Endothelial nitric oxide synthase polymorphisms and hypertension: improved clinical evidence derived from haplotype analysis.
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Genetic Markers↗
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A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations.
Haplotypes consisting of the (CTG)n repeat, as well as several flanking markers at the myotonic dystrophy (DM) locus, were analyzed in normal individuals from 25 human populations (5 African, 2 Middle Eastern, 3 European, 6 East Asian, 3 Pacific/Australo-Melanesian, and 6 Amerindian) and in five nonhuman primate species. Non-African populations have a subset of the haplotype diversity present in Africa, as well as a shared pattern of allelic association. (CTG)18-35 alleles (large normal) were observed only in northeastern African and non-African populations and exhibit strong linkage disequilibrium with three markers flanking the (CTG)n repeat. The pattern of haplotype diversity and linkage disequilibrium observed supports a recent African-origin model of modern human evolution and suggests that the original mutation event that gave rise to DM-causing alleles arose in a population ancestral to non-Africans prior to migration of modern humans out of Africa.
Alleles↗
DNA polymorphism haplotype analysis of beta-thalassemia genes in Taiwan.
Twenty unrelated families of homozygous beta-thalassemia were collected for restriction polymorphism haplotype study of the beta-thalassemia (beta T) genes. DNA was extracted from WBC of the family members. With Southern blotting and DNA hybridization, restriction fragment length polymorphisms (RFLPs) were studied at 7 sites within the beta-globin gene cluster, including 5' epsilon-HincII, G gamma-HindIII, A gamma-HindIII, psi beta-HincII,3' psi beta-HincII, beta-AvaII,3' beta-BamHI. From RFLPs of the family members, restriction polymorphism haplotypes of the 40 beta T chromosomes and the 40 normal beta-globin gene (beta A)-bearing chromosomes were constructed. In beta T chromosomes. 26 (65%) belonged to haplotype I (+----++), 12 (30%) to haplotype II (+-----+), 1 (2.5%) to haplotype III (-++-+-+) and 1 (2.5%) to haplotype IV (++---++) which has not been reported in Chinese before. In beta A chromosomes, 12 different haplotypes were found. Seven (17.5%) belonged to haplotype I, 13 (32.5%) to haplotype II, and 6 (15%) to haplotype V (+----+-). The implications of RFLP and haplotyping of beta T genes in terms of molecular defects and prenatal diagnosis are discussed.
Asian People↗
Haplotype analysis of the myotonic dystrophy type 1 (DM1) locus in Taiwan: implications for low prevalence and founder mutations of Taiwanese myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder caused by a CTG trinucleotide expansion at the DM1 locus. In this study, we investigated the frequency distribution of various CTG repeats in normal alleles and haplotyped the normal and expanded DM1 locus in a group of Taiwanese people. In the 496 normal chromosomes examined, up to 18 alleles with different CTG lengths from 5 to 30 repeats were found and the frequency of (CTG)(>18) alleles was only 1.4% (7/496), predicting a low prevalence of DM1. In addition, there is no absolute association between (CTG)(5-19) alleles and Alu insertion/deletion polymorphism observed on normal chromosomes. All DM1 alleles examined, however, were found to be associated with the Alu insertion. Further detailed genetic analysis demonstrated that at least eight haplotypes, including a new haplotype (L), were present in the Taiwanese population and that all DM1 alleles were with the same haplotype (haplotype A) as that identified in Canadian and Japanese DM1 populations. These findings support the notion that the out-of-Africa DM1 alleles were originated by stepwise expansion from a pool of large-sized normal chromosomes with haplotype A.
Alleles↗
SNP identification, haplotype analysis, and parental origin of mutations in TSC2.
Inactivating mutations in the TSC2 gene, consisting of 41coding exons in 40 kb on 16p13, cause the hamartoma syndrome tuberous sclerosis. During TSC2 mutational analysis we identified ten SNPs that occur within or close to exon boundaries at minor allele frequencies greater than 5%. We determined the haplotypes for six of these SNPs and the microsatellite marker kg8 in the 3' region of TSC2 in a set of 40 parent-child trios. The most common haplotypes accounted for 53%, 11%, 6%, and 5% of chromosomes. Thirty-eight TSC2 mutation-bearing haplotypes had a similar distribution, indicating that there was no haplotype that predisposed to mutation in this region of TSC2. Family analysis was possible in 12 sporadic cases, and indicated that the mother was the parent of origin in 7 cases (3 point mutations, 2 small deletions, 2 large deletions), while the father was in 5 cases (2 point mutations, 3 small deletions). We conclude that TSC2 mutations occur at substantial frequency on both the maternally and paternally derived TSC2 alleles, in contrast to many other genetic diseases including NF1. The observations have implications for genetic counseling in TSC.
Adult↗
Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.
The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
Breast Neoplasms↗
DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population.
Thirty-nine Turkish phenylketonuria (PKU) families were investigated for their DNA haplotypes at the phenylalanine hydroxylase (PAH) locus. There was a threefold higher incidence of consanguinity in the population studied compared with the general Turkish population. The PAH DNA haplotype 6 was found to be almost exclusively associated not only with the mutant PAH genes but also with the classic phenotype in 39% of the Turkish patients. This haplotype was of not importance in northern European populations. The two DNA haplotypes (1 and 4) that were almost equally frequent among the normal and the mutant PAH genes in northern European populations show virtually the same distribution in Turkish individuals. In all populations studied, these haplotypes are associated with different phenotypes.
Blotting, Southern↗
Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension: single locus genotype vs. haplotype analysis.
Although some single polymorphism analyses of the angiotensinogen (AGT) gene have been found to be associated with hypertension, the results are still inconsistent. The objectives of this study are to evaluate the association of the genotype and haplotype distributions of three single-nucleotide polymorphisms (SNPs) (G-217A, A-6G, and M235T) in the AGT gene with hypertension. In a sample of 461 hypertensive and 327 normotensive patients in Taiwan, we found that -217AA and -6GG homozygotes conferred independently an increased risk to hypertension (P = 0.008 and P = 0.037, respectively), as illustrated by their significant associations with hypertension in both single SNP and pair-wise SNPs analyses. Meanwhile, a very weak linkage disequilibrium was found between the G-217A and the A-6G polymorphisms in terms of r2 (<0.05). On the basis of likelihood ratio test, only the set of haplotypes that constituted the A-6G and the M235T polymorphisms was associated with hypertension (chi2 = 20.91, P = 0.0008), which was mainly due to the increased frequency of the recombinant haplotypes (-6A identical with 235M and -6G identical with 235T), and a pathophysiological role in the predisposition to hypertension was hence indicated. In functional assays, the promoter activities of the haplotypes -217A identical with -6A and -217G identical with -6G were significantly higher than the most common haplotype -217G identical with -6A. These results highlight the necessity of a thorough analysis of all reported variants of a candidate gene in the elucidation of genetic susceptibility to a complex disease like hypertension, even when the variants are in the same haplotype block.
Angiotensinogen↗
Familial defective apolipoprotein B-100: detection and haplotype analysis of the Arg(3500)-->Gln mutation in hyperlipidemic Chinese.
Familial defective apolipoprotein (apo) B-100 (FDB) is caused by R3500Q mutation of the apo B gene resulting in decreased binding of LDL to the LDL receptor. Two other apo B mutations, R3500W and R3531C, affecting binding are known to date. We screened the apo B gene segment around codon 3500 by heteroduplex analysis and single strand conformation polymorphism (SSCP) analysis in a total of 373 hyperlipidemic individuals. Two single-base mutations were detected and confirmed by DNA sequencing. One mutation, ACA(3528)-->ACG change, resulted in degenerate codon with no amino acid substitution. The other mutation, CGG(3500)-->CAG mutation, resulted in an Arg(3500)-->Gln substitution (R3500Q). The prevalence of heterozygote in this selected population was 0.3% (95% confidence interval, 0.01-1.5%) for the R3500Q mutation, and 2.4% (95% confidence interval, 1.1-4.5%) for the previously described R3500W mutation. The results suggest that the R3500Q mutation is not a significant factor contributing to moderate hypercholesterolemia in Chinese (P=0.027). Family studies of the R3500Q carrier revealed a further two individuals heterozygous for the mutation, both of whom were hypercholesterolemic. Analysis of the R3500Q allele using six diallelic markers and the 3'HVR marker revealed a haplotype which was the same as that reported in a Chinese American but differed from that reported in a Chinese Canadian. Our data support limited multiple recurrent origins for R3500Q in Chinese population.
Adult↗
Haplotype analysis of identical factor IX mutants using PCR.
We have detected the mutations in the factor IX genes from all of the haemophilia B patients registered at Malmö haemophilia centre and are currently examining the entire UK haemophilia B population. From these studies we have found 13 base substitutions which have recurred in 1-6 other, presumably unrelated, patients. In order to determine the minimum number of independent repeats of each mutation we have used PCR to examine the five factor IX polymorphisms forming the most informative combinations and we have characterised the haplotype of each patient. Patients with different haplotypes are assumed to be unrelated and thus to carry independent mutations. All but one of the 13 mutations occur in at least 2 haplotypes thus pinpointing 12 mutational hotspots and mutations that can be clearly considered detrimental. Two of the 13 substitutions occur at non-CpG sites.
Amino Acid Sequence↗
Beta-globin haplotypes analysis in Afro-Brazilians from the Amazon region: evidence for a significant gene flow from Atlantic West Africa.
Beta-globin gene cluster haplotypes were analysed in betaA-, betaS- and betaC-globin gene-bearing chromosomes in black people from Curiau, Pacoval and Trombetas, three communities made up of descendants of African slaves, located in the Northern region of Brazil. The betaA haplotype distribution is consistent with the African origin of the populations, with some degree of local differentiation and admixture with people of Caucasian ancestry and/or Amerindians. In addition, the betaS haplotype distribution (60% Bantu; 30% Senegal and 10% Benin) suggests that although African slaves brought to Northern region have been predominantly from regions where the Bantu haplotype predominates, there is also evidence of the presence of slaves from West Africa, particularly from the Atlantic West.
Africa, Western↗
Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.
Adult↗
Haplotype analysis and Agamma gene polymorphism associated with the Brazilian type of hereditary persistence of fetal hemoglobin.
We have identified three unrelated individuals and three members of a family with the non-deletion form of Agamma-hereditary persistence of fetal hemoglobin (HPFH). Molecular analysis showed that each individual is a heterozygote for a previously described -195 Agamma (C-->G) mutation. The beta-globin gene cluster was studied using the polymerase chain reaction and related techniques. Haplotyping using nine restriction sites identified two closely related chromosomes with the -195Agamma mutation, differing only in a single site 3' to the beta-globin gene. Further analysis of beta-globin framework indicated that the HPFH allele segregates with haplotype V, according to Orkin's classification. The second haplotype probably originated by a point mutation or DNA rearrangement of a pre-existing -195Agamma chromosome. We also determined the sequences from -622 to +55 bp upstream to the Agamma gene and part of the Agamma IVS-2. We found four polymorphisms associated to the -195Agamma promoter region. All -195Agamma chromosomes had a G at positions -588 and +25 relative to the Agamma gene. One individual was also homozygous for polymorphisms at -398 (G-->A), and another at -369 (C-->G). Cloning and sequencing of the polymorphic patterns of the 3' region of Agamma IVS-2 showed that the mutated allele is linked to beta-globin chromosome B. Some correlations between chromosome characteristics and Agamma point mutations were also observed.
Adult↗
Linkage disequilibrium and haplotype analysis in German Friedreich ataxia families.
The main mutation causing Friedreich ataxia (FRDA) is the expansion of a GAA repeat localized within the intron between exon 1 and exon 2 of the gene X25. This expansion has been observed in 98% of FRDA chromosomes. To analyze frequencies of markers tightly linked to the Friedreich ataxia gene and to investigate wheter a limited number of ancestral chromosomes are shared by German FRDA families, a detailed analysis employing nine polymorphic markers was performed. We found strong linkage disequilibria and association of FRDA expansions with a few haplotypes. FRDA haplotypes differ significantly from control haplotypes. Our results confirm that GAA repeat expansions in intron 1 of the frataxin gene are limited to a few chromosomes and indicate an obvious founder effect in German patients. Based on these analyses, we estimate a minimum age of the mutation of 107 generations.
Evolution, Molecular↗
[Killer Ig-like receptor gene content diversity and haplotype analysis in Chinese Han population in Shanghai].
OBJECTIVE: To detect the diversity of killer Ig-like receptor(KIR) gene content and the combination of haplotypes in Chinese Han population in Shanghai area. METHODS: DNA samples from 87 randomly unrelated healthy individuals in Shanghai Han population were genotyped with SSP/PCR method. RESULTS: (1) Frequencies of KIR genes: All of 18 known KIRs genes, such as 2DL1-5, 2DS1-5, 3DL1-3, 3DS1, KIR1D and the pseudogenes X, Xv and Z(KIR2DP1) were observed in Shanghai Hans. All individuals contain 3DL3, 2DL4, 3DL2 and 3DL1; the most common genes were 2DL3, Z, 2DL1 and X; the following were 2DS4, 1D, 2DL5, 2DS1, 3DS1 and 2DS5; the next were 2DS2, 2DL2, 2DS3 and Xv. (2) Frequencies of KIR gene haplotypes; there were 13 haplotypes detected in 87 Han individuals, among them, the most frequent one was type 2 (haplotypeA-2DS4). (3) Frequencies of KIR genotypes: 18 kinds of the combinations of the haplotypes were observed; the most frequent ones were AJ(2,2), AF (1,2). Also, In this study were identified five new genotypes FZ1 2 9 , FZ2 1 16 , FZ3 6 17 , FZ4 4 13 and FZ5 2 6 ,which had not been observed in Caucasians so far. CONCLUSION: These findings suggest that there are distinctive frequencies of KIR gene content, haplotype as well as genotype in Chinese Han population in Shanghai area.
China↗
An ancient common origin of aboriginal Australians and New Guinea highlanders is supported by alpha-globin haplotype analysis.
The origins of aboriginal Australians and their relationship with New Guineans and neighboring Southeast Asians remains controversial. We have studied the alpha-globin haplotype composition of an aboriginal tribe from central Australia, to address some of the ambiguities of previous studies. Australians have a haplotype repertoire that is shared with New Guinea highlanders, a fact that strongly supports a common origin of these two populations. Further, Australians and New Guinea highlanders have a different set of alpha haplotypes from Southeast Asians and a lower genetic diversity. This, coupled with the presence of many locally specific central Australian haplotypes, suggests that much of the original diversity was lost in a population bottleneck prior to or during the early colonization of Sahul and that subsequent recovery of diversity has been accompanied by the generation of new haplotypes. These conclusions contrast with some previous genetic studies suggesting links between Australians, coastal New Guineans, and present-day Southeast Asians. Much of this discrepancy appears to be due to more recent Southeast Asian admixture on the north coast of Australia.
Australia↗
Genetic structure of Mediterranean populations revealed by Y-chromosome haplotype analysis.
The allelic variability at six Y-chromosome-specific polymorphisms (YAP, DYS19, DYS389-I, DYS390, DYS391, and DYS392) was used to generate male-specific haplotypes in 333 males representing 12 population samples from the region around the Mediterranean sea. Extreme interindividual variation was observed, as more than 160 distinct Y-chromosome variants could be defined as six-locus haplotypes. Concomitant with this high variability, low levels of population genetic structure were observed. In particular, a "core" of populations directly facing the north and the east of the Mediterranean basin, from the Middle East to the Italian Peninsula, was found to be genetically undifferentiated. This observation, supported by a reanalysis of Y-specific binary polymorphisms in the same populations, suggests that at least part of the male-specific gene pools of these populations has either a very recent common origin (that could be related with the Neolithic demic diffusion hypothesis), and/or that gene flow has played a significant role in shaping the patterns of genetic variability in this region. In agreement with both hypotheses, we found that the spatial distribution of DYS392 alleles revealed a marked differentiation between the East and the West of the Mediterranean area. Through the analysis of microsatellite variation, the time to the most recent common ancestor (TMRCA) of the YAP(+) sublineage 4 has been estimated. The estimations, based on two different data sets, turn out to be quite recent (7,000-11,000 YBP), suggesting that this lineage may have been first introduced into Southern Europe through Neolithic migrations from the Middle East.
Chromosomes, Human, Y↗
Haplotype analysis in VEGF gene and increased risk of Alzheimer's disease.
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Alzheimer Disease↗