Estimation of HLA phenotype frequencies from two- and three-locus haplotype frequencies

A procedure for estimating HLA phenotype frequencies from two- and three-locus haplotype frequencies is described. Formulae for this procedure are derived, and examples are presented to illustrate the application. The procedure is useful when multiple-locus phenotype frequencies from a laboratory control series are not available, or when a sufficiently large number of laboratory controls have not yet been typed for recently defined antigens or loci to yield stable multiple-locus rates for comparative purposes.     

HLA gene and haplotype frequencies in Uruguay

A total of 604 individuals living in Montevideo and other places in Uruguay were studied in relation to three I HLA loci. The most common alleles observed (percentages in parentheses) were A2(24), A9(15), A19(11), B12(12), B35(12), and C4(16). The most marked departures from linkage equilibrium (all numbers multiplied by 10⁵) were B35-C4(636), A2-B5(590), A2C3(515), A2B14(494), and A19-B12(485). These findings do not contradict the hypothesis that while most of the Uruguayan population is of Caucasoid origin, significant African and Amerindian genes may exist in its gene pool.     

Chemotaxis in Escherichia coli proceeds efficiently from different initial tumble frequencies.

The relationships between the level of tumbling, tumble frequency, and chemotactic ability were tested by constructing two Escherichia coli strains with the same signaling apparatus but with different adapted levels of tumbling, above and below the level of wild-type E. coli. This was achieved by introducing two different aspartate receptor genes into E. coli: a wild-type (wt-tars) and a mutant (m-tars) Salmonella typhimurium receptor gene. These cells were compared with each other and with wild-type E. coli (containing the wild-type E. coli aspartate receptor gene, wt-tare). It was found that in spite of the differences in the adapted levels of tumbling, the three strains had essentially equal response times and chemotactic ability toward aspartate. This shows that the absolute level of the tumbling can be varied without impairing chemotaxis if the signal processing system is normal. It also appears that a largely smooth-swimming mutant may undergo chemotaxis by increasing tumbling frequency in negative gradients.     

An artificial neural network for estimating haplotype frequencies

The problem of estimating haplotype frequencies from population data has been considered by numerous investigators, resulting in a wide variety of possible algorithmic and statistical solutions. We propose a relatively unique approach that employs an artificial neural network (ANN) to predict the most likely haplotype frequencies from a sample of population genotype data. Through an innovative ANN design for mapping genotype patterns to diplotypes, we have produced a prototype that demonstrates the feasibility of this approach, with provisional results that correlate well with estimates produced by the expectation maximization algorithm for haplotype frequency estimation. Given the computational demands of estimating haplotype frequencies for 20 or more single-nucleotide polymorphisms, the ANN approach is promising because its design fits well with parallel computing architectures.     

A general program for estimation of haplotype frequencies from population diploid data.

The program which is written in FORTRAN estimates haplotype frequencies in two-locus and three-locus genetic systems from population diploid data. It is based on the gene counting method which leads to maximum likelihood estimates, and can be used whenever the possible antigens (one or more) on each chromosome can be specified for each person and for each locus, i.e., ABO-like systems and inclusions are permitted. The number of alleles per locus may be rather large, and both grouped and ungrouped data can be used. Log likelihoods are calculated on the basis of various assumptions, so that likelihood ratio tests can be carried out.     

Mitochondrial DNA haplotype frequencies in natural and experimental populations of Drosophila subobscura.

The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Esporles (Majorca, Balearic Islands, Spain). This population, like other European ones, is characterized by the presence of two very common (>96%) mitochondrial haplotypes (called I and II) and rare and endemic haplotypes that appear at very low frequencies. There is no statistical evidence of positive Darwinian selection acting on the mitochondrial DNA variants according to Tajima''s neutrality test. Two experimental populations, with one replicate each, were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. Both populations were started with the two most frequent mitochondrial haplotypes, but at different initial frequencies. After 13 to 16 generations, haplotype II reached fixation in three cages and its frequency was 0.89 by generation 25 in the fourth cage. Random drift can be rejected as the force responsible for the observed changes in haplotype frequencies. There is not only statistical evidence of a linear trend favoring a mtDNA (haploid) fitness effect, but also of a significant nonlinear deviation that could be due to a nuclear component.     

GCHap: fast MLEs for haplotype frequencies by gene counting

GCHap quickly finds maximum likelihood estimates (MLEs) of frequencies of haplotypes given genotype information on a random sample of individuals. It uses the gene counting method but by excluding haplotypes with zero MLE at an early stage, this implementation uses many orders of magnitude less space and time than naive implementations. A second program, ApproxGCHap, is provided to give alternate estimates for data sets with large numbers of loci or large amounts of missing genotypes. AVAILABILITY: The Java classes and Javadocs pages for GCHap can be obtained from bioinformatics.med.utah.edu/~alun     

HLA antigen,gene, and haplotype frequencies in Thailand

Summary Antigen, gene, and haplotype frequencies as well as phenotype distribution of the HLA system were studied in a series of 213 individuals in northern Thailand. The series consisted of 160 northern Thais, 23 Thai individuals from various other regions of Thailand, and 25 persons of Chinese origin. Most frequently found were the alleles HLA-A11 and HLA-Bw40 and the haplotype HLA-A2, B-. Phenotype distribution followed a Hardy-Weinberg expectation. Significant differences were found especially between our results for the alleles of locus B and the results of a series from Bangkok reported by Chiewsilp and Chanarat (1976).     

Susceptibility of biallelic haplotype and genotype frequencies to genotyping error

With the availability of fast genotyping methods and genomic databases, the search for statistical association of single nucleotide polymorphisms with a complex trait has become an important methodology in medical genetics. However, even fairly rare errors occurring during the genotyping process can lead to spurious association results and decrease in statistical power. We develop a systematic approach to study how genotyping errors change the genotype distribution in a sample. The general M-marker case is reduced to that of a single-marker locus by recognizing the underlying tensor-product structure of the error matrix. Both method and general conclusions apply to the general error model; we give detailed results for allele-based errors of size depending both on the marker locus and the allele present. Multiple errors are treated in terms of the associated diffusion process on the space of genotype distributions. We find that certain genotype and haplotype distributions remain unchanged under genotyping errors, and that genotyping errors generally render the distribution more similar to the stable one. In case-control association studies, this will lead to loss of statistical power for nondifferential genotyping errors and increase in type I error for differential genotyping errors. Moreover, we show that allele-based genotyping errors do not disturb Hardy-Weinberg equilibrium in the genotype distribution. In this setting we also identify maximally affected distributions. As they correspond to situations with rare alleles and marker loci in high linkage disequilibrium, careful checking for genotyping errors is advisable when significant association based on such alleles/haplotypes is observed in association studies.     

Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population

Molecular techniques allow the survey of a large number of linked polymorphic loci in random samples from diploid populations. However, the gametic phase of haplotypes is usually unknown when diploid individuals are heterozygous at more than one locus. To overcome this difficulty, we implement an expectation-maximization (EM) algorithm leading to maximum-likelihood estimates of molecular haplotype frequencies under the assumption of Hardy-Weinberg proportions. The performance of the algorithm is evaluated for simulated data representing both DNA sequences and highly polymorphic loci with different levels of recombination. As expected, the EM algorithm is found to perform best for large samples, regardless of recombination rates among loci. To ensure finding the global maximum likelihood estimate, the EM algorithm should be started from several initial conditions. The present approach appears to be useful for the analysis of nuclear DNA sequences or highly variable loci. Although the algorithm, in principle, can accommodate an arbitrary number of loci, there are practical limitations because the computing time grows exponentially with the number of polymorphic loci. Although the algorithm, in principle, can accommodate an arbitrary number of loci, there are practical limitations because the computing time grows exponentially with the number of polymorphic loci.      

HLA phenotype and haplotype frequencies in the Cantabria (middle north Spain) population.

The gene and haplotype frequencies of the HLA-A and -B locus antigens were determined in 502 unrelated individuals from Cantabria (middle North Spain). Our results were compared with those reported for other European and Spanish populations. The haplotypes with significant linkage disequilibrium were also analyzed in various Spanish population samples in order to establish possible relationships with geographic situation and historical events.     

Estimating haplotype frequencies and standard errors for multiple single nucleotide polymorphisms

Estimating haplotype frequencies becomes increasingly important in the mapping of complex disease genes, as millions of single nucleotide polymorphisms (SNPs) are being identified and genotyped. When genotypes at multiple SNP loci are gathered from unrelated individuals, haplotype frequencies can be accurately estimated using expectation-maximization (EM) algorithms (Excoffier and Slatkin, 1995; Hawley and Kidd, 1995; Long et al., 1995), with standard errors estimated using bootstraps. However, because the number of possible haplotypes increases exponentially with the number of SNPs, handling data with a large number of SNPs poses a computational challenge for the EM methods and for other haplotype inference methods. To solve this problem, Niu and colleagues, in their Bayesian haplotype inference paper (Niu et al., 2002), introduced a computational algorithm called progressive ligation (PL). But their Bayesian method has a limitation on the number of subjects (no more than 100 subjects in the current implementation of the method). In this paper, we propose a new method in which we use the same likelihood formulation as in Excoffier and Slatkin's EM algorithm and apply the estimating equation idea and the PL computational algorithm with some modifications. Our proposed method can handle data sets with large number of SNPs as well as large numbers of subjects. Simultaneously, our method estimates standard errors efficiently, using the sandwich-estimate from the estimating equation, rather than the bootstrap method. Additionally, our method admits missing data and produces valid estimates of parameters and their standard errors under the assumption that the missing genotypes are missing at random in the sense defined by Rubin (1976).     

A recursive method for solving haplotype frequencies with application to genetics

Multiple loci analysis has become popular with the advanced developments in biological experiments. A lot of studies have been focused on the biological and the statistical properties of such multiple loci analysis. In this paper, we study one of the important computational problems: solving the probabilities of haplotype classes from a large linear system Ax = b derived from the recombination events in multiple loci analysis. Since the size of the recombination matrix A increases exponentially with respect to the number of loci, fast solvers are required to deal with a large number of loci in the analysis. By exploiting the nice structure of the matrix A, we develop an efficient recursive algorithm for solving such structured linear systems. In particular, the complexity of the proposed algorithm for the n loci problem is of O(n2(n)) operations and the memory requirement is of O(2(n)) locations for the 2(n)-by-2(n) matrix A. Numerical examples are given to demonstrate the effectiveness of our efficient solver. Finally, we apply our proposed method to analyze the haplotype classes for a set of single nucleotides polymorphisms (SNPs) from Hapmap data.     

HLA gene and haplotype frequencies in galicia (NW Spain)

The genetic structure of six populations of Iran (Turks, Kurds, Lurs, Zabolis, Baluchis and Zoroastrians) was examined using data on blood groups, serum proteins and cell enzymes. Our results show conclusively that there are genetic differences among the six populations and the analysis of superimposed R and S matrices defined by Harpending & Jenkins (1973) show that the dispersion of some of the alleles correspond to the dispersion of the populations. The F_ST estimates are not large enough to favour selection on any of the loci studied. The F_IT and F_IS estimates are positive and moderately high suggesting that the genetic differentiation to some extent is influenced by inbreeding.     

HLA gene and haplotype frequencies in Galicia (NW spain)

The purpose of this paper is to present the genetic distribution at the HLA-A, B and C loci in the Galician population (Spain). A random sample of 264 unrelated individuals from the autochtonous population were tested. The gene frequencies observed at the three loci are within the respective variability ranges found in European populations. The linkage disequilibrium value, D, was calculated using the phenotype frequencies at the A-B, A-C and B-C loci; the most frequent haplotype combinations were A1-B8 and A2-B44, A2-Cw7 and A1-Cw7, and B7-Cw7 and B35-Cw4, respectively.     

HLA-A,B, C gene and haplotype frequencies in Vienna

Summary The HLA-A, B, C haplotype frequencies determined through family investigations in 500 unrelated individuals of the Viennese population were calculated, as well as the gene frequencies of 37 HLA determinants and the linkage disequilibria between the three HLA SD loci (HLA-A, HLA-B, and HLA-C). The existence of HLA-A, B, C superhaplotypes could be confirmed.National Blood Group Reference Laboratory (WHO) and National Tissue Typing Reference Laboratory (Council of Europe)     

Beta-globin gene cluster haplotype frequencies in Khalkhs and Buryats of Mongolia

Beta-globin gene cluster haplotype frequencies of 169 Khalkhs and 145 Buryats were estimated, and their characteristics were compared with those of Evenkis, Oroqens, Koreans, Japanese, and three Colombian Amerindian groups. The present study suggests that Colombian Amerindians diverged first from Asian populations and then Buryats diverged from other Asian populations.