
We have initiated a systematic analysis of the role of cholesterol metabolizing genes as risk factors for Alzheimer's disease pathogenesis. As part of this analysis, we have assessed the NR1H2 gene on chromosome 19 and report here a modest association with the locus in sibpairs with late onset disease.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Cromossomos Humanos Par 19/genética , Receptores Citoplasmáticos e Nucleares/genética , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Aberrações Cromossômicas , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Variação Genética/genética , Heterozigoto , Humanos , Incidência , Receptores X do Fígado , Masculino , Pessoa de Meia-Idade , Receptores Nucleares Órfãos , Polimorfismo Genético , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of approximately 400 kb, where there is a complete loss of LD. The telomeric end is defined by an approximately 150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci.