The region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological and inflammatory diseases. However, strong linkage disequilibrium in the region creates conserved TNF block haplotypes; hampering identification of specific polymorphisms responsible for disease phenotypes. Here we review studies investigating TNF block haplotypes and their links with cytokine production and inflammatory disease risk.Recent work has done much to characterize TNF block haplotypes in different ethnicities and their associations with the larger overall structure of MHC ancestral haplotypes. There have also been studies examining the effects of TNF block haplotypes on levels of inflammatory cytokine production, with others investigating haplotype association with diseases risk. Carriage of specific TNF block haplotypes have been associated with increased risk of Type II Diabetes, Chronic Venous Leg ...
We describe a novel method for assessing the strength of disease association with single nucleotide polymorphisms (SNPs) in a candidate gene or small candidate region, and for estimating the corresponding haplotype relative risks of disease, using unphased genotype data directly. We begin by estimating the relative frequencies of haplotypes consistent with observed SNP genotypes. Under the Bayesian partition model, we specify cluster centres from this set of consistent SNP haplotypes. The remaining haplotypes are then assigned to the cluster with the nearest centre, where distance is defined in terms of SNP allele matches. Within a logistic regression modelling framework, each haplotype within a cluster is assigned the same disease risk, reducing the number of parameters required. Uncertainty in phase assignment is addressed by considering all possible haplotype configurations consistent with each unphased genotype, weighted in the logistic regression likelihood by their probabilities, calculated
Linkage Disequilibrium and haplotype mapping : A number of packages provide haplotype estimation for unrelated individuals with ambiguous haplotypes (due to unknown linkage phase) and allow testing for associations between the estimated haplotypes and phenotypes (including co-variates) under a GLM framework. hapassoc performs likelihood inference of trait associations with haplotypes in GLMs. haplo.stats also contains tests for haplotype associations under a GLM framework, but also provides score tests of association as well as providing novel functionality for building haplotypes in a sequential manner, power and sample-size calculations and the preparation of data matrices for use in other methods. haplo.ccs utilises the haplotype estimation of haplo.stats and performs case-control association tests via weighted logistic regression. tdthap implements transmission/disequilibrium tests for extended marker haplotypes. LDheatmap creates a heat map plot of measures of pairwise LD ...
Linkage Disequilibrium and haplotype mapping : A number of packages provide haplotype estimation for unrelated individuals with ambiguous haplotypes (due to unknown linkage phase) and allow testing for associations between the estimated haplotypes and phenotypes (including co-variates) under a GLM framework. hapassoc performs likelihood inference of trait associations with haplotypes in GLMs. haplo.stats also contains tests for haplotype associations under a GLM framework, but also provides score tests of association as well as providing novel functionality for building haplotypes in a sequential manner, power and sample-size calculations and the preparation of data matrices for use in other methods. haplo.ccs utilises the haplotype estimation of haplo.stats and performs case-control association tests via weighted logistic regression. tdthap implements transmission/disequilibrium tests for extended marker haplotypes. LDheatmap creates a heat map plot of measures of pairwise LD ...
OBJECTIVES Associations of interleukin-10 (IL-10) promoter single nucleotide polymorphisms (SNPs) and their haplotypes with systemic lupus erythematosus (SLE) are unclear. We extended the analysis of established proximal IL-10 promoter haplotypes to a more distal SNP with functional capacity. METHODS Two hundred and ten German caucasian SLE patients fulfilling the ACR criteria and 160 ethnically, age and sex matched controls were genotyped for IL-10 -2849 G | A, -1082 A | G, -819 T | C and -592 C | A. Haplotypes were reconstructed via a mathematical model, then allele and haplotype distributions were compared between patients and controls and patients with different disease manifestations. RESULTS We detected at -2849, -1082, -819 and -592 the four predominant haplotypes GGCC (22% in patients vs. 29% in controls), AGCC (24% vs. 21%), GACC (30% vs. 25%) and GATA (24% vs. 24%). GGCC was underrepresented in SLE patients, suggesting a protective effect (odds ratio (OR) 0.67, 95% confidence interval (CI)
The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of |44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122
BACKGROUND AND AIMS: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohns disease (CD). A locus on chromosome 5q has been implicated in susceptibility to CD, and recently refined by linkage disequilibrium mapping to a conserved 250 kb haplotype (5q31). No data regarding the contribution of this locus to clinical phenotype exist. In this case control study, we investigated the contribution of this haplotype to both susceptibility and phenotype of CD and UC. PATIENTS AND METHODS: We studied 330 Caucasian CD and 457 UC patients recruited from a single UK centre. Association with disease susceptibility and phenotype was analysed with haplotypes reconstructed from three single nucleotide polymorphisms chosen to span thissusceptibility region. Evidence for possible genetic epistasis between IBD5 and NOD2/CARD15 was sought. RESULTS: Linkage disequilibrium across this region was confirmed, with two haplotypes ...
Identifying the genetic components of common diseases has long been an important area of research. Recently, genotyping technology has reached the level where it is cost effective to genotype single nucleotide polymorphism (SNP) markers covering the entire genome, in thousands of individuals, and analyse such data for markers associated with a diseases. The statistical power to detect association, however, is limited when markers are analysed one at a time. This can be alleviated by considering multiple markers simultaneously. The Haplotype Pattern Mining (HPM) method is a machine learning approach to do exactly this. We present a new, faster algorithm for the HPM method. The new approach use patterns of haplotype diversity in the genome: locally in the genome, the number of observed haplotypes is much smaller than the total number of possible haplotypes. We show that the new approach speeds up the HPM method with a factor of 2 on a genome-wide dataset with 5009 individuals typed in 491208 markers using
Haplotypes extracted from human DNA can be used for gene mapping and other analysis of genetic patterns within and across populations. A fundamental problem is, however, that current practical laboratory methods do not give haplotype information. Estimation of phased haplotypes of unrelated individuals given their unphased genotypes is known as the haplotype reconstruction or phasing problem. We define three novel statistical models and give an efficient algorithm for haplotype reconstruction, jointly called HaploRec. HaploRec is based on exploiting local regularities conserved in haplotypes: it reconstructs haplotypes so that they have maximal local coherence. This approach - not assuming statistical dependence for remotely located markers - has two useful properties: it is well-suited for sparse marker maps, such as those used in gene mapping, and it can actually take advantage of long maps. Our experimental results with simulated and real data show that HaploRec is a powerful method for the large
This study investigated polymorphisms of genes in two regions of the T-cell antigen receptor beta-subunit (TCRB) locus, including BV9S2P, and BV6S7 in a 5 linkage group, and BV8S3, BV24S1, BV25S1, BV18S1, BV2S1, BV15S1 and BV3S1 in a 3 linkage group. These loci have been genotyped in individuals from five regions in Africa, including The Gambia, Nigeria, Cameroon, Tanzania, and Zambia, and in individuals from northern Britain, northern India, and Papua New Guinea (PNG). In the 3 linkage group, 11 unique haplotypes were identified in the combined African populations; two equally frequent haplotypes represent the majority of African chromosomes. One haplotype was found in all four regions studied. This is the most frequent haplotype in the northern British, northern Indian and PNG populations. Although present, it is infrequent in the African populations. A North-South gradient in the frequency of a common African haplotype was observed. The distribution did not represent that of a known disease.
TY - JOUR. T1 - Making a haplotype catalog with estimated frequencies based on SNP homozygotes. AU - Yamaguchi-Kabata, Yumi. AU - Tsunoda, Tatsuhiko. AU - Takahashi, Atsushi. AU - Hosono, Naoya. AU - Kubo, Michiaki. AU - Nakamura, Yusuke. AU - Kamatani, Naoyuki. PY - 2010/8. Y1 - 2010/8. N2 - Understanding the structure and frequencies of haplotypes is important for associating genetic polymorphisms with a given trait and for inferring the genetic genealogy of alleles in a population. Single nucleotide polymorphism (SNP) haplotypes can be determined without ambiguity when an individual does not have more than one heterozygous site in a given genomic region. Using genome-wide SNP genotypes for 3397 individuals from the Japanese population, we detected SNP homozygotes in the genomic regions of 1955 genes, determined haplotypes, and examined the efficiency of haplotype frequency estimation based on the proportion of SNP homozygotes in the sample. The estimated haplotype frequencies were very ...
Tables 4 and 5 show the results of eight SNP haplotype analyses (rs941798, rs3787345, rs754118, rs2282147, rs718049, rs718050, rs3787348, and 1484insG) with Si (Table 4) and fasting glucose (Table 5), respectively. The SNPs were chosen to tag all common haplotypes (≥10% frequency) and ,85% of the variation in the LD block and, in addition, includes 1484insG. The Tables show the common (,1%) haplotypes, their frequency, P values for association under different models of inheritance, the mean trait values for the different haplotype combinations, and the effect of the specific haplotype on the trait. The haplotype ACTTCAG0 is significantly associated with lower Si (e.g., greater insulin resistance) and higher fasting glucose in the dominant model, and the haplotype GTCCTGT0 is significantly associated with higher Si (e.g., greater insulin sensitivity) and lower fasting glucose in the additive and recessive models. The remaining haplotype, ATCCTGG0, shows evidence of association with Si under the ...
In the original publications, the haplotypes identified as being of highest risk consisted of the combination of two SNPs together, rs1048661(G) and rs3825942(C), oriented with respect to the dbSNP entry. In the two populations studied combined (from Iceland and Sweden), the (G;C) haplotype has an odds ratio of 27.05, and the (T;C) haplotype has an OR of 8.90, relative to the (G;T) haplotype. The (T;T) haplotype is presumed to be at even lower risk than the (G;T) haplotype, but due at least in part to the high frequency of the rs1048661(G) allele, no individuals in this study carried it. In the populations studied, ~25% of all individuals in the population carry two copies of the (G;C), highest risk haplotype. If the risk of carrying two such haplotypes is multiplicative (which isnt known actually), the authors estimate that individuals carrying two copies of the (G;C) high risk haplotype would have 700 times the risk of developing this type of glaucoma compared to individuals carrying two ...
TY - JOUR. T1 - Complex SNP-based haplotypes in three human helicases. T2 - Implications for cancer association studies. AU - Trikka, Dimitra. AU - Fang, Zhe. AU - Renwick, Alex. AU - Jones, Sally H.. AU - Chakraborty, Ranajit. AU - Kimmel, Marek. AU - Nelson, David L.. PY - 2002/4/25. Y1 - 2002/4/25. N2 - We have initiated a candidate gene approach to study variation and predisposition to cancer in the four major ethnic groups that constitute the U.S. population (African Americans, Caucasians, Hispanics, and Asians). We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs). Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes. Approximately 10% of the predicted haplotypes were shared among all ethnic groups. Linkage disequilibrium and recombination effects showed that each locus has taken a diverse evolutionary path. Primate DNA analysis of the same ...
NK cells react to cells that lack self-MHC class I. Yet, since many NK cells cannot recognize self-MHC, mechanisms such as NK cell licensing protect against autoreactivity. To become licensed, i.e. functionally competent to be triggered through its activation receptors, an NK cell must engage host MHC class I via at least one of its MHC class I-specific inhibitory receptors, such as the Ly49 family of receptors in the mouse. However, the general determinants of this process remain largely unknown. Herein, we investigated the licensing impact of the b, d, f, k, q, r, and s H2 haplotypes on Ly49A+ NK cells in MHC-congenic mice. Ex vivo PK136 (anti-NK1.1) stimulation assays indicated that licensing may not be a binary phenomenon as some Ly49A-MHC class I haplotype combinations produced an intermediate licensing phenotype. Ly49A surface accessibility, a measure of cis binding with MHC class I, and Ly49A tetramer binding displayed a similar variability among the MHC haplotypes. Taken together, the ...
A haplogroup is a group of similar and ancestrally related haplotypes that all have the same single nucleotide polymorphism (SNP) mutation. It is a genetic marker for a group of organisms with a common ancestor. In human genetics, the haplogroups usually studied are Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups. Both can be used to define genetic populations. Y-DNA is passed only from father to son, while mtDNA is passed only from mother to children. Neither recombines, and thus Y-DNA and mtDNA change only by chance mutations with no intermixture between parents genetic material. Haplogroups are used in some forms of genetic ancestry research such as research determining the most common haplotype(s) in different populations and argued genetic ancestry relationships between the populations based on this. However, haplogroups are not races or some kind of racial essences that define races. Y-DNA and mtDNA haplogroups represent only a very small part of the human ...
We present a method for obtaining long haplotypes, of over 3 kb in length, using a short-read sequencer, Barcode-directed Assembly for Extra-long Sequences (BAsE-Seq). BAsE-Seq relies on transposing a template-specific barcode onto random segments of the template molecule and assembling the barcoded short reads into complete haplotypes. We applied BAsE-Seq on mixed clones of hepatitis B virus and accurately identified haplotypes occurring at frequencies greater than or equal to 0.4%, with |99.9% specificity. Applying BAsE-Seq to a clinical sample, we obtained over 9,000 viral haplotypes, which provided an unprecedented view of hepatitis B virus population structure during chronic infection. BAsE-Seq is readily applicable for monitoring quasispecies evolution in viral diseases.
In a molecular systematic analysis, the haplotypes are determined for a defined area of genetic material; a substantial sample of individuals of the target species or other taxon is used; however, many current studies are based on single individuals. Haplotypes of individuals of closely related, yet different, taxa are also determined. Finally, haplotypes from a smaller number of individuals from a definitely different taxon are determined: these are referred to as an outgroup. The base sequences for the haplotypes are then compared. In the simplest case, the difference between two haplotypes is assessed by counting the number of locations where they have different bases: this is referred to as the number of substitutions (other kinds of differences between haplotypes can also occur, for example, the insertion of a section of nucleic acid in one haplotype that is not present in another). The difference between organisms is usually re-expressed as a percentage divergence, by dividing the number ...
This track shows alignments of alternate locus (also known as alternate haplotype) reference sequences to main chromosome sequences in the reference genome assembly. Some loci in the genome are highly variable, with sets of variants that tend to segregate into distinct haplotypes. Only one haplotype can be included in a reference assembly chromosome sequence. Instead of providing a separate complete chromosome sequence for each haplotype, which could cause confusion with divergent chromosome coordinates and ambiguity about which sequence is the official reference, the Genome Reference Consortium (GRC) adds alternate locus sequences, ranging from tens of thousands of bases up to low millions of bases in size, to represent the distinct haplotypes. ...
This track shows alignments of alternate locus (also known as alternate haplotype) reference sequences to main chromosome sequences in the reference genome assembly. Some loci in the genome are highly variable, with sets of variants that tend to segregate into distinct haplotypes. Only one haplotype can be included in a reference assembly chromosome sequence. Instead of providing a separate complete chromosome sequence for each haplotype, which could cause confusion with divergent chromosome coordinates and ambiguity about which sequence is the official reference, the Genome Reference Consortium (GRC) adds alternate locus sequences, ranging from tens of thousands of bases up to low millions of bases in size, to represent the distinct haplotypes. ...
This track shows alignments of alternate locus (also known as alternate haplotype) reference sequences to main chromosome sequences in the reference genome assembly. Some loci in the genome are highly variable, with sets of variants that tend to segregate into distinct haplotypes. Only one haplotype can be included in a reference assembly chromosome sequence. Instead of providing a separate complete chromosome sequence for each haplotype, which could cause confusion with divergent chromosome coordinates and ambiguity about which sequence is the official reference, the Genome Reference Consortium (GRC) adds alternate locus sequences, ranging from tens of thousands of bases up to low millions of bases in size, to represent the distinct haplotypes. ...
This track shows alignments of alternate locus (also known as alternate haplotype) reference sequences to main chromosome sequences in the reference genome assembly. Some loci in the genome are highly variable, with sets of variants that tend to segregate into distinct haplotypes. Only one haplotype can be included in a reference assembly chromosome sequence. Instead of providing a separate complete chromosome sequence for each haplotype, which could cause confusion with divergent chromosome coordinates and ambiguity about which sequence is the official reference, the Genome Reference Consortium (GRC) adds alternate locus sequences, ranging from tens of thousands of bases up to low millions of bases in size, to represent the distinct haplotypes. ...
Background: In ecology and forensics, some population assignment techniques use molecular markers to assign individuals to known groups. However, assigning individuals to known populations can be difficult if the level of genetic differentiation among populations is small. Most assignment studies handle independent markers, often by pruning markers in Linkage Disequilibrium (LD), ignoring the information contained in the correlation among markers due to LD. Results: To improve the accuracy of population assignment, we present an algorithm, implemented in the HaploPOP software, that combines markers into haplotypes, without requiring independence. The algorithm is based on the Gain of Informativeness for Assignment that provides a measure to decide if a pair of markers should be combined into haplotypes, or not, in order to improve assignment. Because complete exploration of all possible solutions for constructing haplotypes is computationally prohibitive, our approach uses a greedy algorithm ...
We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a ...
The genetic diversity and phylogeny of western Palaearctic members of the Gerris lacustris group was investigated on the basis of 822 bp from the 3´end of the mitochondrial gene encoding COI obtained from 34 specimens of G. lacustris, 16 specimens of G. gibbifer, eight specimens of G. maculatus and seven specimens of G. brasili. Nine haplotypes represented G. lacustris, nine haplotypes represented G. gibbifer, six haplotypes represented G. maculatus, four haplotypes represented G. brasili, and a single haplotype was shared between G. gibbifer and G. brasili. Uncorrected p genetic distances within species averaged from 0.5% in G. gibbifer and G. brasili to 0.8 in G. lacustris and as much as 2.2 in G. maculatus. A phylogenetic analysis showed that G. gibbifer and G. brasili are not reciprocally monophyletic in their mtDNA probably due to relatively recent speciation and incomplete lineage sorting. G. maculatus was poorly supported as the sister taxon to G. gibbifer and G. brasili despite morphological
In 2009, Tregouet et al. identified the SLC22A3-LPAL2-LPA gene cluster as a risk cluster and haplotypes CTTG and CCTC formed by rs2048327, rs3127599, rs7767084 and rs10755578 as risk haplotypes for CAD in six White populations [1]. From then on, several GWHS have focused on this hot spot. In a study consisted of 3657 patients with MI and 1211 control individuals, Koch et al. observed significant association between haplotypes formed by the same four SNPs in the SLC22A3-LPAL2-LPA region and MI (P = 0.0005), and found 3 risk haplotypes (CTTG, CCTC, and TTTC) [10]. Later, Sawabe M etal analyzed rs2048327 (C/T) and rs10755578 (C/G) in 1,150 Japanese autopsy cases, and ascertained that haplotypes TC and TG worked as risk factors for both coronary sclerosis and CAD [12]. In addition, Shaw et al. found that genetic variants at the SLC22A3-LPAL2-LPA locus were associated with decreased early-outgrowth colony-forming units, thereby increased the risk of MI [13], which may support the findings in ...
Here you can Read online or download a free book: Algorithms for Haplotype Inference and Block Partitioning: Perfect Phylogeny Based Approaches for the Haplotype Inference Problem.pdf Language: English by Ravi Vijaya Satya (Author) A convenient format for reading on any device
DETECTING genetic differentiation of subpopulations is an important problem in several areas of population biology, including areas of evolutionary genetics, ecology, and conservation biology. When data are obtained from two or more localities in the form of allele frequencies at one or more unlinked loci, standard chi-square tests (or likelihood-ratio tests) of homogeneity are appropriate (Workman and Niswander 1970) and can be quite powerful for detecting differentiation. Even when the expected counts in some cells are small, permutation methods can be utilized to give good results (Lewontin and Felsenstein 1965; Roff and Bentzen 1989). If the data consist of DNA sequences, or haplotyping at two or more linked sites, the same methods can be employed, if distinct sequences or haplotypes are treated as alleles. However, if the haplotype diversity is very high and the sample sizes are small, most haplotypes may appear in the sample only once and the methods based on haplotype frequencies will ...
The patterns of linkage disequilibrium (LD) between dense polymorphic markers are shaped by the ancestral population history. It is therefore possible to use multilocus predictors of LD to infer past population history and to infer sharing of identical alleles in quantitative trait locus (QTL) studies. We develop a multilocus predictor of LD for pairs of haplotypes, which we term haplotype homozygosity (HHn) : the probability that any two haplotypes share a given number of n adjacent identical markers or runs of homozygosity. Our method, based on simplified coalescence theory, accounts for recombination and mutation. We compare our HHn predictions, with HHn in simulated populations and with two published predictors of HHn. Our method performs consistently better across a range of population parameters, including populations with a severe bottleneck followed by expansion, compared to two published methods. We demonstrate that we can predict the pattern of HHn observed in dense single nucleotide ...
Khwaja, HA and Green, FR (2004) Analysis of the functional role of interleukin-6 promoter haplotype in a macrophage cell model In: 5th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology, 2004-05-06 - 2004-05-08, San Francisco, CA. Full text not available from this repository ...
Sequencing of the LARS2 cDNA, including 159 bp of the promoter region in 25 type 2 diabetic subjects, revealed eight different SNPs (Fig. 1). We did not find aberrant splicing in any of the samples investigated. Haplotype analysis using four SNPs with allele frequencies ≥2.5% suggests at least six different haplotypes (frequency ≥4%). Two variants (−109 g/a and H324Q) potentially affecting gene function were subsequently investigated in more detail. Double heterozygous subjects were not found, and haplotype and linkage disequilibrium analyses suggest that the two SNPs are present on different haplotypes and haploblocks (D′ = −1, r2 = 0.013; Fig. 1).. Genotype distributions for both SNPs in the different cohorts were all in Hardy-Weinberg equilibrium. The −109 g/a variant was tested for association in the two Dutch cohorts. Allele frequencies were 31.3 and 32.6% for control (n = 329) and type 2 diabetic (n = 215) subjects in the Hoorn study (P , 0.5) and 26.0 and 30.3% for control (n ...
The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in ...
Results In a Han population, the distribution of SNP3 (rs3890011) genotypes showed a significant difference between CAD and control subjects (p=0.030), the distribution of the recessive model of SNP3 (GG vs CC+GC) was significantly higher in CAD patients than control subjects (p=0.011), the significant difference was retained after adjustment for covariates (95%CI: 1.137-2.423, p=0.009). Three SNPs (SNP1, SNP3, SNP4) were located in one haplotype block, and the overall distribution of haplotypes constructed with these SNPs was significant (p=0.023). The G-G-T haplotype in CAD was significantly higher than that in control group (p=0.037). In a Uygur population, neither the distribution of genotypes and alleles for the 4 SNPs showed significant difference nor the distribution of haplotypes constructed with the same three SNPs between CAD and control subjects.. ...
The systematic analysis of polymorphisms across large parts of the human genome has begun to provide the first information on haplotypes and the problem of linkage disequilibrium across large genomic regions. These data suggest that significant regions of the genome show highly conserved haplotypes, potentially enhancing the ability to detect disease associations.
Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a womans life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here. Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using
TY - JOUR. T1 - Four common HLA haplotypes and their association with diseases in the Japanese population. AU - Sasazuki, T.. AU - Kaneoka, H.. AU - Ohta, N.. AU - Hayase, R.. AU - Iwamoto, I.. PY - 1979/12/1. Y1 - 1979/12/1. UR - http://www.scopus.com/inward/record.url?scp=0018567739&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0018567739&partnerID=8YFLogxK. M3 - Article. C2 - 43610. AN - SCOPUS:0018567739. VL - 11. SP - 1871. EP - 1873. JO - Transplantation Proceedings. JF - Transplantation Proceedings. SN - 0041-1345. IS - 4. ER - ...
David R. Cox, of Perlegen Sciences in Santa Clara, California, and colleagues scanned 20 copies of chromosome 21 using high-density microarrays. In all, they found nearly 36,000 SNPs in the samples. Using the scan data, they identified groups of related SNPs, or haplotypes. Most of these structures turned up on all the chromosomes. Only eight percent of the haplotypes were specific to a particular ethnic group. It is remarkable that such a large fraction of globally diverse chromosomes are represented by such limited haplotype diversity, the researchers write in Science. Three common haplotypes accounted for 80 percent of the genetic diversity among the samples. This means that, for any region of the chromosome, the most common haplotype was found in 50 percent of individuals, the second most common in 25 percent of individuals, and the third most common in 12.5 percent of individuals. The discovery that chromosome 21 is less structurally diverse than expected is potentially good news. It may ...
In admixed populations originating from different base breeds, such as Nordic Red dairy cattle, haplotypes of chromosomal segments instead of single SNP are expected to improve prediction accuracy in genomic evaluations, because linkage disequilibrium with QTL is likely to be more consistent for haplotypes than for SNP. The suggested evaluation approach consists of (i) pre-selecting a limited number of chromosomal segments based on a genome-wide QTL-scan with BayesB, (ii) estimating relative variances of haplotype markers with BayesA, and (iii) obtaining solutions for haplotype effects from mixed model equations including pedigree-based animal effects. For three production traits (milk, protein, fat) and fertility, the highest validation test reliabilities R2 were 0.48, 0.41, 0.42 and 0.33, respectively. For milk, protein and fertility, we observed an improvement over G-BLUP of 3, 1 and 3 %-units, respectively, whereas for fat, a decline of 1 %-unit.. ...
The present invention provides a novel method for specifically isolating and separating large segments of genomic DNA that can subsequently be used to determine a genomic haplotype. The invention relies on using a solid phase having a flat surface arrayed with oligonucleotides designed to specifically hybridize to each particular haplotype of an individual sample, e.g., oligonucleotides designed to specifically hybridize with each of the two HLA-B haplotypes, HLA-A, HLA-C, HLA-DR, HLA-DQ, and the like. The genomic DNA is contacted and hybridized to the arrayed oligonucleotides to form a genomic DNA/oligonucleotide complex. The excess genomic DNA is washed away and the haplotype separated genomic DNA is denatured from the oligonucleotide probe and collected. The method of the present invention allows for the separation of genomic DNA fragments of between approximately 2 to about 4 megabases (Mb). Separation of the haplotypes of large genomic DNA fragments allows for linkage analysis of other HLA alleles
DESCRIPTION. Haploscope is a software package that facilitates flexible rendering of images to aid interpretation of model-based summaries of population haplotypes. Haploscope is designed to accept haplotype frequency input directly from output files of fastPHASE (Scheet & Stephens, 2006), though output from other cluster-based models for population haplotypes could be adapted for input to Haploscope.. ::DEVELOPER. paul scheet lab. :: SCREENSHOTS. N/A. :: REQUIREMENTS. ...
mtDNA is usually treated as a non-recombining locus, and so it should evolve along a tree. A rooted global tree has therefore been produced for humans, based on parsimony analysis of the mtDNA genome (Torroni et al. 2000; van Oven and Kayser 2009). Groups and subgroups of this tree have been labelled as haplotypes, such as haplotype group M shown in the top figure, and sub-haplogroups, such as M4b, M49 and M61. These are (monophyletic) clades in the mtDNA tree that have been highlighted for convenience. Parsimony analysis has been used to reconstruct the ancestral sequences in the tree (Behar et al. 2012), and these ancestral sequences can be used to assign new sequences to their appropriate place in the rooted tree (Blanco et al. 2011 ...
mtDNA is usually treated as a non-recombining locus, and so it should evolve along a tree. A rooted global tree has therefore been produced for humans, based on parsimony analysis of the mtDNA genome (Torroni et al. 2000; van Oven and Kayser 2009). Groups and subgroups of this tree have been labelled as haplotypes, such as haplotype group M shown in the top figure, and sub-haplogroups, such as M4b, M49 and M61. These are (monophyletic) clades in the mtDNA tree that have been highlighted for convenience. Parsimony analysis has been used to reconstruct the ancestral sequences in the tree (Behar et al. 2012), and these ancestral sequences can be used to assign new sequences to their appropriate place in the rooted tree (Blanco et al. 2011 ...
A new type of insertion flanked by long stretches of TA repeats, hence named TAFTs for TA-flanked transposons, was discovered during the course of this investigation. TAFTs have the following properties. (i) They are flanked by TA microsatellites with as many as 50 copies of the TA repeat on either side of the insertion. (ii) The corresponding vacant site in haplotypes that lack TAFTs consists generally of a few (three or four) copies of the TA repeat, but there are exceptions. (iii) The elements identified so far possess imperfect TIRs of ≈40 bp and are relatively large (,2 kb). (iv) Related copies are found at other locations in the maize genome, where they are also flanked by TA repeats.. The TAFT1 element in CML258 and Coroico is 2.2-kb long and is flanked on either side by multiple copies of TA. The vacant site in the other haplotypes has three copies of the TA dinucleotide. TAFT1 is 85% identical to oligo-TA flanked sequences of similar length that occur in B73 locus 9009 (GenBank ...
The goal of this study was to determine whether variants associated with age at onset of CFRD affected the expression of SLC26A9. We discovered that the alleles of the CFRD-risk variants are coinherited as 2 common haplotypes, one that is associated with later onset of CFRD (LR), and another that is associated with earlier onset of CFRD (HR). A third less common haplotype similar to HR was also associated with earlier onset of diabetes, and it is possible that other, less common, haplotypes bearing the majority of the CFRD-risk variants also correlate with CFRD, but are not sufficiently frequent to allow detection of association in the 762 individuals studied here. There was no evidence that a coding or rare variant accounted for the CFRD association. Mapping of the major TSS indicated that the noncoding first exon of SLC26A9 was placed in the middle of the cluster of CFRD-risk variants in the 5′ region of SLC26A9. These results suggested that the HR and LR CFRD haplotypes affect ...
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Twenty four CML-patients, 22 (91.7%) with chronic phase and 2 (8.3%) under blast crisis, were studied. Thirteen (54.2%) were males, and 11 (45.8%) were females. The Sokal risk was low in 7 (29.2%), intermediate in 7 (29.2%), high in 6 (25%), and not evaluated in 4 (16.6%). Age, gender, phase of disease, TKI treatment and doses, molecular responses (at 6, 12, and 18 months) and haplotypes are listed in Table 1.. A total of seventeen different haplotypes were identified in CML-patients and controls. The frequency distribution indicates that 6 were only detected in CML-patients, 7 only in controls, and 4 in both groups. Heterozygous T-variant genotypes were observed in all 25 controls (100%), and in 18 CML-patients (75%). In this last group, 9 different T-variant haplotypes were identified as follows: full mutated-homozygote (TT-TT-TT) in 3 (12.5%), full mutated-heterozygous (CT-GT/A-CT) in 6 (25%), and other combinations of T-variants in 9 cases (37.5%). The remaining 6 (25%) CML-patients were ...
Recent advances in RNA sequencing technology can generate deep coverage data containing millions of reads. RNA-Seq data are used to identify genetic variants and alternatively spliced isoforms, a common mechanism for diversity in a gene, that may play a role in heritable traits and diseases. Using this type of data, connections can be drawn between genetic expression and one of the two parental haplotypes identified in a diploid organisms transcript. In other words, we can potentially identify the parent from which an individual inherited a group of genes.. These multi-kilobase reads are longer than most transcripts and enable sequencing of complete haplotype isoforms. New computational methods are required for efficient analysis of this highly complex data. In a recent paper, we present HapIso (Haplotype-specific Isoform Reconstruction), a comprehensive method that can accurately reconstruct the haplotype-specific isoforms of a diploid cell. Our software package is the first method capable of ...
Increasing phylogenetic resolution of the Y chromosome haplogroup tree has led to finer temporal and spatial resolution for studies of human migration. Haplogroup T, initially known as K2 and defined by mutation M70, is found at variable frequencies across West Asia, Africa, and Europe. While several SNPs were recently discovered that extended the length of the branch leading to haplogroup T, only two SNPs are known to mark internal branches of haplogroup T. This low level of phylogenetic resolution has hindered studies of the origin and dispersal of this interesting haplogroup, which is found in Near Eastern non-Jewish populations, Jewish populations from several communities, and in the patrilineage of President Thomas Jefferson. Here we map 10 new SNPs that, together with the previously known SNPs, mark 11 lineages and two large subclades (T1a and T1b) of haplogroup T. We also report a new SNP that links haplogroups T and L within the major framework of Y chromosome evolution. Estimates of the ...
Increasing phylogenetic resolution of the Y chromosome haplogroup tree has led to finer temporal and spatial resolution for studies of human migration. Haplogroup T, initially known as K2 and defined by mutation M70, is found at variable frequencies across West Asia, Africa, and Europe. While several SNPs were recently discovered that extended the length of the branch leading to haplogroup T, only two SNPs are known to mark internal branches of haplogroup T. This low level of phylogenetic resolution has hindered studies of the origin and dispersal of this interesting haplogroup, which is found in Near Eastern non-Jewish populations, Jewish populations from several communities, and in the patrilineage of President Thomas Jefferson. Here we map 10 new SNPs that, together with the previously known SNPs, mark 11 lineages and two large subclades (T1a and T1b) of haplogroup T. We also report a new SNP that links haplogroups T and L within the major framework of Y chromosome evolution. Estimates of the ...
Mitochondrial DNA haplotypes from the displacement-loop (D-loop) region (436 bp) were genotyped and sequenced in Japanese Black beef cattle raised in the same herd. Correlation coefficients between mitochondrial DNA haplotypes, maternal lineage, birth weight, preweaning average daily gain, weaning weight, post weaning average daily gain and yearling weight were computed. The objective was to study the relationship between maternal and postnatal growth traits and to investigate if postnatal growth of calves to yearling age could be accurately predicted from mitochondrial DNA haplotypes. Results of the phylogenetic analysis revealed 17 maternal lineages and four mitochondrial DNA haplotypes. There were strong, positive and highly significant (p,0.001) correlations among maternal traits ranging from 0.52 to 0.98. Similarly, among postnatal growth traits, most of the correlations were also strong, positive and highly significant (p,0.001); the highest correlation of 0.94 was between preweaning ...
In this large prospective study of a general population of Northern European descent, no evidence was found for consistent and robust associations between mitochondrial haplogroups and risk of ischemic cardiovascular disease, morbidity from other causes, or mortality. In contrast, several smaller case-control studies have shown associations between mitochondrial haplogroups and myocardial infarction, cerebral infarction, cancer, diabetes mellitus, and neurodegenerative diseases.18-36. The Asian N9b haplogroup (defined by polymorphisms at positions mt5147 and mt16519) has been reported to protect against myocardial infarction in Japanese men (odds ratio [95% CI], 0.2 [0.1 to 0.5]; 920 cases/522 controls) but not in Japanese women (695 cases/434 controls).19 It has been speculated that this reduction in risk of myocardial infarction could be due to a reduction in the production of superoxide and other reactive oxygen species associated with this particular haplogroup19 that thus might confer ...
From previous studies, it is known that the low OA risk haplogroup J is associated with lower serum levels of markers of collagen type-II degradation and of matrix metalloproteinases, but all of these studies failed to address the key question arising from this large body of evidence: What is the functional role of these mtDNA haplogroups?. To answer this question, Fernandez-Moreno et al7 used cytoplasmic hybrid (cybrid) cell lines. Cybrids incorporate mitochondria from human subjects and perpetuate the mtDNA-encoded components while maintaining the nuclear background of different cybrid lines as constant.16 Thus, this technique allows investigators to assess the influence of mtDNA variation on cell function. To investigate the role of mtDNA haplogroups, they also created cybrids using osteosarcoma cell lines with the same nuclear background, one of them harbouring the haplogroup J (which protects against OA) and another harbouring the haplogroup H (linked to higher risk of OA).. The cybrids ...
Haplogroup L1 is believed to have appeared approximately 110,000 to 170,000 years ago.[citation needed] Haplogroup L1 is a daughter of L1-6 and genetic marker changes are 3666, 7055, 7389, 13789, 14178 and 14560. Although it is typically used to denote a group of lineages found within Africa, L1 is sometimes referred to as haplogroup L1-6. The latter is the macrohaplogroup that includes the majority of Africa-based clades and all haplogroups centered outside of the continent. Haplogroup L1-6 is the macrohaplogroup that includes subclades L1, L2, L4, L5, L6, and also L3, which gave rise to the two non-African haplogroups M and N. Haplogroup L1-6 and its only sibling haplogroup L0 are united by the matrilineal most recent common ancestor, (MRCA) of all living humans, Mitochondrial Eve. The existence of these two lineages, implies that Mitochondrial Eve had at least two daughters, one of whom is the maternal common ancestor of haplogroup L1-6 lineages.[citation needed] ...
Effective identification of disease-causing gene locations can have significant impact on patient management decisions that will ultimately increase survival rates and improve the overall quality of health care. Linkage disequilibrium mapping is the process of finding disease gene locations through comparisons of haplotype frequencies between disease chromosomes and normal chromosomes. This work presents a new method for linkage disequilibrium mapping. The main advantage of the proposed algorithm, called LinkageTracker, is its consistency in producing good predictive accuracy under different conditions, including extreme conditions where the occurrence of disease samples with the mutation of interest is very low and there is presence of error or noise. We compared our method with some leading methods in linkage disequilibrium mapping such as HapMiner, Blade, GeneRecon, and Haplotype Pattern Mining (HPM). Experimental results show that for a substantial class of problems, our method has good predictive
TY - JOUR. T1 - Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population. AU - Liu, Jixia. AU - Shi, Yongyong. AU - Tang, Wei. AU - Guo, Tingwei. AU - Li, Dawei. AU - Yang, Yifeng. AU - Zhao, Xinzhi. AU - Wang, Hongsheng. AU - Li, Xingwang. AU - Feng, Guoyin. AU - Gu, Niufan. AU - Zhu, Shaomin. AU - Liu, Huijun. AU - Guo, Yangling. AU - Shi, Jianguo. AU - Sang, Hong. AU - Yan, Lijuan. AU - He, Lin. N1 - Funding Information: We are grateful to all the participants as well as the psychiatrists and mental health workers working on this project. This work was supported by grants from the Ministry of Education, PRC, the national 973 and 863 Programs of China, the National Natural Science Foundation of China, and the Shanghai Municipal Commission for Science and Technology. PY - 2005/9/2. Y1 - 2005/9/2. N2 - A converging body of evidence implicates the γ-amino butyric acid neurotransmitter system in the pathogenesis of ...
We had previously found that 6-month survival in sepsis patients was significantly associated with platelet COX quantity [4]. However, 1-month survival is a more frequently used parameter in critically ill patients; and we have found that this parameter is also significantly associated with platelet COX quantity. We had previously observed that COX levels can be determined by mtDNA genetic background [6], and other investigators showed that mtDNA haplogroups modified 6-month survival [9]. Here we show that the mtDNA haplogroup determines the platelet COX quantity in sepsis patients and that those patients from the JT mtDNA haplogroup had higher survival rate than those from other mtDNA haplogroups.. The JT mtDNA haplogroup is defined by polymorphisms in nucleotide positions m.4216T , C/MT-ND1, m.11251A , G/MT-ND4, m.15452C , A/MT-CYB and m.16126T , C/MT-DLOOP. The last polymorphism is located in the control region, out of any important sequence for the regulation of mtDNA replication and ...
BACKGROUND:Cholesterol 7-alpha-hydroxylase (CYP7A1) is the rate limiting enzyme for converting cholesterol into bile acids. Genetic variations in the CYP7A1 gene have been associated with metabolic disorders of cholesterol and bile acids, including hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and gallstone disease. Current genetic studies are focused mainly on analysis of a single nucleotide polymorphism (SNP) at A-278C in the promoter region of the CYP7A1 gene. Here we report a genetic approach for an extensive analysis on linkage disequilibrium (LD) blocks and haplotype structures of the entire CYP7A1 gene and its surrounding sequences in Africans, Caucasians, Asians, Mexican-Americans, and African-Americans.RESULT:The LD patterns and haplotype blocks of CYP7A1 gene were defined in Africans, Caucasians, and Asians using genotyping data downloaded from the HapMap database to select a set of haplotype-tagging SNPs (htSNP). A low cost, microarray-based platform on thin-film ...
To determine the genetic architecture of trout in Albania, 87 individuals were collected from 19 riverine and lacustrine sites in Albania, FYROM and Greece. All individuals were analyzed for sequence variation in the mtDNA control region. Among fourteen haplotypes detected, four previously unpublished haplotypes, bearing a close relationship to haplotypes of the Adriatic and marmoratus lineages of Salmo trutta, were revealed. Ten previously described haplotypes, characteristic of S. ohridanus, S. letnica and the Adriatic and Mediterranean lineages of S. trutta, were also detected. Haplotypes detected in this study were placed in a well supported branch of S. ohridanus, and a cluster of Mediterranean - Adriatic - marmoratus haplotypes, which were further delimited into three subdivisions of Mediterranean, marmoratus, and a previously non-described formation of four Adriatic haplotypes (Balkan cluster). Haplotypes of the Balkan cluster and the other Adriatic haplotypes, do not represent a contiguous
This study is to survey 10 Y-STR loci in 241 males from Turkey. In this study, the 241 healthy and unrelated males living in different parts of Turkey for at least three generations were included. Genomic DNAs were isolated from peripheral blood samples by standard phenol-chloroform extraction method. 10 Y-STR loci including DYS19, DYS385a/b, DYS388, DYS389I/II, DYS390, DYS391, DYS392, DYS393, and YCAIIa/b were analyzed by using PCR and denaturing PAGE. Allele frequencies, gene diversities and haplotype frequencies were analyzed. Gene diversity per locus varied from 0.5788 (DYS388) to 0.8903 (DYS385a/b). The numbers of haplotypes in minHt recommended by YCC and Ht10 have been 208 and 186, respectively. When our minHt haplotypes frequencies compared with the other seven populations, we have found statistically significant differences between our results and other populations (P 0.05). We suggest that an alternative haplotype designated as aHt maybe alternative to minHt in respect of its Y-STR
Human 12/15-lipoxygenase (ALOX15) catalyzes the oxidation of polyunsaturated fatty acids and has been implicated in the pathogenesis of atherosclerosis. We previously reported that a common haplotype of the ALOX15 gene is associated with higher prevalence of coronary artery calcification in a cohort of middle-aged African-Americans. This haplotype was uniquely tagged by a promoter variant (rs2255888). We carried out an in vitro characterization of this promoter variant to further investigate regulatory mechanisms of the ALOX15 gene. We evaluated the activity of ALOX15 variant A-carrying and wild type G-carrying promoter haplotypes using a luciferase assay. We demonstrated a 65% higher activity of the A-carrying promoter haplotype as compared to the G-carrying promoter haplotype. Using mass-spectrometry and electrophoretic mobility shift assay we showed that vimentin, a structural protein, specifically binds to both A-carrying and G-carrying promoter haplotypes in vitro. However, the A ...
Eight Y-chromosome STRs were investigated in a male population sample from Córdoba region (Argentina). Complete Y-chromosomal STRs haplotypes were obtained in 100 individuals, among which 91 different haplotypes were observed. The most common haplotype was shared by 4% of the sample, while 86 haplotypes were unique. The gene diversity was 0.9875 and the discrimination capacity was 0.8600. The combined polymorphism provides a powerful discrimination tool for routine forensic applications.
Holyoake, A. J., McHugh, Patrick C, Wu, M., OCarroll, S., Benny, P., Sin, I. L. and Sin, F. Y. T. (2002) Research of single mitochondrial nucleotide substitutions in male infertility should consider human mitochondrial haplogroups - Reply. International Journal of Andrology, 25 (6). p. 374. ISSN 0105-6263 Metadata only available from this repository ...
Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10-4, permutation p = 1.0×10-3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 ...
Little is known about the extent of allelic diversity of genes in the complex polyploid, sugarcane. Using sucrose phosphate synthase (SPS) Gene (SPS) Family III as an example, we have amplified and sequenced a 400 nt region from this gene from two sugarcane lines that are parents of a mapping population. Ten single nucleotide polymorphisms (SNPs) were identified within the 400 nt region of which seven were present in both lines. In the elite commercial cultivar Q165A, 10 sequence haplotypes were identified, with four haplotypes recovered at 9% or greater frequency. Based on SNP presence, two clusters of haplotypes were observed. In IJ76-514, a Saccharum officinarum accession, 8 haplotypes were identified with 4 haplotypes recovered at 13% or greater frequency. Again, two clusters of haplotypes were observed. The results suggest that there may be two SPS Gene Family III genes per genome in sugarcane, each with different numbers of different alleles. This suggestion is supported by sequencing results in
t haplotypes are naturally occurring, variant forms of the t complex on mouse chromosome 17, characterized by the presence of four inversions with respect to wild-type. They harbour mutations causing male sterility, male transmission ratio distortion (TRD) and embryonic lethality. Mice carrying t haplotypes have been found throughout the world, and genetic studies of the lethal mutations have identified at least 16 complementation groups. The embryonic lethal phenotypes of many t haplotypes have been characterized in detail, and are thought to be the consequence of homozygosity for single gene mutations. However, the existence of additional mutations in genes that function at later stages of development would be obscured. Here we investigated the possibility of multiple mutations in t haplotypes by screening the t(w73) haplotype for the presence of novel mutations. Since genetic analysis of t haplotype mutations is hindered by recombination suppression due to the inversions, deletion
The importance of haplotype association and gene-environment interactions (GxE) in the context of rare variants has been underlined in voluminous literature. Recently, a software based on logistic Bayesian LASSO (LBL) was proposed for detecting GxE, where G is a rare (or common) haplotype variant (rHTV)-it is called LBL-GxE. However, it required relatively long computation time and could handle only one environmental covariate with two levels. Here we propose an improved version of LBL-GxE, which is not only computationally faster but can also handle multiple covariates, each with multiple levels. We also discuss details of the software, including input, output, and some options. We apply LBL-GxE to a lung cancer dataset and find a rare haplotype with protective effect for current smokers. Our results indicate that LBL-GxE, especially with the improvements proposed here, is a useful and computationally viable tool for investigating rare haplotype interactions ...
Genetic results also include the Y-STR haplotype, the set of results from the Y-STR markers tested. Unlike the UEPs, the Y-STRs mutate much more easily, which allows them to be used to distinguish recent genealogy. But it also means that, rather than the population of descendants of a genetic event all sharing the same result, the Y-STR haplotypes are likely to have spread apart, to form a cluster of more or less similar results. Typically, this cluster will have a definite most probable center, the modal haplotype (presumably similar to the haplotype of the original founding event), and also a haplotype diversity - the degree to which it has become spread out. The further in the past the defining event occurred, and the more that subsequent population growth occurred early, the greater the haplotype diversity will be for a particular number of descendants. However, if the haplotype diversity is smaller for a particular number of descendants, this may indicate a more recent common ancestor, or a ...
We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting ...
As resistance to insecticides increases in disease vectors, it has become exceedingly important to monitor populations for susceptibility. Most studies of field populations of Aedes aegypti have largely characterized resistance patterns at the spatial scale of the city or country, which may not be completely informative given that insecticide application occurs at the scale of the house or city block. Phenotypic resistance to pyrethroids dominates in Ae. aegypti, and it has been partially explained by mutations in the voltage-gated sodium channel gene. Here, we assess community-level patterns of four knockdown resistance (kdr) haplotypes (C1534/I1016, F1534/I1016, C1534/V1016 and F1534/V1016) in Ae. aegypti in 24 randomly chosen city blocks from a city in Yucatán State, Mexico, during both the dry and wet season and over two years. Three of the four haplotypes, C1534/I1016, C1534/V1016 and F1534/V1016 were heterogeneous between city blocks at all four sampling time points, and the double mutant
Genotype imputation is the process of predicting unobserved genotypes in a sample of individuals using a reference panel of haplotypes. In the last 10 years reference panels have increased in size by more than 100 fold. Increasing reference panel size improves accuracy of markers with low minor allele frequencies but poses ever increasing computational challenges for imputation methods. Here we present IMPUTE5, a genotype imputation method that can scale to reference panels with millions of samples. This method continues to refine the observation made in the IMPUTE2 method, that accuracy is optimized via use of a custom subset of haplotypes when imputing each individual. It achieves fast, accurate, and memory-efficient imputation by selecting haplotypes using the Positional Burrows Wheeler Transform (PBWT). By using the PBWT data structure at genotyped markers, IMPUTE5 identifies locally best matching haplotypes and long identical by state segments. The method then uses the selected haplotypes as
A background study is important for the conservation and stock management of a species. Terapon jarbua is a coastal Indo-Pacific species, sourced for human consumption. This study examined 134 samples from the central west and east coasts of Peninsular (West) Malaysia and East Malaysia. A 1446-bp concatenated dataset of mtDNA COI and Cyt b sequences was used in this study and 83 haplotypes were identified, of which 79 are unique haplotypes and four are shared haplotypes. Populations of T. jarbua in Malaysia are genetically heterogenous as shown by the high level of haplotype diversity ranging from 0.9167-0.9952, low nucleotide diversity ranging from 0.0288-0.3434, and high FST values (within population genetic variation). Population genetic structuring is not distinct as shown by the shared haplotypes between geographic populations and mixtures of haplotypes from different populations within the same genetic cluster. The gene flow patterns and population structuring observed among these regions are
Because 4 of the 13 genes identified in the single SNP serous analysis contained multiple candidate SNPs, we carried out haplotype analyses to better understand the patterns of risk in these genes. CDK6 haplotypes of the 4 SNPs (rs2282990, rs3731348, rs17690388, and rs2282983) were suggestive of association with risk of serous invasive ovarian cancer (global haplotype association P = 0.0034; Supplementary Table S5a). The first CDK6 risk haplotype was perfectly tagged by the minor allele (A) of rs17690388 and was associated with a decrease in risk of serous ovarian cancer (OR = 0.63, 95% CI: 0.40-0.99; P = 0.044). The second CDK6 risk haplotype captured the minor alleles of rs2282990 (T) and rs2282983 (C) and the major allele at rs3731348 (G) and was associated with an increase in serous ovarian cancer risk (OR = 2.42, 95% CI: 1.30-4.50; P = 0.0054). SIK3 and TEX14 each contained haplotypes associated with risk of serous ovarian cancer that were captured by variation at single SNPs (Supplementary ...
Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Abstract Genetic studies of the distribution of mitochondrial DNA (mtDNA) haplogroups in human populations residing within the Carpathian Mountain range have been scarce. We present an analysis of mtDNA haplogroup composition of the Boykos, Hutsuls, and Lemkos, three population groups of the Carpathian highlands. In our study Hutsuls had the highest frequency of subhaplogroup H1 in central and eastern Europe. Lemkos shared the highest frequency of haplogroup I ever reported and the highest frequency of haplogroup M* in the region. MtDNA haplogroup frequencies in Boykos were different from most modern European populations. We interpreted these unique mtDNA frequencies to be evidence of diverse and dynamic population histories in the Carpathian highland region. ...
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G,A-codon214 AC(C/T) haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the ...
The Y chromosome has recently been suggested to have an association with prostate cancer risk in human populations. Since this chromosome is haploid and lacks recombination over most of its length, haplotypes constructed from binary markers throughout the chromosome can be used for association studies. To assess the possible Y-chromosomal contribution to prostate cancer risk, we have therefore analyzed 14 Y-chromosomal binary markers in 106 prostate cancer cases and 110 controls from the Korean population. In contrast to previous findings in the Japanese population, no statistically significant difference in the distribution of Y-chromosomal haplogroup frequencies was observed between the case and control groups of Koreans. Thus, our data imply that the previously reported associations between Y-chromosomal lineages and a predisposition to, or protection against, prostate cancer might be explained by statistical fluctuations, or by genetic effects that are seen only in some environments.
Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (-251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (-251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, -251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype,
Single Nucleotide Polymorphism (SNP) information has enabled the use of linkage disequilibrium to detect and localize loci affecting phenotypes. The first methods developed searched for disequilibrium between one or a few marker loci and loci responsible for disease susceptibility. Case-control designs were used [1]. Typically, data were analyzed to compare the frequency of marker alleles between healthy and diseased individuals, for instance using the relative risk criterion [2]. A similar approach for quantitative traits (including production traits in animals or plants) was to model the expectation of their distribution as a linear combination of marker genotype, allele or haplotype effects. Grapes et al. [3] and Zhao et al. [4] demonstrated that the single marker regression model is as powerful and precise as other more sophisticated techniques, such as multiple regression, regression on haplotypes, or the IBD method proposed by Meuwissen and Goddard [5].. Detection of spurious associations ...
Phylogeny estimation from aligned haplotype sequences has attracted more and more attention in the recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from medical research, to drug discovery, to epidemiology, to population dynamics. The literature on molecular phylogenetics proposes a number of criteria for selecting a phylogeny from among plausible alternatives. Usually, such criteria can be expressed by means of objective functions, and the phylogenies that optimize them are referred to as optimal. One of the most important estimation criteria is the parsimony which states that the optimal phylogeny T∗for a set of n haplotype sequences over a common set of variable loci is the one that satisfies the following requirements: (i) it has the shortest length and (ii) it is such that, for each pair of
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Results: In this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure ...
We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
Background: The haplotypes of the X chromosome are accessible to direct count in males, whereas the diplotypes of the females may be inferred knowing the haplotype of their sons or fathers. Here, we investigated: 1) the possible large-scale haplotypic structure of the X chromosome in a Caucasian population sample, given the single-nucleotide polymorphism ( SNP) maps and genotypes provided by Illumina and Affimetrix for Genetic Analysis Workshop 14, and, 2) the performances of widely used programs in reconstructing haplotypes from population genotypic data, given their known distribution in a sample of unrelated individuals. Results: All possible unrelated mother-son pairs of Caucasian ancestry ( N = 104) were selected from the 143 families of the Collaborative Study on the Genetics of Alcoholism pedigree files, and the diplotypes of the mothers were inferred from the X chromosomes of their sons. The marker set included 313 SNPs at an average density of 0.47 Mb. Linkage disequilibrium between ...
Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G , T (rs3745274), 785 A , G (rs2279343) and 983 T , C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adaptation of detoxifying ...
Single nucleotide polymorphisms (SNPs) are important markers which can be used in association studies searching for susceptible genes of complex diseases. High-throughput methods are needed for SNP genotyping in a large number of samples. In this study, we applied polyacrylamide gel-based microarray combined with dual-color hybridization for association study of four BDNF polymorphisms with autism. All the SNPs in both patients and controls could be analyzed quickly and correctly. Among four SNPs, only C270T polymorphism showed significant differences in the frequency of the allele (χ2 = 7.809, p = 0.005) and genotype (χ2 = 7.800, p = 0.020). In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (χ2 = 28.19,p = 3.44e-005). We suggest that BDNF has a possible role in the pathogenesis of autism. The study also show that the polyacrylamide gel-based microarray combined with dual-color hybridization is a rapid, simple and high
The t-haplotype is a chromosomal region in Mus musculus characterized by meiotic drive such that heterozygous males transmit t-bearing chromosomes to roughly 90% of their offspring. Most naturally occurring t-haplotypes express a recessive embryonic lethality, preventing fixation of the t-haplotype. Surprisingly, the t-haplotype occurs in nature as a persistent, low-frequency polymorphism. Early modeling studies led LEWONTIN to hypothesize that this low level polymorphism results from a balance between genetic drift in small demes and interdemic migration. Here, we show that while combination of deme size and migration rate that predict natural t-haplotype frequencies exist, the range of such values is too narrow to be biologically plausible, suggesting that small deme size and interdemic migration alone do not explain the observed t-haplotype frequencies. In response, we tested other factors that might explain the observed t-polymorphism. Two led to biologically plausible models: substantially reduced
In 2006, Laoise T. Moore and the folks at Trinity College in Dublin published a paper famous for identifying the modal haplotype of Irish High King Niall of the Nine Hostages. In their work, they used seventeen Y-DNA STR markers. While time to most recent common ancestor (TMRCA) calculations have accuracy issues, having only 17 markers gives a common ancestor over 2,000 years ago. What the Trinity folks really accomplished was the identification of Nialls paternal ancestor from over 400 years earlier. The media in 2006 had a field day in their interpretation that most of Ireland is descended from Niall. Niall may be the most prolific male in Irish history. Also at 17 markers, there is a very high probability of convergence. Through normal mutations, haplotypes can change over time to appear similar or identical to other haplotypes. The lower the number of markers, the higher the chance of convergence. At that time only high level SNPs were tested to determine haplogroup. Without terminal SNPs ...
In 2006, Laoise T. Moore and the folks at Trinity College in Dublin published a paper famous for identifying the modal haplotype of Irish High King Niall of the Nine Hostages. In their work, they used seventeen Y-DNA STR markers. While time to most recent common ancestor (TMRCA) calculations have accuracy issues, having only 17 markers gives a common ancestor over 2,000 years ago. What the Trinity folks really accomplished was the identification of Nialls paternal ancestor from over 400 years earlier. The media in 2006 had a field day in their interpretation that most of Ireland is descended from Niall. Niall may be the most prolific male in Irish history. Also at 17 markers, there is a very high probability of convergence. Through normal mutations, haplotypes can change over time to appear similar or identical to other haplotypes. The lower the number of markers, the higher the chance of convergence. At that time only high level SNPs were tested to determine haplogroup. Without terminal SNPs ...
Networks of STR haplotypes based on penta- and hexanucleotide STRs, with and without SNPs.Median joining networks of Y chromosome STR haplotypes with balanced s
2: 42%, VKORC1*3: 38%, and VKORC1*4: 20%), which were in complete linkage disequilibrium. These haplotypes were further subdivided by additional polymorphisms. Haplotype VKORC1*2 includes a SNP in the promoter region (c.-1639G>A, dbSNP:rs17878363 that was identified as a marker for low dose warfarin requirement.. In a cohort of 50 consecutive patients without mutations in the VKORC1 coding region who presented with phenotypes of either increased coumarin sensitivity or partial coumarin resistance we found a strong association of VKORC1 haplotypes and the observed phenotype. 93% of patients with increased coumarin sensitivity but none of patients with partial coumarin resistance were found to be homozygous for VKORC1*2. Vice versa, non VKORC1*2 haplotypes were found homozygous in 86% of patients with partial coumarin resistance but in none of patients with increased coumarin sensitivity.. The VKORC1*2 haplotype also explains inter-ethnic differences in coumarin requirement. Haplotype analysis ...