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PubMed1983

A note on positive identification of paternity by using genetic markers.

To see the efficiency of the statistical methods for positive identification of fathers using genetic markers, the statistical properties of the paternity index are studied algebraically and numerically. It is found that the currently used statistical methods are not powerful enough to discriminate between true fathers and non-excluded non-fathers, and, more often than not, may lead to false attributions of paternity. It is, therefore, suggested that exclusion of paternity is the only conclusive evidence that can be accepted by courts of law until better methods are devised.

Adult↗
PubMed1985

TWINAN: twin data analysis program for microcomputers.

A BASIC computer program designed to facilitate analysis of twin data is presented. The program estimates genetic parameters and tests their statistical significance based on the genetic and environmental hypothesis.

Computers↗
PubMed1999

Population genetics of the yellow fever mosquito in Trinidad: comparisons of amplified fragment length polymorphism (AFLP) and restriction fragment length polymorphism (RFLP) markers.

Recent development of DNA markers provides powerful tools for population genetic analyses. Amplified fragment length polymorphism (AFLP) markers result from a polymerase chain reaction (PCR)-based DNA fingerprinting technique that can detect multiple restriction fragments in a single polyacrylamide gel, and thus are potentially useful for population genetic studies. Because AFLP markers have to be analysed as dominant loci in order to estimate population genetic diversity and genetic structure parameters, one must assume that dominant (amplified) alleles are identical in state, recessive (unamplified) alleles are identical in state, AFLP fragments segregate according to Mendelian expectations and that the genotypes of an AFLP locus are in Hardy-Weinberg equilibrium (HWE). The HWE assumption is untestable for natural populations using dominant markers. Restriction fragment length polymorphism (RFLP) markers segregate as codominant alleles, and can therefore be used to test the HWE assumption that is critical for analysing AFLP data. This study examined whether the dominant AFLP markers could provide accurate estimates of genetic variability for the Aedes aegypti mosquito populations of Trinidad, West Indies, by comparing genetic structure parameters using AFLP and RFLP markers. For AFLP markers, we tested a total of five primer combinations and scored 137 putative loci. For RFLP, we examined a total of eight mapped markers that provide a broad coverage of mosquito genome. The estimated average heterozygosity with AFLP markers was similar among the populations (0.39), and the observed average heterozygosity with RFLP markers varied from 0.44 to 0.58. The average FST (standardized among-population genetic variance) estimates were 0.033 for AFLP and 0.063 for RFLP markers. The genotypes at several RFLP loci were not in HWE, suggesting that the assumption critical for analysing AFLP data was invalid for some loci of the mosquito populations in Trinidad. Therefore, the results suggest that, compared with dominant molecular markers, codominant DNA markers provide better estimates of population genetic variability, and offer more statistical power for detecting population genetic structure.

Aedes↗
PubMed2004

Influence of nutrient application rate on growth and rooting potential of the West African hardwood Triplochiton scleroxylon.

Effects of stock plant nutrition on growth and subsequent rooting of leafy stem cuttings of the commercially important west African tree Triplochiton scleroxylon K. Schum. were investigated to identify the primary morphological variables influencing adventitious root formation. Potted plants were watered as required with one of four balanced nutrient solutions (0, 15, 63 or 125 mg N l(-1)). Increasing the nutrient supply to stock plants increased growth rate and rate of adventitious root production of subsequently harvested cuttings, but an optimum nutrient regime was not identified. Rooting percentage increased from 27% in cuttings harvested from stock plants receiving a low nutrient supply to 64% for cuttings harvested from stock plants receiving eight times the amount of nutrients extractable from plants under typical field conditions in West Africa. The ability of a cutting to retain its leaf during propagation and the length of the cutting were the primary measured characteristics associated with rooting and accounted for 43% of the variance fitted in the model. The length of the new shoot, total leaf area and within-shoot position (node position) were also significantly associated with rooting. After these characteristics were fitted to the model, the genetic origin (clone) was not statistically significant. We conclude that genetic variation in rooting potential is mediated through variations in morphological and physiological traits, rather than through genetic variation in cell differentiation or related aspects of root initiation.

Malvaceae↗
PubMed2005

A statistical framework for haplotype block inference.

The existence of haplotype blocks transmitted from parents to offspring has been suggested recently. This has created an interest in the inference of the block structure and length. The motivation is that haplotype blocks that are characterized well will make it relatively easier to quickly map all the genes carrying human diseases. To study the inference of haplotype block systematically, we propose a statistical framework. In this framework, the optimal haplotype block partitioning is formulated as the problem of statistical model selection; missing data can be handled in a standard statistical way; population strata can be implemented; block structure inference/hypothesis testing can be performed; prior knowledge, if present, can be incorporated to perform a Bayesian inference. The algorithm is linear in the number of loci, instead of NP-hard for many such algorithms. We illustrate the applications of our method to both simulated and real data sets.

Algorithms↗
PubMed1993

Immunogenetic analysis of silicosis in Japan.

We previously reported that a gene in linkage disequilibrium with HLA-Bw54, DR4, and DRw53 might control the susceptibility to silicosis (K. Honda et al. 1988. N. Engl. J. Med. 319:1610). To further define the HLA-linked gene and other genetic factors for predisposition of silicosis, we determined for HLA-DQ and DP alleles using the polymerase chain reaction and sequence-specific oligonucleotide probes and made a restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes, immunoglobulin lambda variable chain (IGLV) gene, and T-cell receptor alpha and beta genes in 46 Japanese patients with silicosis. The frequency of DQB1*0401 (relative risk [RR] = 2.2, P < 0.02) was increased and that of DQB1*0601 (RR = 0.36, P < 0.01) was decreased in the patients. RFLP analysis of C4 and IGLV genes showed significant association between silicosis and a specific RFLP pattern of C4A3-C4B5 allotype (RR = 2.3, P < 0.05) and that of IGLV 5.3 kb (RR = 0.33, P < 0.003). No other genetic markers showed significant association. Statistical analyses of the associated genetic markers revealed that the HLA-Bw54 was the allele that showed primary association with silicosis and the frequencies of the C4 and HLA-DQ alleles were suggested to be increased due to their linkage disequilibrium with the HLA-Bw54. We conclude that the major gene for silicosis may be mapped near the HLA-B locus.

Adolescent↗
PubMed2001

[Complex segregation analysis of systemic lupus erythematosus].

OBJECTIVE: To explore the genetic model of systemic lupus erythematosus(SLE). METHODS: Complex segregation analysis was performed by using statistical analysis for genetic epidemiology-REGTL(SAGE-REGTL). The genetic model and gene frequency were estimated. 300 pedigrees with SLE were collected from 300 patients as probands. RESULTS: The complex segregation analysis found the genetic model of SLE to be additive,the gene frequency 0.336. The authors believe the possibility of some different modes coexisting under different circumstances. The genetic effect on young man is stronger than that on old one. CONCLUSION: This study suggests that the genetic mode of SLE could be the major gene trait, and additive mode is the best fitted one.

Adolescent↗
PubMed2004

Influence of spatial and temporal heterogeneities on the estimation of demographic parameters in a continuous population using individual microsatellite data.

Drift and migration disequilibrium are very common in animal and plant populations. Yet their impact on methods of estimation of demographic parameters was rarely evaluated especially in complex realistic population models. The effect of such disequilibria on the estimation of demographic parameters depends on the population model, the statistics, and the genetic markers used. Here we considered the estimation of the product Dsigma2 from individual microsatellite data, where D is the density of adults and sigma2 the average squared axial parent-offspring distance in a continuous population evolving under isolation by distance. A coalescence-based simulation algorithm was used to study the effect on Dsigma2 estimation of temporal and spatial fluctuations of demographic parameters. Estimation of present-time Dsigma2 values was found to be robust to temporal changes in dispersal, to density reduction, and to spatial expansions with constant density, even for relatively recent changes (i.e., a few tens of generations ago). By contrast, density increase in the recent past gave Dsigma2 estimations biased largely toward past demographic parameters values. The method was also robust to spatial heterogeneity in density and estimated local demographic parameters when the density is homogenous around the sampling area (e.g., on a surface that equals four times the sampling area). Hence, in the limit of the situations studied in this article, and with the exception of the case of density increase, temporal and spatial fluctuations of demographic parameters appear to have a limited influence on the estimation of local and present-time demographic parameters with the method studied.

Algorithms↗
PubMed1999

[The risk factors for the development of multiple sclerosis in the Moscow population. II. The combination of exogenous and hereditary factors].

Simultaneous study of both external and hereditary risk factors of the development of multiple sclerosis (MS) was carried out in Moscow population. As a result of the genotyping of HLA-DR locus on the chromosome 6, there were found markers of the predisposition to MS: by HLA-DR: DR2(15) way, especially, in homozygous heredity and in the absence of such specificity--alleles of DR3 group. The data were confirmed concerning both the elevation of frequency of the alleles of tumor necrosis factor (TNF)a1 and alpha 2 and the decrease of frequency of TNF-alpha 7 allele in MS. There was also confirmed association of the disease with the external factors, such as "predominance of the meat nutrition at the age under 15 years" and "tonsillitis at the age under 15 years". There were two combinations of the external and hereditary factors, when the power of the association increased significantly: "predominance of meat nutrition at the age under 15 years" and DR2(15) and "tonsillitis at the age under 15 years" and DR3. When genetic factors were excluded, the relation of MS with the external factors was considerably reduced; when the external factors were excluded, the association of MS with genetic markers became statistically insignificant. A combination of these external factors, which were the sources for the additional antigenic immunostimulation, with certain genetic factors in DR region suggested the presence of the genetically determined peculiarities of the composition of antigen presentation HLA-DR in the individuals with DR2(15) and DR3. There was no statistically confirmed presence of a combination of the external factors with TNF-alpha alleles which increased additionally MS risk. The presence of immunostimulating antigen-containing external factors may be significant for the influence of TNF-alpha in less degree than for the realization of predisposition in form of the certain composition of HLA molecules.

Adolescent↗
PubMed2002

A comparison of combinatorial partitioning and linear regression for the detection of epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms on plasma PAI-1 levels.

The detection and characterization of epistasis or non-additive gene-gene interactions remains a statistical challenge in genetic epidemiology. The recently developed combinatorial partitioning method (CPM) may overcome some of the limitations of linear regression for the exploratory analysis of non-additive epistatic effects. The goal of this study was to compare CPM with linear regression analysis for the exploratory analysis of non-additive interactive effects of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms on plasma PAI-1 levels in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. Using linear regression, we documented the additive effects of the ACE and PAI-1 genes on plasma PAI-1 levels in African American females (R(2) = 0.10), African American males (R(2) = 0.16), Caucasian females (R(2) = 0.11), and Caucasian males (R2 = 0.09). Using CPM, we found evidence for non-additive effects of the ACE and PAI-1 genes in both African American females (R(2) = 0.22) and African American males (R(2) = 0.24) but not in Caucasian females (R(2) = 0.10) or Caucasian males (R(2) = 0.11). The results of this exploratory data analysis support previous experimental, clinical, and epidemiological studies that have proposed as a working hypothesis that the ACE gene mediates interaction effects of the fibrinolytic and renin-angiotensin systems on plasma levels of PAI-1.

Black People↗
PubMed1999

A more powerful method to evaluate p-values in GENEHUNTER.

The determination of statistical significance in genetic linkage studies is complicated by many factors, such as missing individuals or uninformative markers, and the validity of theoretical results is often questionable. Although many simulation-based methods have been proposed to determine empirically the statistical significance, they are either not generally applicable to complex pedigree structures, or not able to preserve the observed genetic information content at each locus in the pedigrees. We have developed and implemented a general and computationally efficient randomization procedure in GENEHUNTER that applies to arbitrary pedigree structure and preserves the observed information content at each locus. We applied this method to the Problem 1 data set of the Genetic Analysis Workshop 11. The performance of this new method was similar to the method implemented in GENEHUNTER-PLUS, and both outperformed the conservative approach in GENEHUNTER.

Alcoholism↗
PubMed2003

Human genetic diversity: Lewontin's fallacy.

In popular articles that play down the genetical differences among human populations, it is often stated that about 85% of the total genetical variation is due to individual differences within populations and only 15% to differences between populations or ethnic groups. It has therefore been proposed that the division of Homo sapiens into these groups is not justified by the genetic data. This conclusion, due to R.C. Lewontin in 1972, is unwarranted because the argument ignores the fact that most of the information that distinguishes populations is hidden in the correlation structure of the data and not simply in the variation of the individual factors. The underlying logic, which was discussed in the early years of the last century, is here discussed using a simple genetical example.

Data Interpretation, Statistical↗
PubMed1999

The population genetic structure of a large temperate pollinator species, Bombus pascuorum (Scopoli) (Hymenoptera: Apidae)

The genetic population structure of the bumble bee Bombus pascuorum was studied using six microsatellite loci and a partial sequence of the mitochondrial gene cytochrome b. Eighteen populations from central and northern Europe were included in the analysis. Observed levels of genetic variability and heterozygosity were high. Estimates of population differentiation based on F- and phi-statistics revealed significant genetic differentiation among B. pascuorum populations and suggest that two partially isolated gene pools, separated by the Alps, do exist. The distribution of mtDNA haplo-types supports this view and presents direct evidence for gene flow across the Alps. Estimates of the number of migrants exchanged among populations north of the Alps suggest that historical events may have left a strong imprint on population structure.

Journal Article↗
PubMed1999

Multipoint linkage analysis. A cautionary note.

Multipoint linkage analysis is commonly used to evaluate linkage of a disease to multiple markers in a small region. Multipoint analysis is particularly powerful when the IBD relations of family members at the trait locus are ambiguous. The increased power arises because, unlike single-marker analyses, multipoint analysis uses haplotype information from several markers to infer the IBD relations. We wish to temper this advantage with a cautionary note: multipoint analysis is sensitive to power loss due to misspecification of intermarker distances. Such misspecification is especially problematic when dealing with closely spaced markers. We present computer simulations comparing the power of single-point and multipoint analyses, both when IBD relations are ambiguous, and when the intermarker distances are misspecified. We conclude that when evaluating markers in a small region to confirm or refute previous findings, a situation in which p values of modest statistical significance are important, single marker analyses may provide more reliable measures of the strength of support for linkage than multipoint statistics.

Computer Simulation↗
PubMed2005

Environmental correlates of population differentiation in Atlantic herring.

The marine environment is characterized by few physical barriers, and pelagic fishes commonly show high migratory potential and low, albeit in some cases statistically significant, levels of genetic divergence in neutral genetic marker analyses. However, it is not clear whether low levels of differentiation reflect spatially separated populations experiencing gene flow or shallow population histories coupled with limited random genetic drift in large, demographically isolated populations undergoing independent evolutionary processes. Using information for nine microsatellite loci in a total of 1951 fish, we analyzed genetic differentiation among Atlantic herring from eleven spawning locations distributed along a longitudinal gradient from the North Sea to the Western Baltic. Overall genetic differentiation was low (theta = 0.008) but statistically significant. The area is characterized by a dramatic shift in hydrography from the highly saline and temperature stable North Sea to the brackish Baltic Sea, where temperatures show high annual variation. We used two different methods, a novel computational geometric approach and partial Mantel correlation analysis coupled with detailed environmental information from spawning locations to show that patterns of reproductive isolation covaried with salinity differences among spawning locations, independent of their geographical distance. We show that reproductive isolation can be maintained in marine fish populations exhibiting substantial mixing during larval and adult life stages. Analyses incorporating genetic, spatial, and environmental parameters indicated that isolating mechanisms are associated with the specific salinity conditions on spawning locations.

Age Distribution↗
PubMed2006

Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies.

Coronary artery disease (CAD) has a polygenic basis, and identification of CAD susceptibility genes has the potential to aid the development of new treatments and enhance prediction of disease risk. Thus far, the strategy has firstly been to choose "candidate" genes coding for important "rate-limiting" proteins in the homeostatic systems involved in maintaining cardiovascular health; secondly to identify common variants in these candidate genes; thirdly to carry out genotyping and statistical analysis using genetic association studies; and finally to test the functional effects of the identified variants in vitro and in vivo. However, lack of reproducibility of genetic association studies has led to uncertainty about the nature and number of genes involved. In part this is because many of the studies conducted have not been adequately powered to detect small risk effects, or to permit adequate exploration of gene-gene or gene-environment interactions in a robust manner. Spurious positive and negative associations due to type I and type II statistical errors are likely to co-exist with real associations in the published literature. By utilising all available data to increase statistical power, meta-analysis of genetic association studies is increasingly being used to identify genotypic risk with a greater degree of precision. Though potentially powerful, this approach may be prone to publication bias. Therefore, very large genetic association studies will also be required to identify risk genes for CAD. This review lays out the framework for the candidate gene approach for CAD and illustrates this with published results from a UK prospective study of 3000 middle-aged men.

Cardiovascular Diseases↗
PubMed2006

A statistical model to analyse quantitative trait locus interactions for HIV dynamics from the virus and human genomes.

Viruses can be considered 'parasites' because they cannot survive outside of a host. The progression rate to AIDS caused by human immunodeficiency virus type-1 (HIV-1) is therefore a consequence of HIV-host cell interactions. In this article, we present an innovative statistical model for detecting the effects of genetic interactions on HIV-1 dynamics triggered by different quantitative trait loci (QTL) from the HIV and human genomes. Our model integrates the principles of functional mapping for longitudinal traits and of linkage disequilibrium analysis for high-resolution mapping of QTL within the maximum likelihood context and is implemented with the EM algorithm. We performed Monte Carlo simulation studies to investigate the impacts of different heritability levels and sample sizes on the power to detect interacting QTL. Our model allows for the tests of a number of clinically meaningful hypotheses and provides a powerful tool for unravelling the genetic architecture of HIV-1 dynamics and therefore AIDS progression rate.

Algorithms↗