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PubMed2003

Haplotype inference by maximum parsimony.

MOTIVATION: Haplotypes have been attracting increasing attention because of their importance in analysis of many fine-scale molecular-genetics data. Since direct sequencing of haplotype via experimental methods is both time-consuming and expensive, haplotype inference methods that infer haplotypes based on genotype samples become attractive alternatives. RESULTS: (1) We design and implement an algorithm for an important computational model of haplotype inference that has been suggested before in several places. The model finds a set of minimum number of haplotypes that explains the genotype samples. (2) Strong supports of this computational model are given based on the computational results on both real data and simulation data. (3) We also did some comparative study to show the strength and weakness of this computational model using our program. AVAILABILITY: The software HAPAR is free for non-commercial uses. Available upon request (lwang@cs.cityu.edu.hk).

Algorithms↗

PubMed2005

Recovering haplotype structure through recombination and gene conversion.

MOTIVATION: Understanding haplotype evolution subject to mutation, recombination and gene conversion is fundamental to understand genetic specificities of human populations and hereditary bases of complex disorders. The goal of this project is to develop new algorithmic tools assisting the reconstruction of historical relationships between haplotypes and the inference of haplotypes from genotypes. RESULTS: We present two new algorithms. The first one finds an optimal pathway of mutations, recombinations and gene conversions leading to a given haplotype of size m from a population of h haplotypes. It runs in time O(mhs(2)), where s is the maximum number of contiguous sites that can be exchanged in a single gene conversion. The second one finds an optimal pathway of mutations and recombinations leading to a given genotype, and runs in time O(mh(2)). Both algorithms are based on a penalty score model and use a dynamic programming approach. We apply the second one to the problem of inferring haplotypes from genotypes, and show how it can be used as an independent tool, or to improve the performance of existing methods. AVAILABILITY: The algorithms have been implemented in JAVA and are available on request.

Algorithms↗

PubMed2005

Inference of missing SNPs and information quantity measurements for haplotype blocks.

MOTIVATION: Missing data in genotyping single nucleotide polymorphism (SNP) spots are common. High-throughput genotyping methods usually have a high rate of missing data. For example, the published human chromosome 21 data by Patil et al. contains about 20% missing SNPs. Inferring missing SNPs using the haplotype block structure is promising but difficult because the haplotype block boundaries are not well defined. Here we propose a global algorithm to overcome this difficulty. RESULTS: First, we propose to use entropy as a measure of haplotype diversity. We show that the entropy measure combined with a dynamic programming algorithm produces better haplotype block partitions than other measures. Second, based on the entropy measure, we propose a two-step iterative partition-inference algorithm for the inference of missing SNPs. At the first step, we apply the dynamic programming algorithm to partition haplotypes into blocks. At the second step, we use an iterative process similar to the expectation-maximization algorithm to infer missing SNPs in each haplotype block so as to minimize the block entropy. The algorithm iterates these two steps until the total block entropy is minimized. We test our algorithm in several experimental data sets. The results show that the global approach significantly improves the accuracy of the inference. AVAILABILITY: Upon request.

Algorithms↗

PubMed2005

Haplotype-based linkage disequilibrium mapping via direct data mining.

MOTIVATION: With the availability of large-scale, high-density single-nucleotide polymorphism markers and information on haplotype structures and frequencies, a great challenge is how to take advantage of haplotype information in the association mapping of complex diseases in case-control studies. RESULTS: We present a novel approach for association mapping based on directly mining haplotypes (i.e. phased genotype pairs) produced from case-control data or case-parent data via a density-based clustering algorithm, which can be applied to whole-genome screens as well as candidate-gene studies in small genomic regions. The method directly explores the sharing of haplotype segments in affected individuals that are rarely present in normal individuals. The measure of sharing between two haplotypes is defined by a new similarity metric that combines the length of the shared segments and the number of common alleles around any marker position of the haplotypes, which is robust against recent mutations/genotype errors and recombination events. The effectiveness of the approach is demonstrated by using both simulated datasets and real datasets. The results show that the algorithm is accurate for different population models and for different disease models, even for genes with small effects, and it outperforms some recently developed methods.

Algorithms↗

PubMed2005

Functional haplotypes in the promoter of matrix metalloproteinase-2 and lung cancer susceptibility.

Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer initiation and progression. Our previous studies revealed that the -1306C-->T and -735C-->T polymorphisms in MMP2 promoter significantly influence transcriptional activity and their genotypes and haplotypes are associated with susceptibility to several cancers. This case-control study examined the contribution of these two polymorphisms to the risk of developing lung cancer. MMP2 genotypes and haplotypes were determined in 770 cases and 777 controls and the associations with risk of lung cancer were estimated by logistic regression. We observed a 2-fold [odds ratio (OR), 2.12; 95% confidence interval (CI), 1.64-2.72] or 1.6-fold (OR, 1.57; 95% CI, 1.27-1.95) excess risk of developing lung cancer for the -1306CC or -735CC genotype carriers compared with non-carriers, respectively. A greater risk of lung cancer was associated with the C(-1306)-C(-735) haplotype (OR, 5.01; 95% CI, 2.57-9.78) compared with the T(-1306)-T(-735) haplotype, suggesting a synergic effect of these two polymorphisms. Furthermore, a greater than additive joint effect of the polymorphisms and smoking increased an even higher risk of lung cancer. The OR for smokers with the C(-1306)-C(-735) haplotype was 6.24 (95% CI, 4.51-8.64), which was significantly higher than that (OR, 4.10; 95% CI, 2.89-5.81) of smokers with the T(-1306) or T(-735)-containing haplotypes (P < 0.001). These results are consistent with our previous findings and further support the hypothesis that gain-of-function of MMP2 resulting from genetic polymorphisms plays an important role in human carcinogenesis.

Case-Control Studies↗

PubMed2006

The association of oestrogen receptor alpha-haplotypes with cardiovascular risk factors in the British Women's Heart and Health Study.

AIMS: One previous study among women with established coronary heart disease found a gene-treatment interaction between the oestrogen receptor gene (ESR1) and hormone replacement in their association with high density lipoprotein cholesterol (HDL-c). We aimed to replicate these findings in a general population sample. METHODS AND RESULTS: Cross-sectional associations were assessed in a study of 3404 women from 23 towns across Britain who were aged 60-79 at the time of assessment and were described as white by the examining nurse. Women with the T-A haplotype [constructed from two single nucleotide polymorphisms (SNPs) in the first intron of ESR1: c454-397T > C (rs2234693) and c454-351A > G (rs9340799)], which was predicted to be associated with reduced oestrogen response, were more likely to have been past [per haplotype odds ratio 1.16 (95% CI 1.01, 1.33), P = 0.02] or to be current users [per haplotype odds ratio 1.19 (95% CI 0.99, 1.42), P = 0.05] of hormone replacement. However, there was no association between haplotype or either SNP and HDL-c or other cardiovascular disease risk factors and no statistical evidence of an interaction between hormone replacement use and haplotype or either SNP with respect to HDL-c or any other cardiovascular disease risk factors. CONCLUSION: Women with the T-A haplotype are more likely to use hormone replacement. However, genotyping of ESR1 rs2234693 or rs9340799 in post-menopausal women to tailor hormone replacement is unlikely to markedly improve cardiovascular risk.

Aged↗

PubMed1992

Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data.

We present here a framework for the study of molecular variation within a single species. Information on DNA haplotype divergence is incorporated into an analysis of variance format, derived from a matrix of squared-distances among all pairs of haplotypes. This analysis of molecular variance (AMOVA) produces estimates of variance components and F-statistic analogs, designated here as phi-statistics, reflecting the correlation of haplotypic diversity at different levels of hierarchical subdivision. The method is flexible enough to accommodate several alternative input matrices, corresponding to different types of molecular data, as well as different types of evolutionary assumptions, without modifying the basic structure of the analysis. The significance of the variance components and phi-statistics is tested using a permutational approach, eliminating the normality assumption that is conventional for analysis of variance but inappropriate for molecular data. Application of AMOVA to human mitochondrial DNA haplotype data shows that population subdivisions are better resolved when some measure of molecular differences among haplotypes is introduced into the analysis. At the intraspecific level, however, the additional information provided by knowing the exact phylogenetic relations among haplotypes or by a nonlinear translation of restriction-site change into nucleotide diversity does not significantly modify the inferred population genetic structure. Monte Carlo studies show that site sampling does not fundamentally affect the significance of the molecular variance components. The AMOVA treatment is easily extended in several different directions and it constitutes a coherent and flexible framework for the statistical analysis of molecular data.

Analysis of Variance↗

PubMed2002

Specific haplotypes of the P-selectin gene are associated with myocardial infarction.

P-selectin is a cellular adhesion molecule that may be involved in the development of atherosclerosis and its complications. We have previously identified thirteen polymorphisms of the P-selectin gene among which five were located in the coding region of the gene (S290N, N562D, V599L, T715P, T741T (A/G)). These polymorphisms were tested individually for association with myocardial infarction (MI) and only the T715P polymorphism was shown to be associated with MI. We here extend this work by performing a haplotype analysis which enables us to assess the consequences on the phenotype of the co-presence of several variants on the same chromosome. For this purpose, a new maximum likelihood method was developed for estimating simultaneously haplotype frequencies and haplotype-phenotype effects. While haplotypes defined by the polymorphisms located in the promoter region of the gene were unrelated to MI, those defined by the polymorphisms in the coding region were globally associated with MI in a sample of 582 cases and 630 controls from the Etude Cas-Témoin sur l'Infarctus du Myocarde. Detailed haplotype analysis confirmed the protective effect of the P715 allele but additionally revealed that the presence of two asparagine codons at sites S290N and N562D was associated with a higher risk of MI, consistenly in France and Northern Ireland, but only when they were carried by the same haplotype. This finding illustrates the complexity of the relationship between gene variability and disease and the necessity to explore in detail the polymorphisms of candidate genes.

Adult↗

PubMed2002

Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.

The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n=419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12% of Caucasians, 14% of African-Americans and 28% of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25-50% of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

Apolipoprotein A-V↗

PubMed2000

Integrated analysis of sequence evolution and population history using hypervariable compound haplotypes.

We have examined compound haplotypes from a highly informative region of human chromosome 16, in which information from the rapid evolution of a highly unstable minisatellite is integrated with data on the longer-term evolution of this segment from 10 flanking substitutional polymorphisms. Combined with sequence data from non-human primates, analysis of relationships between these compound haplotypes allows the reconstruction of a rooted network of the evolutionary pathways between them. Most relationships can be explained via simple substitutional mutations, although the origins of some haplotypes involve recurrent events at a hotspot for substitutional mutation and/or gene conversion. For compound haplotypes including the minisatellite array, the network found in a range of world-wide populations constitutes a highly informative data set for the analysis of population history (437 different compound haplotypes were discriminated among 658 studied). Since the mutation rates and processes of the minisatellite array are known from direct studies, ages for individual lineages have been estimated using associated minisatellite diversity. These analyses suggest that the higher information content and sampling depth of these compound haplotypes may allow more precise calibration of lineage ages than is possible using coalescent analysis of DNA sequence. Using this method we have dated the oldest Eurasian lineage as 52,000-66,000 years and the oldest European specific lineage as 37,600-56,200 years.

Africa↗

PubMed2003

A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.

Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl(-) currents and HCO3(-) -transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.

Alleles↗

PubMed2003

Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects.

We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.

Female↗

PubMed2005

Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study.

Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mellitus. Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variability in PLA2G2A were identified and distinguished six common haplotypes (frequencies > 5%). In the 523 Caucasian T2D patients, levels of sPLA(2)IIa, independent of CRP, were negatively correlated with total antioxidant status (P = 0.003) and high-density lipoprotein cholesterol (P = 0.006) in men and correlated with CAD status in women (P = 0.002) (Odds ratio of top two tertiles versus bottom = 2.50) [95% CI (1.13-5.53) P = 0.024]. Overall, tSNP haplotypes showed a highly significant association with sPLA(2)IIa levels (P < 0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA(2)IIa levels [3.25 ng/ml (+/- 0.14)] compared with the combined other haplotypes [2.13 ng/ml (+/- 0.09), P < 0.00001]. Five of the six tSNPs were associated with significant effects on sPLA(2)IIa levels but the raising haplotype could not be distinguished by a single tSNP and none are likely to be functional. These data confirm the relationship between elevated sPLA(2)IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA(2)IIa levels will help clarify the causality of this association.

Aged↗

PubMed2006

Effect of ATM, CHEK2 and ERBB2 TAGSNPs and haplotypes on endometrial cancer risk.

Family history of endometrial cancer increases the risk of developing the disease, but it is still largely unknown which germ-line genetic factors are involved in the aetiology of endometrial cancer. In a Swedish population-based case-control study including 705 cases and 1565 controls, we examined common variation in the ATM, CHEK2 and ERBB2 genes in relation to endometrial cancer risk overall, restricted to tumours of certain characteristics or stratified by various endometrial cancer risk factors. We genotyped a large number of single-nucleotide polymorphisms (SNPs) in the genes and selected seven haplotype-tagging SNPs (tagSNPs) in ATM, six tagSNPs in CHEK2 and seven tagSNPs in ERBB2 that could predict common variants and haplotypes (frequency > or =0.03) in each gene with R(2) > or = 0.8. We included the tagSNPs or their haplotypes as explanatory variables in unconditional logistic regression models adjusted for age. Our results indicated an increased risk of developing endometroid endometrial cancer for homozygous carriers of the rare allele (AA) of a tagSNP (rs4987886) in CHEK2 (P = 0.005) when contrasted with GG carriers. We also found a decreased endometrial cancer risk among non-smoking carriers of a haplotype in ATM (P = 0.0007) and among carriers of a haplotype in CHEK2, who had experienced menopause below 49 years of age (P = 0.0009) compared with non-carriers of these haplotypes. We found no effect of genetic variation in ERBB2 on endometrial cancer risk. In conclusion, it is possible that common variants in the ATM and CHEK2 genes, in interaction with oestrogen-related exposures, are involved in endometrial cancer aetiology.

Age Factors↗

PubMed2005

Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia.

We determined whether polymorphisms in the promoter region of the tumour necrosis factor alpha (TNF-alpha) gene contributes to differences in susceptibility to develop pre-eclampsia. The study involved 133 pre-eclamptic and 115 healthy pregnant women who were genotyped for the G-308A polymorphism of the TNF-alpha gene. The frequency of the G-308A allele was more common in the pre-eclampsia group than among the controls (P=0.046), giving an odds ratio of 0.57 (95% CI: 0.32-0.99), but there were no differences in the genotype distribution. The data from the G-308A polymorphism was combined with the previously published genotype and allele data from the C-850T polymorphism of the TNF-alpha gene, and used to assess a haplotype estimation analysis. Estimated overall pair of loci haplotype frequencies differed significantly between the groups (P=0.023+/-0.004). In the single haplotype association analysis, the haplotype C-A versus others was over-represented in the pre-eclampsia group (P=0.041+/-0.003), whereas the haplotype T-G versus others was less common in the pre-eclampsia group (P=0.035+/-0.003), compared with the controls. In conclusion, the polymorphisms of the TNF-alpha gene showed a significant haplotype association with susceptibility to pre-eclampsia in the Finnish population.

Adult↗

PubMed1993

Phylogenetic analysis of the alpha-globin pseudogene-4 (Hba-ps4) locus in the house mouse species complex reveals a stepwise evolution of t haplotypes.

A parsimony analysis was performed on restriction sites at the Hba-ps4 pseudogene locus within one of four inversions associated with mouse t haplotypes. The results suggest that all t haplotypes form a monophyletic group and that the in (17)4 inversion originated before the radiation of the Mus musculus species complex but after the divergence of the lineages leading to M. spretus, M. abbotti, and M. hortulanus. A time frame based on the evolutionary rate of mouse pseudogenes places the origin of this t haplotype inversion at 1.5 Mya, or approximately 1.5 Myr after the origin of the more proximal t complex inversion, in (17)2. The accumulated evidence indicates that complete t haplotypes have been assembled in a stepwise manner, with each of these inversions occurring on separate chromosomal lineages and at different evolutionary times. In addition, the evolutionary relationships of pseudogene sequences resulting from genetic exchange between wild-type and t haplotype alleles were examined. Analysis of sequences from the 5' and 3' sides of a putative site of recombination resulted in cladograms with different topologies. The implications for hypotheses concerning the evolutionary forces acting on t haplotypes and their rapid propagation throughout worldwide populations of mice are discussed.

Alleles↗

PubMed2002

Utility of Y-STR haplotype and mtDNA sequence in personal identification of human remains.

The utility of Y-STR haplotype and mtDNA sequence in personal identification from human remains is demonstrated. In five cases, severely damaged human remains were identified by Y-chromosomal short tandem repeat (STR) (Y-STR) haplotyping and mitochondrial DNA (mtDNA) sequencing. DNA was extracted from highly adipoceratous tissues using the phenol-chloroform method and polymerase chain reaction amplified for Y-STR haplotyping and sequencing of two hypervariable regions, HV1 and HV2, of the mtDNA. The authors also profiled the Y-STR haplotype and mtDNA sequence of a blood sample that was obtained from the presumptive brother of the decedent. Y-STR haplotyping and mtDNA sequencing results were compared with one another and with the Anderson sequence. It was concluded from these data that the lower part of the body (Case 1), the human head (Case 2), the upper part of the body (Case 3), and the right arm (Case 4) were from the same individual, whereas another lower part of a body (Case 5) was from a relative of the presumptive brother. A novel descriptive way of a statistical characteristic, gene or haplotype diversity, is shown.

Adult↗

PubMed1991

Genetic study of ossification of the posterior longitudinal ligament in the cervical spine with human leukocyte antigen haplotype.

To evaluate the genetic background of ossification of the posterior longitudinal ligament, the relationship between the presence of absence of ossification and human leukocyte antigen haplotypes was studied in 33 families of patients with ossification of the posterior longitudinal ligament. The study revealed that human leukocyte antigen haplotypes formed certain types of clusters, and that some human leukocyte antigen haplotypes were very rare in the Japanese population, suggesting the involvement of human leukocyte antigen-linked factors in the pathogenesis of ossification of the posterior longitudinal ligament of the cervical spine. In the families of these patients, ossification of the posterior longitudinal ligament was demonstrated by radiography in 56% (10/18) of the siblings. Each of these siblings shared both human leukocyte antigen haplotypes with the patient. None of those who shared only one human leukocyte antigen haplotype with the patient had developed ossification of the posterior longitudinal ligament. From these findings, the presence of both pathogenic human leukocyte antigen haplotypes is considered to be necessary for the development of ossification of the posterior longitudinal ligament, and this genetic predisposition may be activated by multiple factors, including regressive degeneration due to aging and the environment.

Cervical Vertebrae↗