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PubMed1999

Haplotype frequencies of eight Y-chromosome STR loci in Barcelona (North-East Spain).

Haplotype frequencies for eight Y-chromosomal short tandem repeat (STR) loci were determined in paragraph signa population sample from Barcelona (NE Spain). After PCR amplification and denaturing PAGE electrophoresis, DYS19, DYS388, DYS389 I/II, DYS390, DYS391, DYS392 and DYS393 loci were typed. Complete eight paragraph signY-chromosomal STRs haplotypes could be formed for 223 subjects, among which 137 different haplotypes were observed. The most common haplotype was shared by 13% of the sample, while 108 haplotypes were unique. The discrimination capacity was 61.5% and the gene diversity was 0.978. From the forensic point of view the combined polymorphisms provide a high diagnostic efficiency.

Base Sequence↗

PubMed2004

Mapping genes for resistance to Verticillium albo-atrum in tetraploid and diploid potato populations using haplotype association tests and genetic linkage analysis.

Verticillium wilt disease of potato is caused predominantly by Verticillium albo-atrum and V. dahliae. StVe1 -a putative QTL for resistance against V. dahliae -was previously mapped to potato chromosome 9. To develop allele-specific, SNP-based markers within the locus, the StVe1 fragment from a set of 30 North American potato cultivars was analyzed. Three distinct and highly diverse haplotypes can be distinguished at the StVe1 locus. These were detected in 97%, 33%, and 10% of the cultivars analyzed. We tested for haplotype association and for genetic linkage between the StVe1 haplotypes and resistance of tetraploid potato to V. albo-atrum. Moreover, field resistance was assessed in diploid populations with known molecular linkage maps in order to identify novel QTLs. Resistance QTLs against V. albo-atrum were detected on four chromosomes (2, 6, 9, and 12) at the diploid level, with one QTL on chromosome 2 contributing over 40% to the total phenotypic variation of the trait. At the tetraploid level, a significant association between the StVe1-839-C haplotype and susceptibility to the disease was detected, suggesting that resistance-related genes directed against V. albo-atrum and V. dahliae are located in the same genomic region of chromosome 9. However, on the basis of the present analysis, we cannot determine whether these genes are closely linked or if a single gene provides resistance against both Verticillium species. To assess the usefulness of the StVe1-839-C haplotype for marker-assisted selection, we subjected the resistance data to Bayesian analysis, and calculated positive (0.65) and negative (0.75) predictive values, and overall predictive accuracy (0.72). Our results indicate that tagging of additional genes for resistance to Verticillium with molecular markers will be required for efficient marker-assisted selection.

Base Sequence↗

PubMed1996

Linkage disequilibrium between the four most common cystic fibrosis mutations and microsatellite haplotypes in the Celtic population of Brittany.

Microsatellite haplotypes were determined for 117 chromosomes carrying the four most frequent mutations in the cystic fibrosis (CF) gene identified in the Breton population of Celtic origin, as well as for 83 normal chromosomes (noncarriers of a CF mutation). Each of the three non-delta F508 mutations was associated with a single haplotype: 1078deIT with 16-31-13, G55ID with 16-7-17, and W846X with 16-32-13. Although these results suggest identity-by-descent for each mutation, recurrent mutations, although unlikely, could not be completely ruled out. The four most frequent haplotypes on normal chromosomes and the three most frequent haplotypes on delta F508 chromosomes are the same as those found in Ireland, Spain, and Italy. This suggests that some haplotypes, associated or not with the delta F508 mutation, were present in an ancestral population from which all four populations descended.

Cystic Fibrosis↗

PubMed1996

Novel polymorphisms and haplotypes in the human coagulation factor XIII A-subunit gene.

Novel polymorphic sites within the coding region of the human coagulation factor XIII A-subunit (F13A) gene and their haplotypic combinations with the other polymorphic sites thus far reported are presented. Polymorphic bands were detected in exons 2, 5, 8, 12 and 14 by using single strand conformational polymorphism analysis and antithetic forms of the polymorphic exons were linked with each other, cosegregating as distinct sequence haplotypes. In Finnish, German, and Russian populations a total of 18 haplotypes were observed of possible 72 haplotypic combinations of the 5 exons. Ten of the haplotypes detected were found to have no novel mutations but to be only combinations of preexisting mutations. No tightly associated combinations in pairwise comparisons between antithetic forms of the polymorphic exons were observed, indicating that there may be recombinational hotspots within the F13A gene region.

Amino Acid Sequence↗

PubMed1998

Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD).

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31-33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138-192-147-183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder's were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder's have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170.

Chromosomes, Human, Pair 9↗

PubMed2000

Molecular analysis of Wilson disease in Taiwan: identification of one novel mutation and evidence of haplotype-mutation association.

Wilson disease (WND) is caused by a deficiency of the copper-transporting enzyme, P-type ATPase (ATP7B). Twelve different mutations have previously been identified in Taiwan Chinese with Wilson disease. We, herein, report another 4 missense mutations, 1 of which is novel. We did haplotype analysis of Taiwanese WND chromosomes, using three well characterized short tandem repeat markers (haplotype was assigned in the order of D13S314-D13S301-D13S316). Association correlation was found between the mutations and their respective haplotypes. Haplotype-deduced pedigree analysis was shown to be helpful in the mutation analysis of WND chromosomes and in the molecular assessment of both pre-symptomatic WND patients and carriers. Given the complexity and heterogeneity of the mutation spectrum of ATP7B, we suggest that haplotype analysis should be performed before full-scale mutation analysis.

Adenosine Triphosphatases↗

PubMed2006

Distribution of chloroplast DNA haplotypes in the contact zone of Fagus crenata in the southwest of Kanto District, Japan.

We have investigated cpDNA haplotype distribution in 24 populations of Fagus crenata in the southwest of Kanto District, Japan, and clarified the extent of intermixing of haplotypes in the contact zone by additional fine-scale analysis of two areas. Two cpDNA haplotypes belonging to different lineages were detected, and their distribution had geographical structure. Intermixed populations with the two haplotypes were limited to a narrow area. The geographical boundary between the haplotypes extended from Hakone to the west of the Kanto Mountains through the northern foot of Mt Fuji. No relationship was observed between the boundary location and the current topography of the southwest of Kanto District.

DNA, Chloroplast↗

PubMed2006

Phylogeography of haplotypes of five microsatellites located in a low-recombination region of the X chromosome: studies worldwide and in Brazilian populations.

We studied five microsatellites (DXS995, DXS8076, DXS8114, DXS1002 and DXS1050) located in a region of very low recombination rate in the long arm of the human X chromosome (Xq13.3-Xq21.3). No recombination was seen in 291 meioses in CEPH families. To test whether haplotypes composed of the five microsatellites could differentiate among distinct human continental populations, we studied an international panel containing 72 males from Africa, Europe, Asia and the America. Haplotypic diversity was very high within these groups and no haplotypes were shared among them. This led to the hope that we might be able to identify continent-specific lineages. However, in a median joining network there was no clear discrimination of the different continental groups. We then tested whether we could identify X chromosomal lineages from different continental origins in Brazilians. We typed 180 white Brazilians from four different geographical regions and examined their proportions of haplotype sharing with Africans, Asians, Europeans and Amerindians. No phylogeographical patterns emerged from the data. Moreover, there were several instances of the same haplotype being shared by many (and in one instance all) groups, suggesting that recombination might be occurring. We thus studied pairwise the level of linkage disequilibrium (LD) between the microsatellites. No detectable linkage disequilibrium between the most external loci DXS995 and DXS1050 was observed. Thus, even though recombination may be absent on short time spans, as seen in the CEPH pedigrees, on a long term basis it occurs often enough to dissipate all linkage disequilibrium. On the other hand, we observed very strong linkage disequilibrium between the pairs DXS995/DXS8076 and DXS1002/DXS8114, raising the possibility of resequencing the segment between them to identify single nucleotide polymorphisms (SNPs) in their intervals. The combination of X-linked microsatellites and SNPs in strong linkage disequilibrium might provide a powerful new tool to investigate human demographic history.

Brazil↗

PubMed2004

Analysis of the S-locus structure in Prunus armeniaca L. Identification of S-haplotype specific S-RNase and F-box genes.

The gametophytic self-incompatibility (GSI) system in Rosaceae has been proposed to be controlled by two genes located in the S -locusan S-RNase and a recently described pollen expressed S -haplotype specific F-box gene (SFB). However, in apricot (Prunus armeniaca L.) these genes had not been identified yet. We have sequenced 21 kb in total of the S -locus region in 3 different apricot S -haplotypes. These fragments contain genes homologous to the S-RNase and F-box genes found in other Prunus species, preserving their basic gene structure features and defined amino acid domains. The physical distance between the F-box and the S-RNase genes was determined exactly in the S2-haplotype (2.9 kb) and inferred approximately in the S 1-haplotype (< 49 kb) confirming that these genes are linked. Sequence analysis of the 5' flanking regions indicates the presence of a conserved region upstream of the putative TATA box in the S-RNase gene. The three identified S-RNase alleles (S1, S2 and S4) had a high allelic sequence diversity (75.3 amino acid identity), and the apricot F-box allelic variants (SFB1, SFB2 and SFB4) were also highly haplotype-specific (79.4 amino acid identity). Organ specific-expression was also studied, revealing that S1- and S2-RNases are expressed in style tissues, but not in pollen or leaves. In contrast, SFB1 and SFB2 are only expressed in pollen, but not in styles or leaves. Taken together, these results support these genes as candidates for the pistil and pollen S-determinants of GSI in apricot.

5' Flanking Region↗

PubMed1994

Variation in expression of MHC class II antigens on horse lymphocytes determined by MHC haplotype.

A panel of monoclonal antibodies was used to characterize the expression of equine Major Histocompatibility Complex (MHC) class II antigens on lymphocytes of horses of different MHC types. MHC class II antigen expression was compared between adult horses and foals, and the level of expression of MHC class II antigens on horse T cell subpopulations was also determined. Peripheral blood lymphocytes (PBL) from young and adult healthy horses of different MHC haplotypes were labeled with the antibodies and assayed by single- and two-color immunofluorescence flow cytometry. A variation in the expression of equine MHC class II antigens on PBL was identified that was determined by MHC haplotype. Both young and old animals carrying the MHC class II haplotype D3 expressed lower levels of MHC class II antigens on their PBL than did horses of other MHC class II types. D3 heterozygotes had an intermediate level of expression. Neonates and foals of any MHC haplotype had lower levels of expression of MHC class II antigens than did adults. MHC class II antigens were identified on surface immunoglobulin positive (sIg+) B cells as well as on T cells, with the B cells staining brightest. Dual staining for MHC class II antigens and markers for equine T cell subsets demonstrated that both EqCD4+ and EqCD8+ T cells expressed MHC class II molecules. These results suggest that the relatively low levels of MHC class II antigen expression on foal and neonate lymphocytes may be developmentally regulated, and not determined by environmental factors. The cause of the low expression of MHC class II antigens linked to the MHC class II haplotype D3 is not known, but it appears to reflect a decreased expression by all lymphocyte subpopulations.

Animals↗

PubMed1989

Some disease-associated ancestral haplotypes carry a polymorphism of TNF.

We describe here an Nco I restriction fragment length polymorphism of tumor necrosis factor carried by the 8.1 (HLA-A1,B8,BfS,C4AQ0,C4B1,DR3) and the 44.1 (HLA-B44,BfS,C4A3,C4BQ0,DR4) ancestral haplotypes associated with complications of rheumatoid arthritis. By examining multiple examples of these and other ancestral haplotypes it was seen that 8.1 and 44.1 ancestral haplotypes yield fragments of approximately 5.5 kb while many other ancestral haplotypes carry fragments of approximately 10.5 kb. The polymorphism is associated with the ancestral haplotype rather than the HLA-B or -DR allele defined by conventional serology.

Cell Line, Transformed↗

PubMed1991

Additional complexity within the HLA-D region: sequence analysis of two new DRw13-DQw7 haplotypes.

HLA-DRB1 is by far the most polymorphic locus within the HLA-D region with now well over 40 alleles. Nearly one fourth of these alleles are subtypes of DRw6, and these are in most cases undetectable by routine typing procedures. In this paper we present the molecular characterization of two new Caucasian DRw13-DQw7 haplotypes by DNA sequencing of the polymorphic first domain exons of DRB1 and DRB3 loci. The first haplotype, DRB1*1301-DRB3*0101-DQB1*0301, has arisen by a recombination between locus DRB1 from a DRw13-DQw6 haplotype and DQA1 from a DR4-DQw7 haplotype, as determined by DNA sequencing, DQ oligotyping, and restriction fragment length polymorphism typing. The second haplotype, DRB1*1305-DQB1*0301, is characterized by the novel DRB1*1305 allele differing from DRB1*1301 by three amino acids. It probably arose by a gene conversion event between a DRw13-DQw6 allele and DRB1*1101. This allele represents a DRw11/DRw13 hybrid DR molecule with a DRw13 serological epitope in the second hypervariable region and a Dw5 cellular epitope in the third hypervariable region. As determined by sequencing of locus DRB3, this allele is associated with DRw52b. Our molecular analysis of the complex HLA-DRw13 group now allows unambiguous DNA typing of all five DRw13 alleles with seven oligonucleotides, a significant improvement in the context of organ transplantation.

Amino Acid Sequence↗

PubMed1991

DRw11 haplotypes: continuum of DRB1 diversity augmented by unique DQ/DRw52 associations.

cDNA sequencing of the first domains of DRB1, DRB3, DQA1, and DQB1 alleles was used to examine the extent of diversity in American black individuals expressing several DRw11 haplotypes. In addition to previously described DRw11 alleles, DRB1*1102 and DRB1*1103, two new DRB1 alleles, DRB1*11012 and DRB1*11042, were identified which differ from previously described alleles at the nucleic acid but not at the protein level. Gene conversion-like events have likely generated the DRw11 microvariation resulting in the merging of DRw11 with the DRw13 allele family. The DRw11 alleles are associated with various DQ alleles: DQw1 (DQw5 and DQw6), DQw7, and a serologically undefined DQ allele. This undefined DQ molecule, comprised of a DQ alpha/beta combination encoded by a DQw7 alpha gene (DQA1*0301) and a DQw2 beta gene (DQB1*0201), was previously observed in some DR7 and DR9 haplotypes. DRw11 haplotype diversity is augmented by the association of one of the DRw11 alleles with the DRw52c allele in contrast to the more common DRw11, DRw52b association. The extensive diversity exhibited by the DRw11 and DRw13 family of haplotypes coupled with their high frequency in populations of African ancestry suggest that the DRw11/w13 allele family may be very old and/or that these haplotypes carry some selective advantage.

Amino Acid Sequence↗

PubMed1992

HLA DQA, DQB, and DRB genotyping by oligonucleotide analysis: distribution of alleles and haplotypes in British caucasoids.

A precise method for comprehensive HLA DQA and DQB genotyping using gene amplification and hybridization with sequence-specific oligonucleotide (SSO) probes is described. Twenty-four SSO probes were used to detect all DQ allotypes defined by nucleotide sequence variation in the second exons of the DQ genes, using a standard set of conditions for all probes at each locus. Five hundred individuals were genotyped for 8 DQA1 and 16 DQB1 alleles by using this method and for 33 alleles of the DRB1, DRB3, DRB4, and DRB5 genes by using previously described SSO probes. The 4-locus DQB1-DQA1-DRB1-DRB3/4/5 haplotypes present were characterized on the basis of known linkage disequilibrium between class II alleles. Fifty-two different haplotypes that have previously been described were further characterized at the nucleotide sequence level and two novel haplotypes were identified. The distributions of these alleles and haplotypes in 177 randomly selected healthy Caucasoid controls from the United Kingdom are reported. These results identify further haplotypic diversity in the HLA class II region, even though strong linkage disequilibrium exists between the DR and DQ gene loci.

Adult↗

PubMed1993

MHC class II haplotypes and linkage disequilibrium in primates.

The loci encoding the major histocompatibility class II cell surface antigens DR, DQ, and DP exhibit a remarkable degree of allelic polymorphism. Strong linkage disequilibrium is also found between these loci in the human population. To study the evolutionary conservation of this disequilibrium the DQA1, DQB1, and DRB1-6 loci were analyzed in chimpanzee and gorilla by sequencing or/and oligonucleotide hybridization of PCR-amplified DNA. This analysis revealed several new DRB sequences. The distribution of DRB loci differs between human and nonhuman primate haplotypes, and the strong disequilibrium found on human haplotypes between alleles at DQA1 and DQB1 as well as between the DQ loci and the DRB1 locus was not detected in the nonhuman hominoids. Extensive recombination within and between the DR and DQ region appears to have occurred during the 3-7 million years since the divergence of the three species, resulting in little similarity of haplotypes between species. The strong disequilibrium found in the human species between these loci may either reflect haplotype-specific barriers to recombination, recent founder effects in the evolution of humans, or selection for specific haplotypes.

Amino Acid Sequence↗

PubMed1993

Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia.

The Sardinian population has an extremely high incidence of IDDM (30.2 of 100.000 in the age group of 0-14 years). This study reports the molecular characterization of HLA class II genes in 120 IDDM sporadic patients and 89 healthy subjects of Sardinian origin. Compared with other Caucasians, both Sardinian patients and controls had an unusual distribution of haplotypes and genotypes. In particular, there was a high gene frequency of the DRB1*0301, DQA1*0501, DQB1*0201 susceptibility haplotype both in patients (0.58) and controls (0.23) while a reduction of the DRB1*1501, DQA1*0102, DQB1*0602 protective haplotype (0.03) was observed in the healthy population. This distribution may partially explain the high incidence of IDDM reported in Sardinia. The analysis of the DQ beta 57 and DQ alpha 52 residues showed that the absence of Asp 57 and the presence of Arg 52 were associated with IDDM in a dose-response manner. On the other hand, we found that (a) a very similar distribution of these residues was found when comparing Sardinians with another healthy Caucasian population from the same latitude but with a lower rate of IDDM incidence; (b) several genotypes encoding the identical DQ alpha 52/DQ beta 57 phenotype carried very different relative risks; and (c) the DRB1*0403, DQA1*0301, DQB1*0304 haplotype (DQ beta 57 Asp-neg and DQ alpha 52 Arg-pos) was found in 40% of the DR4-positive controls but not in patients (p = 0.00034), while the DRB1*0405, DQA1*0301, and DQB1*0302 haplotype carrying the same residues at the same positions was found in 70% of the DR4-positive patients and in only one control (p = 0.00003). These findings suggest that IDDM susceptibility cannot be completely explained by the model in which only DQ alpha 52 and DQ beta 57 residues are taken into account.

Adolescent↗

PubMed1995

A rare neutral polymorphism in 21-hydroxylase genes as HLA haplotype marker. Evidence for strong founder effect in the Finnish population.

The usefulness of rare neutral gene polymorphisms as an HLA haplotype marker and as a probe for founder effect in small populations was tested by determining the frequency and MHC associations of an NcoI polymorphism in the P450c21 genes in the Finnish population. In the general population, 13% (9 of 70) of samples had the NcoI site. A very strong association with the HLA-B62, Bf*F, C4A*3, C4B*Q0, DRB1*13, DQA1*0103, DQB1*0603 alleles was observed. P450c21A and P450c21B gene-specific amplifications mapped the polymorphic site to both P450c21A pseudogene and P450c21B functional gene of this haplotype in all cases. The majority of haplotypes with the NcoI cutting site found in this population may thus have derived from a single ancestral haplotype. The HLA homozygous cell lines with the NcoI site showed heterogeneous HLA associations. Our results suggest that in small populations the variety of MHC haplotypes may be surprisingly low and rare polymorphisms can serve as informative markers.

Base Sequence↗

PubMed1995

Polymerase chain reaction analysis of the Xba I polymorphism of the human complement C4 genes provides evidence for strong haplotype conservation.

The genes coding for the two isotypes of the fourth component of human complement, C4A and C4B, are located between the HLA-B and -DR loci of the MHC. We studied the linkage relationship of the previously described XbaI RFLP to obtain further insight into the evolution of the tandemly arranged C4 genes. Using exon-specific PCR amplification followed by restriction analysis and direct DNA sequencing, the polymorphic site could be located in exon 40 of the C4 gene (cDNA position 5095). The polymorphism does not change an amino acid residue. Using nested PCR amplification with isotype-specific primers to amplify either C4A or C4B alleles the haplotype arrangement of the XbaI sites in both isotypic C4 genes was analyzed independently. It was observed that the XbaI restriction site was either present or absent in both C4 genes of a given haplotype. In a study of 106 Caucasian haplotypes, only two different haplotypes could be identified carrying a C4A gene with and a C4B gene without the XbaI restriction site. Also, the XbaI site could only be detected in long C4 genes possessing the 6.5-kb insertion in intron 9. Our findings provide evidence that the mutation creating the XbaI polymorphism occurred in an ancestral C4 gene already carrying the long intron 9. The duplicating resulting in the presence of two isotypic genes, C4A and C4B, must have taken place subsequently giving rise to haplotypes with or without the XbaI site.

Base Sequence↗