Estimated Haplotype Frequencies Research Articles

Genetic epidemiology of lymphatic filariasis in American Samoa after mass drug administration

Over 892 million people in 48 countries are at risk of infection by nematodes that cause lymphatic filariasis. As part of the Global Programme to Eliminate Lymphatic Filariasis, mass drug administration is distributed to communities until surveillance indicates infection rates are below target prevalence thresholds. In some countries, including American Samoa, lymphatic filariasis transmission persists despite years of mass drug administration and/or has resurged after cessation. Nothing is known about the population genetics of Wuchereria bancrofti worms in Polynesia, or whether local transmission is persisting and/or increasing due to inadequate mass drug administration coverage, expansion from residual hotspots, reintroduction from elsewhere, or a combination. We extracted DNA from microfilariae on blood slides collected during prevalence surveys in 2014 and 2016, comprising 31 pools of five microfilariae from 22 persons living in eight villages. We sequenced 1104 bp across three mitochondrial markers (ND4, COI, CYTB). We quantified parasite genetic differentiation using variant calls and estimated haplotypes using principal components analysis, F-statistics, and haplotype networks. Of the variants called, all but eight were shared across the main island of Tutuila, and three of those were from a previously described hotspot village, Fagali’i. Genotypic data did not support population genetic structure among regions or villages in 2016, although differences were observed between worms collected in Fagali’i in 2014 and those from 2016. Because estimated haplotype frequency varied between villages, these statistics suggested genetic differentiation, but were not consistent among villages. Finally, haplotype networks demonstrated American Samoan sequence clusters were related to previously published sequences from Papua New Guinea. These are, to our knowledge, the first reports of W. bancrofti genetic variation in Polynesia. The resurgent parasites circulating on the main island of American Samoa represent a single population. This study is the first step towards investigating how parasite population structure might inform strategies to manage resurgence and elimination of lymphatic filariasis.

High resolution allele genotyping and haplotype frequencies for NGS based HLA 11 loci of 5266 Hong Kong Chinese bone marrow donors

Next-generation sequencing (NGS) at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 loci was performed on 5,266 southern Chinese unrelated donors of the Hong Kong Bone Marrow Donor Registry. High-resolution HLA genotypes defined by full sequencing of class I loci and extended coverage of class II loci were attained to determine allele frequencies and estimate haplotype frequencies. This study provides allele and haplotype frequencies on 11 loci estimated for the first time in the Hong Kong Chinese population. These results describe extended haplotypes including the less frequently typed HLA-DPA1, -DPB1 and -DQA1 loci and distinctive haplotype associations. The present data are timely in that they allow the permissible matching in HLA-DPB1 for Chinese patients awaiting haematopoietic stem cell transplantation upon applying the latest requirement of NMDP matching guidelines. Overall, these results provide a useful reference source for population genetics studies, HLA-disease association studies and for improving donor recruitment and selection strategies of bone marrow registries. The allele and haplotype data are available in the Allele Frequencies Net Database under the population name ‘‘Hong Kong Chinese HKBMDR, HLA 11 loci’’ and the identifier (AFND3724) [1].

Two Synthetic 18-Way Outcrossed Populations of Diploid Budding Yeast with Utility for Complex Trait Dissection.

Advanced-generation multiparent populations (MPPs) are a valuable tool for dissecting complex traits, having more power than genome-wide association studies to detect rare variants and higher resolution than F2 linkage mapping. To extend the advantages of MPPs in budding yeast, we describe the creation and characterization of two outbred MPPs derived from 18 genetically diverse founding strains. We carried out de novo assemblies of the genomes of the 18 founder strains, such that virtually all variation segregating between these strains is known, and represented those assemblies as Santa Cruz Genome Browser tracks. We discovered complex patterns of structural variation segregating among the founders, including a large deletion within the vacuolar ATPase VMA1, several different deletions within the osmosensor MSB2, a series of deletions and insertions at PRM7 and the adjacent BSC1, as well as copy number variation at the dehydrogenase ALD2 Resequenced haploid recombinant clones from the two MPPs have a median unrecombined block size of 66 kb, demonstrating that the population is highly recombined. We pool-sequenced the two MPPs to 3270× and 2226× coverage and demonstrated that we can accurately estimate local haplotype frequencies using pooled data. We further downsampled the pool-sequenced data to ∼20-40× and showed that local haplotype frequency estimates remained accurate, with median error rates 0.8 and 0.6% at 20× and 40×, respectively. Haplotypes frequencies are estimated much more accurately than SNP frequencies obtained directly from the same data. Deep sequencing of the two populations revealed that 10 or more founders are present at a detectable frequency for > 98% of the genome, validating the utility of this resource for the exploration of the role of standing variation in the architecture of complex traits.

German population data for 18 X-STRs: a hexaplex PCR adding two clusters of X-STRs to the Argus X-12 set and expanding the German haplotype databases.

In kinship analysis, large data sets with estimated haplotype frequencies for marker clusters are very important for the likelihood calculation. Practical use of the X-STRs demonstrated that in some complex kinship cases, the marker set of the Investigator Argus X-12 kit can be insufficient. This study aimed to extend the German data base of the Argus X-12 kit (1037 haplotypes) and for a cluster in Xq21 (806 haplotypes) with additional 700 male haplotypes and to include a further cluster in Xp22.3 to complete the X-STR marker set for complex kinship cases.

Distribution of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and haplotypes in Jingpo minority in Yunnan province of China

HLA-A, HLA-B, HLA-C, and HLA-DRB1 allele frequencies and estimated haplotype frequencies from 105 unrelated healthy Jingpo ethnic subjects who living in Dehong Dai-Jingpo Autonomous Prefectures, Yunnan Province, southwest China has been reported. HLA genes were genotyped by SSOP typing method using Luminex Multi-Analyte Profiling system. Jingpo ethnic nationality belongs to southern group of East Asians, but with its specific HLA alleles and haplotypes characteristic.

Estimation of German KIR Allele Group Haplotype Frequencies.

The impact of the highly polymorphic Killer-cell immunoglobulin-like receptor (KIR) gene cluster on the outcome of hematopoietic stem cell transplantation (HCST) is subject of current research. To further understand the involvement of this gene family into Natural Killer (NK) cell-mediated graft-versus-leukemia reactions, knowledge of haplotype structures, and allelic linkage is of importance. In this analysis, we estimate population-specific KIR haplotype frequencies at allele group resolution in a cohort of n = 458 German families. We addressed the polymorphism of the KIR gene complex and phasing ambiguities by a combined approach. Haplotype inference within first-degree family relations allowed us to limit the number of possible diplotypes. Structural restriction to a pattern set of 92 previously described KIR copy number haplotypes further reduced ambiguities. KIR haplotype frequency estimation was finally accomplished by means of an expectation-maximization algorithm. Applying a resolution threshold of ½ n, we were able to identify a set of 551 KIR allele group haplotypes, representing 21 KIR copy number haplotypes. The haplotype frequencies allow studying linkage disequilibrium in two-locus as well as in multi-locus analyses. Our study reveals associations between KIR haplotype structures and allele group frequencies, thereby broadening our understanding of the KIR gene complex.

Estimating linkage disequilibrium from genotypes under Hardy-Weinberg equilibrium

BackgroundMeasures of linkage disequilibrium (LD) play a key role in a wide range of applications from disease association to demographic history estimation. The true population LD cannot be measured directly and instead can only be inferred from genetic samples, which are unavoidably subject to measurement error. Previous studies of r2 (a measure of LD), such as the bias due to finite sample size and its variance, were based on the special case that the true population-wise LD is zero. These results generally do not hold for non-zero {r}_{true}^2 values, which are more common in real genetic data.ResultsThis work generalises the estimation of r2 to all levels of LD, and for both phased and unphased data. First, we provide new formulae for the effect of finite sample size on the observed r2 values. Second, we find a new empirical formula for the variance of the observed r2, equals to 2E[r2](1 − E[r2])/n, where n is the diploid sample size. Third, we propose a new routine, Constrained ML, a likelihood-based method to directly estimate haplotype frequencies and r2 from diploid genotypes under Hardy-Weinberg Equilibrium. While serving the same purpose as the pre-existing Expectation-Maximisation algorithm, the new routine can have better convergence and is simpler to use. A new likelihood-ratio test is also introduced to test for the absence of a particular haplotype. Extensive simulations are run to support these findings.ConclusionMost inferences on LD will benefit from our new findings, from point and interval estimation to hypothesis testing. Genetic analyses utilising r2 information will become more accurate as a result.

Variations in Interleukin-10 Gene Underlying Trypanotolerance in Nigerian Indigenous Cattle

This study looked into trypanotolerance as one of the interesting physiological traits of indigenous Nigerian cattle (Muturu) which has been well adapted to the tsetse infested zone of the middle belt and southern parts of Nigeria. Interleukin-10 gene amplification, sequencing and bioinformatics methods were applied to the genetic data of the Nigerian Muturu cattle to detect the genetic divergence that may be associated with trypanotolerance in the Muturu cattle as compared to the White Fulani cattle. Trypanosomosis in livestock and man is characterized by cellular changes and damages resulting in great loss in production and sometimes death. IL-10 has been implicated as a candidate gene in trypanotolerance in N’Dama. Thus, to uncover Muturu genetic signatures underlying trypanotolerance, this study compared variations in IL-10 gene of Muturu and White Fulani cattle. Variations in IL-10 gene (exon 1) were identified using DNA sequence polymorphism programme (DnaSP) version 5.10.01 to estimate haplotype frequencies, nucleotide diversity and sequence conservation. The results revealed twenty-four single nucleotide polymorphisms (SNPs) present in White Fulani while only one SNP was present in Muturu, showing that IL-10 gene was more conserved in the Muturu cattle. Eight haplotypes were present in exon 1 of IL-10 gene of White Fulani while that of Muturu was one. Three motifs were common to the two cattle breeds, while two others were found in White Fulani population alone. Prediction of secondary protein structure showed that the gene is a mixed folding protein in White Fulani while it is not in Muturu. The study concluded that the Muturu displayed clear genetic differences compared to White Fulani breed. SNPs (24) detected in White Fulani and one in Muturu could serve as useful marker for association studies with trypanotolerance while improvement of trypanotolerance in susceptible breeds can be achieved through gene manipulation using IL-10 gene.

Interleukin-1 single nucleotide polymorphisms and risk of systemic lupus erythematosus among Iraqi patients

Present case-control study explored the association between five single nucleotide polymorphisms (SNPs) of interleukin-1 (IL-1) gene family (IL1A−889; rs1800587, IL1B−511; rs16944, IL1B+3962; rs1143634, IL1Rpsti 1970; rs2234650 and IL1RAmspa 11,100; rs315952) and SLE. A sample of 103 Iraqi female patients and 113 healthy matched females were investigated. Serological testing revealed that 91.1 and 88.9% of patients were seropositive for anti-nuclear and anti-double-stranded DNA antibodies, respectively, while none of the control females were seropositive. Serum level of C3 (54 vs. 108 mg/dL) and C4 (5 vs. 21 mg/dL) showed a significant decreased median in patients compared to control. Inspecting IL1 gene SNPs demonstrated a significant increased frequency of IL1A−889C allele in patients compared to control (72.8 vs.56.0%, odds ratio = 1.94, 95% confidence interval = 1.30–2.91), while T allele frequency was significantly decreased (27.2 vs.42.0%). For IL1B−511, IL1B+3962, IL1Rpsti 1970 and IL1RAmspa 11,100 SNPs, allele and genotype frequencies showed no significant variation between patients and control. A significant two-locus linkage disequilibrium (LD) was recorded between IL1B−511 and IL1RAmspa 11,100 SNPs in SLE patients only (log of likelihood odds ratio = 5.69, correlation coefficient = 0.241, LD coefficient = 0.517). Five-locus haplotype frequency estimation revealed that CCCTC and CCTCT haplotypes were positively associated with SLE risk. It is concluded that IL1A−889 SNP is associated with susceptibility to SLE, while, IL1B−511, IL1B+3962, IL1Rpsti 1970 and IL1RAmspa 11,100 SNPs may have no influence on SLE risk. Specific allelic combinations (haplotypes) between the five SNPs may also have a susceptibility role in SLE.

Exploiting gene-environment independence in haplotype-based inferences for population-based case-control studies with complex sampling.

The use of complex sampling in population-based case-control studies is becoming more common. Although most single nucleotide polymorphism-based association studies with complex sampling account for the design complications, many of haplotype-based genetic association studies with complex sampling tend to ignore them when estimating haplotype frequencies, regression coefficients, or both. In this article, we develop innovative one-step and two-step statistical methods that account for the design complications in haplotype-based association studies when cases and/or controls are sampled with complex sampling. Attracted by the efficiency advantage of the retrospective method, we explore the assumptions of Hardy-Weinberg equilibrium and gene-environment independence in the underlying population. Results of our simulation studies demonstrate superior performance of the proposed methods over selected existing methods under various complex sampling designs. An application of the proposed methods is illustrated using a population-based case-control study of kidney cancer.

The mitochondrial DNA control region sequences from the Chinese Miao population of southeastern China

Background: Miao people are an officially recognised ethnic group living in southwest China, but have seldom been studied genetically, especially with respect to mtDNA data.Aim: To investigate the sequences and haplogroups of the mtDNA control region in a typical Miao population, with the aim of providing a good start for the expansion of the East Asian mtDNA reference database for forensic DNA analysis.Subjects and methods: We analysed 203 Miao individuals, looking at mtDNA control region sequences. We calculated and illustrated the haplotype frequencies, haplogroup distribution and pairwise Fst values between the Miao and six other worldwide populations to explore genetic polymorphisms and population relationships.Results: We observed 121 haplotypes with corresponding frequencies ranging from 0.0049 to 0.0690 in the Miao population. All the samples were assigned to 71 different haplogroups. The haplotype diversity and the random match probability were estimated to be 0.9844 and 0.0204, respectively. The pairwise Fst values and associated p values among seven populations suggest that the Miao population has significant differences to the other six populations, and is relatively isolated compared with them.Conclusions: Our results suggest that frequency estimates for mtDNA haplotypes in Miao ethnic groups should be determined independently rather than being pooled with other populations.

Sequencing of full mitochondrial genomes for NIST population samples

The U.S. National Institute of Standards and Technology in collaboration with the Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory has undertaken a population sequencing study of 607 mitochondrial genomes (mtGenomes). The goal of the study is to increase the availability of high-quality whole mtGenome sequences for haplotype frequency estimations, allowing the increased discrimination power of the entire extranuclear genome to be used. Whole mtGenome sequencing is enabled by next generation sequencing workflows, which are vastly simplified compared to Sanger-type sequencing. Here we evaluated the relative performance of mtGenome versus sequencing the control region of the mtGenome alone.

Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors.

Although HLA-DPB1 has long been considered of lesser importance in the selection of an unrelated donor (URD) hematologic stem cell transplantation, currently in many instances the DPB1 type of the donor is relevant or even critical. At present, however, only a minority of registry donors are DPB1 typed. It is also unclear to what extent the DPB1 alleles are linked to the 5-locus HLA-A-, B-, C-, DRB1, -DQB1 haplotypes. We sought to study whether there is such a linkage by using donors in the Finnish Stem Cell Registry as the study population. The 6-locus HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 haplotype frequencies were estimated from a group of 43,365 Finnish registry donors using the German National Bone Marrow Registry algorithm. Five-locus haplotype (HLA-A, -B, -C, -DRB1, -DQB1) and HLA-DPB1 allele frequencies were calculated as marginal frequencies of the estimated 6-locus haplotype frequencies. The Finnish average frequency of individual DPB1 alleles was compared with their respective frequencies in association with individual 5-locus HLA haplotypes (haplotype-specific frequencies). Finally, the probability of DPB1 matching in 10/10 matched URD transplants was assessed. Haplotype-specific DPB1 frequencies differed significantly from the average DPB1 frequencies in 81 of 100 most frequent Finnish 5-locus HLA haplotypes, including some infrequent DPB1 alleles that were associated almost exclusively with certain individual 5-locus haplotypes. Five-locus haplotypes that are enriched in Finland but rare among other Europeans carried stronger DPB1 associations than haplotypes that are frequent European-wide. Finally, 10/10 matched transplants from domestic registry donors were significantly more likely to also be DPB1 matched than those from foreign donors. The results indicate an extension of linkage disequilibrium in the MHC complex in the Finnish population. With continuing upfront DPB1 typing of registry donors, it will be possible to perform similar extended 6-locus haplotype frequency estimations also in other registries. The associations are likely to be population specific but may be weaker in more heterogeneous populations. In the future the results might be used to predict the probability of DPB1 match or permissive/nonpermissive DPB1 mismatch for non-DPB1 typed donors in registry donor searches.

Adiponectin (ADIPOQ) gene variants and haplotypes in Saudi Arabian women with polycystic ovary syndrome (PCOS): a case–control study

The aim of this study is to assess the association of nine SNPs on ADIPOQ on the PCOS risk among Saudi Arabian Women. A case–control study, including 162 cases and 162 controls in Saudi Arabia, was enrolled. Genotyping was carried out by the allelic discrimination method. Estimated haplotype frequencies were assessed using the maximum likelihood method. Results showed that ADIPOQ SNPs were not associated with PCOS for allelic and genotypic frequencies (p > .05). In haplotype estimation analysis, a significant positive association was detected between 21211 haplotype (rs2241766/rs1501299/rs2241767/rs3774261/rs17366743) in additive model with increased risk of PCOS (p = .009, OR = 2.16 [1.22–3.82] CI 95%). None of the nine SNPs illustrated significant association with the quantitative traits after multiple test corrections. These results support a significant association of 21211 haplotype (rs2241766/rs1501299/rs2241767/rs3774261/rs17366743) of ADIPOQ gene in Saudi women with polycystic ovary syndrome.

Y‐chromosome short tandem repeats in forensics—Sexing, profiling, and matching male DNA

AbstractThe analysis of short tandem repeat (STR) markers located on the Y chromosome is an established method in forensic casework analysis. Usually this method is applied in cases of male‐on‐female sexual assault, in which the victim's DNA is in great excess and masked the male contribution. Y‐STR analysis is able to detect the presence of minuscule amounts of male DNA of one or multiple donors and resulting genetic profiles can be compared to known reference samples. The expert has to determine whether the Y‐STR result of a trace is suitable for a biostatistical calculation in case of a match. The Discrete Laplace method which is implemented in the Y chromosome haplotype reference database (YHRD) can be used to estimate haplotype frequencies with a better approximation than other methods namely the counting method. Moreover, Y‐SNPs in combination with Y‐STRs can infer the biogeographical origin of an unknown male person with comparably high precision due to the availability of a robust phylogenetic tree and large reference data collections. Y‐based ancestry prediction and familial searching can, therefore, provide important investigative leads in crime cases without suspect.This article is categorized under: Forensic Biology > Haploid Markers Forensic Biology > Ancestry Determination using DNA Methods Forensic Biology > DNA Databases and Biometrics Forensic Biology > Forensic DNA Technologies

ULK1 polymorphisms confer susceptibility to pulmonary tuberculosis in a Chinese population.

The autophagy pathway is a critical process in Mycobacterium tuberculosis infection, and can be regulated by uncoordinated 51-like kinase 1 (ULK1). We investigated the associations between single-nucleotide polymorphisms (SNPs) in ULK1 and risk of tuberculosis (TB) in a Chinese Han population. We recruited 380 pulmonary tuberculosis (PTB) cases, 242 extra-pulmonary tuberculosis (EPTB) cases and 606 healthy controls from a Chinese Han population and sequenced ULK1. Five SNPs in ULK1 were selected to investigate the correlations between ULK1 polymorphisms and TB susceptibility. The rs7138581 C allele was associated with a reduced risk of PTB (P = 0.001), whereas the rs9481 A allele was associated with an increased risk (P = 0.025). The rs7138581 CG genotype was significantly associated with a low risk of PTB, with a higher PTB disease severity in clinical parameters. Estimation of haplotype frequencies in ULK1 revealed a protective haplotype CCGAA (P = 0.007) and a potential risk haplotype TGAAA (P = 0.010) for PTB. These results demonstrated that ULK1 polymorphisms have significant associations with susceptibility to PTB.

Distribution of HLA-DRB1, DPB1 and DQB1 alleles and haplotypes in Mongolian Minority in China

HLA-DRB1, -DQB1 and -DPB1 allele frequencies and estimated haplotype frequencies from 496 unrelated healthy Mongol subjects who living in Inner Mongolia Autonomous Region of China has been reported. HLA genes were genotyped using high-resolution sequence-based typing method. Chinese-Mongolian belongs to northern group of East Asians, but with its specific HLA-DRB1, DPB1 and DQB1 alleles and haplotypes characteristic.

CSHAP: efficient haplotype frequency estimation based on sparse representation.

Estimating haplotype frequencies from genotype data plays an important role in genetic analysis. In silico methods are usually computationally involved since phase information is not available. Due to tight linkage disequilibrium and low recombination rates, the number of haplotypes observed in human populations is far less than all the possibilities. This motivates us to solve the estimation problem by maximizing the sparsity of existing haplotypes. Here, we propose a new algorithm by applying the compressive sensing (CS) theory in the field of signal processing, compressive sensing haplotype inference (CSHAP), to solve the sparse representation of haplotype frequencies based on allele frequencies and between-allele co-variances. Our proposed approach can handle both individual genotype data and pooled DNA data with hundreds of loci. The CSHAP exhibits the same accuracy compared with the state-of-the-art methods, but runs several orders of magnitude faster. CSHAP can also handle with missing genotype data imputations efficiently. The CSHAP is implemented in R, the source code and the testing datasets are available at http://home.ustc.edu.cn/∼zhouys/CSHAP/. Supplementary data are available at Bioinformatics online.

Haplotypes in vitamin D receptor gene encode risk in diabetic nephropathy

BackgroundDiabetic Nephropathy (DN) is one of the microvascular complications of diabetes and its early diagnosis can improve patient's quality of life. Genetic factors may increase the risk of DN development. This study aimed to evaluate the association of vitamin D receptor (VDR) gene polymorphisms and DN. MethodA total of 313 Iranian participants including 104 diabetic patients with nephropathy (DN), 100 diabetic patients without nephropathy (D) and 109 healthy people (HC) were studied. The frequencies of rs7975232, rs731236 and rs4516035 variants of VDR gene were determined and compared between three groups. Estimated haplotype frequencies between polymorphisms in the cases and controls were also calculated. ResultsNo significant differences were identified for allele /genotype frequencies in HC, D and DN groups. However haplotype analysis showed that haplotype encompassing CCC alleles for rs7975232, rs731236 and rs4516035 variants, respectively was more frequent in DN subjects compared to HC (p-value = 0.01) and also, haplotype comprising TCC alleles was more frequent in DN group compared to both HC and D groups (p-value = 0.004 and 0.007, respectively). ConclusionOur study identified that CCC and TCC VDR haplotypes are risk factors for DN in patients with diabetes type 2.

Common and well-documented HLA alleles of German stem cell donors by haplotype frequency estimation.

We present a catalog of common and well‐documented (CWD) alleles of the German population for the six HLA loci A, B, C, DRB1, DQB1, and DPB1. This study is based on a sample of over 5 million volunteer adult hematopoietic stem cell donors from the 26 German donor centers. To establish the catalog, allele and haplotype frequencies were estimated with a validated implementation of the expectation‐maximization algorithm. CWD criteria similar to existing CWD catalogs were applied in order to be able to put our findings into the context of relevant existing references. Overall, 2155 HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1 alleles were identified as CWD in the German donor population representing about 20% of the HLA alleles at two‐field resolution in the IPD‐IMGT/HLA Database release v3.25.0 from July 2016 for these six loci. We found a substantial concordance of CWD alleles between the three catalogs and showed the contribution of the German donor population to the CWD alleles domain. In conclusion, the definition of CWD criteria that allow interoperability, scalability, and flexibility will be crucial for the development of a worldwide CWD catalog.