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Haplotype Reconstruction (haplotype + reconstruction)

Distribution by Scientific Domains

Life Sciences	85%

Selected Abstracts

Haplotype association analysis for late onset diseases using nuclear family data

GENETIC EPIDEMIOLOGY, Issue 3 2006
Chun Li
Abstract In haplotype-based association studies for late onset diseases, one attractive design is to use available unaffected spouses as controls (Valle et al. [1998] Diab. Care 21:949,958). Given cases and spouses only, the standard expectation-maximization (EM) algorithm (Dempster et al. [1977] J. R. Stat. Soc. B 39:1,38) for case-control data can be used to estimate haplotype frequencies. But often we will have offspring for at least some of the spouse pairs, and offspring genotypes provide additional information about the haplotypes of the parents. Existing methods may either ignore the offspring information, or reconstruct haplotypes for the subjects using offspring information and discard data from those whose haplotypes cannot be reconstructed with high confidence. Neither of these approaches is efficient, and the latter approach may also be biased. For case-control data with some subjects forming spouse pairs and offspring genotypes available for some spouse pairs or individuals, we propose a unified, likelihood-based method of haplotype inference. The method makes use of available offspring genotype information to apportion ambiguous haplotypes for the subjects. For subjects without offspring genotype information, haplotypes are apportioned as in the standard EM algorithm for case-control data. Our method enables efficient haplotype frequency estimation using an EM algorithm and supports probabilistic haplotype reconstruction with the probability calculated based on the whole sample. We describe likelihood ratio and permutation tests to test for disease-haplotype association, and describe three test statistics that are potentially useful for detecting such an association. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source]

Rapid haplotype reconstruction in pedigrees with dense marker maps

JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 1 2004
J. J. Windig
Summary Reconstruction of marker phases is not straightforward when parents are untyped. In these cases information from other relatives has to be used. In dense marker maps, however, the space of possible haplotype configurations tends to be too large for procedures such as Monte Carlo Markov chains (MCMC) to be finished within a reasonable time. We developed an algorithm that is fast and generally finds the most probable haplotype. The basic idea is to use, the smallest informative marker brackets in offspring, for each marker interval. By using only information from the offspring and analysing each marker interval separately, the lengthy analysis of large numbers of different haplotype configurations is avoided. Nevertheless the most probable haplotype can be found quickly provided the marker map is dense and enough offspring are available. Simulations are provided to indicate how well the algorithm works at different combinations of marker density, number of offspring and number of alleles per marker. In situations where the algorithm reconstruction of the most probable haplotype is not guaranteed, the algorithm may still provide a haplotype close to the optimum, i.e. a suitable starting point for numeric optimization algorithms. Zusammenfassung Die Rekonstruktion der Kopplungsphasen von Markern ist nicht unkompliziert, wenn die Typisierung der Eltern fehlt. In derartigen Fällen müssen Informationen von Verwandten genutzt werden. In dichten Markerkarten tendiert der Bereich für mögliche Haplotypenkonfigurationen jedoch dazu, zu groß zu werden, um Verfahren wie Monte Carlo Markov Chains (MCMC) in einem angemessenen Zeitrahmen anzuwenden. Wir entwickelten einen Algorithmus, der schnell ist und im Allgemeinen die wahrscheinlichsten Haplotypen findet. Die grundlegende Idee dabei bestand darin, für jeden Markerintervall erstfolgende informative Markern am linker und rechter Zeite in den Nachkommen zu nutzen. Durch die ausschließliche Nutzung von Nachkommeninformationen und durch die separate Analyse von Markerintervallen, wird die langatmige Analyse großer Anzahlen unterschiedlicher Haplotypenkonfigurationen umgangen. Dennoch kann der wahrscheinlichste Haplotyp schnell gefunden werden, vorausgesetzt die Markerkarte ist dicht und ausreichend Nachkommen sind verfügbar. Simulationen werden zur Verfügung gestellt, um zu zeigen wie gut der Algorithmus bei unterschiedlichen Kombinationen von Markerdichte, Anzahl von Nachkommen und Allelen pro Marker arbeitet. In Situationen, wo die algorithmische Rekonstruktion des wahrscheinlichsten Haplotypen nicht garantiert werden kann, kann der Algorithmus dennoch einen Haplotypen nahe des Optimums bereitstellen, z.B. einen geeigneten Startpunkt für numerische Optimierungsalgorithmen. [source]

Internal algorithm variability and among-algorithm discordance in statistical haplotype reconstruction

MOLECULAR ECOLOGY, Issue 8 2009
ZU-SHI HUANG
The potential effectiveness of statistical haplotype inference makes it an area of active exploration over the last decade. There are several complications of statistical inference, including: the same algorithm can produce different solutions for the same data set, which reflects the internal algorithm variability; different algorithms can give different solutions for the same data set, reflecting the discordance among algorithms; and the algorithms per se are unable to evaluate the reliability of the solutions even if they are unique, this being a general limitation of all inference methods. With the aim of increasing the confidence of statistical inference results, consensus strategy appears to be an effective means to deal with these problems. Several authors have explored this with different emphases. Here we discuss two recent studies examining the internal algorithm variability and among-algorithm discordance, respectively, and evaluate the different outcomes of these analyses, in light of Orzack (2009) comment. Until other, better methods are developed, a combination of these two approaches should provide a practical way to increase the confidence of statistical haplotyping results. [source]

Brief communication: Allelic and haplotypic structure at the DRD2 locus among five North Indian caste populations

AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 4 2010
Kallur N. Saraswathy
Abstract The dopamine D2 receptor (DRD2) gene, with its known human-specific derived alleles that can facilitate haplotype reconstruction, presents an important locus for anthropological studies. The three sites (TaqIA, TaqIB, and TaqID) of the DRD2 gene are widely studied in various world populations. However, no work has been previously published on DRD2 gene polymorphisms among North Indian populations. Thus, the present study attempts to understand the genetic structure of North Indian upper caste populations using the allele and haplotype frequencies and distribution patterns of the three TaqI sites of the DRD2 gene. Two hundred forty-six blood samples were collected from five upper caste populations of Himachal Pradesh (Brahmin, Rajput and Jat) and Delhi (Aggarwal and Sindhi), and analysis was performed using standard protocols. All three sites were found to be polymorphic in all five of the studied populations. Uniform allele frequency distribution patterns, low heterozygosity values, the sharing of five common haplotypes, and the absence of two of the eight possible haplotypes observed in this study suggest a genetic proximity among the selected populations. The results also indicate a major genetic contribution from Eurasia to North Indian upper castes, apart from the common genetic unity of Indian populations. The study also demonstrates a greater genetic inflow among North Indian caste populations than is observed among South Indian caste and tribal populations. Am J Phys Anthropol, 2010. © 2010 Wiley-Liss, Inc. [source]

PedStr Software for Cutting Large Pedigrees for Haplotyping, IBD Computation and Multipoint Linkage Analysis

ANNALS OF HUMAN GENETICS, Issue 5 2009
Anatoly V. Kirichenko
Summary We propose an automatic heuristic algorithm for splitting large pedigrees into fragments of no more than a user-specified bit size. The algorithm specifically aims to split large pedigrees where many close relatives are genotyped and to produce a set of sub-pedigrees for haplotype reconstruction, IBD computation or multipoint linkage analysis with the help of the Lander-Green-Kruglyak algorithm. We demonstrate that a set of overlapping pedigree fragments constructed with the help of our algorithm allows fast and effective haplotype reconstruction and detection of an allele's parental origin. Moreover, we compared pedigree fragments constructed with the help of our algorithm and existing programs PedCut and Jenti for multipoint linkage analysis. Our algorithm demonstrated significantly higher linkage power than the algorithm of Jenti and significantly shorter running time than the algorithm of PedCut. The software package PedStr implementing our algorithms is available at http://mga.bionet.nsc.ru/soft/index.html. [source]

Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample

CLINICAL GENETICS, Issue 6 2009
ML Mostacciuolo
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with a partial deletion on chromosome 4q35. Few relevant investigations have been reported on its epidemiology and were essentially based on clinical diagnosis, having been performed before recognition of the molecular mutation. We report an epidemiological survey on FSHD patients, in which the diagnosis was obtained by combined clinical and molecular evaluation. The survey concerned the north-east Italian province of Padova, an area of 871,190 inhabitants (1 January 2004). We identified 40 patients affected by FSHD based on clinical diagnosis. In 33 of them, the EcoRI fragment size in the 4q35 region ranged from 14 to 35 kb. Four other patients belonging to the same family harbored a 38-kb fragment. In these four cases, the relationship between the borderline deletion with the mild FSHD phenotype was corroborated by additional haplotype reconstruction and segregation analysis. Interestingly, the same mild facial-sparing clinical pattern was apparent only in one other patient with an EcoRI fragment of 32 kb, suggesting that this unusual FSHD phenotype may be due to very small 4q35 deletions. On the whole, estimating a prevalence rate of 44 × 10,6, our survey confirmed FSHD as one of the most frequent neuromuscular disorders in Western populations. [source]