Distribution of lod scores under uncertain mode of inheritance.

We consider probability distributions of alternative lod statistics, differing in their treatment of segregation parameters when mode of inheritance is uncertain. A particular pedigree structure and a dominant genetic system displaying incomplete penetrance are analyzed. Lod scores calculated assuming an incorrect segregation model appear to conform quite well to the chi 2 distribution in the absence of linkage. In the presence of linkage, some power is lost. However, if lod scores are calculated under several different segregation models and the best one is accepted, opportunity for chance occurrence of high lod scores is enhanced. The distribution is still chi 2, but with extra degrees of freedom. These results hold over a wide range of sample sizes and segregation models, including small samples and low levels of penetrance.     

Allele-sharing models: LOD scores and accurate linkage tests.

Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested.     

Further evidence for the increased power of LOD scores compared with nonparametric methods.

In genetic analysis of diseases in which the underlying model is unknown, "model free" methods-such as affected sib pair (ASP) tests-are often preferred over LOD-score methods, although LOD-score methods under the correct or even approximately correct model are more powerful than ASP tests. However, there might be circumstances in which nonparametric methods will outperform LOD-score methods. Recently, Dizier et al. reported that, in some complex two-locus (2L) models, LOD-score methods with segregation analysis-derived parameters had less power to detect linkage than ASP tests. We investigated whether these particular models, in fact, represent a situation that ASP tests are more powerful than LOD scores. We simulated data according to the parameters specified by Dizier et al. and analyzed the data by using a (a) single locus (SL) LOD-score analysis performed twice, under a simple dominant and a recessive mode of inheritance (MOI), (b) ASP methods, and (c) nonparametric linkage (NPL) analysis. We show that SL analysis performed twice and corrected for the type I-error increase due to multiple testing yields almost as much linkage information as does an analysis under the correct 2L model and is more powerful than either the ASP method or the NPL method. We demonstrate that, even for complex genetic models, the most important condition for linkage analysis is that the assumed MOI at the disease locus being tested is approximately correct, not that the inheritance of the disease per se is correctly specified. In the analysis by Dizier et al., segregation analysis led to estimates of dominance parameters that were grossly misspecified for the locus tested in those models in which ASP tests appeared to be more powerful than LOD-score analyses.     

Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases.

Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease models (MMLS) and the "nonparametric" linkage (NPL) statistic. In previous work, we evaluated the increase of type I error when maximizing over two or more genetic models, and we compared the power of MMLS to detect linkage, in a number of complex modes of inheritance, with analysis assuming the true model. In the present study, we compare MMLS and NPL directly. We simulated 100 data sets with 20 families each, using 26 generating models: (1) 4 intermediate models (penetrance of heterozygote between that of the two homozygotes); (2) 6 two-locus additive models; and (3) 16 two-locus heterogeneity models (admixture alpha = 1.0,.7,.5, and.3; alpha = 1.0 replicates simple Mendelian models). For LOD scores, we assumed dominant and recessive inheritance with 50% penetrance. We took the higher of the two maximum LOD scores and subtracted 0.3 to correct for multiple tests (MMLS-C). We compared expected maximum LOD scores and power, using MMLS-C and NPL as well as the true model. Since NPL uses only the affected family members, we also performed an affecteds-only analysis using MMLS-C. The MMLS-C was both uniformly more powerful than NPL for most cases we examined, except when linkage information was low, and close to the results for the true model under locus heterogeneity. We still found better power for the MMLS-C compared with NPL in affecteds-only analysis. The results show that use of two simple modes of inheritance at a fixed penetrance can have more power than NPL when the trait mode of inheritance is complex and when there is heterogeneity in the data set.     

Power and type I error rate of false discovery rate approaches in genome-wide association studies

In genome-wide genetic studies with a large number of markers, balancing the type I error rate and power is a challenging issue. Recently proposed false discovery rate (FDR) approaches are promising solutions to this problem. Using the 100 simulated datasets of a genome-wide marker map spaced about 3 cM and phenotypes from the Genetic Analysis Workshop 14, we studied the type I error rate and power of Storey's FDR approach, and compared it to the traditional Bonferroni procedure. We confirmed that Storey's FDR approach had a strong control of FDR. We found that Storey's FDR approach only provided weak control of family-wise error rate (FWER). For these simulated datasets, Storey's FDR approach only had slightly higher power than the Bonferroni procedure. In conclusion, Storey's FDR approach is more powerful than the Bonferroni procedure if strong control of FDR or weak control of FWER is desired. Storey's FDR approach has little power advantage over the Bonferroni procedure if there is low linkage disequilibrium among the markers. Further evaluation of the type I error rate and power of the FDR approaches for higher linkage disequilibrium and for haplotype analyses is warranted.     

Testing the protein error theory of ageing: a reply to Baird, Samis, Massie and Zimmerman.

A major prediction of Orgel's theory is that the misincorporation of amino acids into proteins will increase with age. This has not yet been tested experimentally. Indirect methods have been used to search for the presence of altered proteins in ageing cells or organisms, but these would not necessarily detect a low level of mistakes, nor do they distinquish between errors in synthesis and post-synthetic changes. Nevertheless, some experimental results have been obtained from genetic and biochemical studies with fungi and fibroblasts which confirm certain predictions of the protein error theory.     

Index measures for assessing the mode of inheritance of continuously distributed traits: I, theory and justifications

A class of indices that may be applied to quantitative data on nuclear families and that can help to assess degrees of mode of inheritance is developed. Given phenotype values of spouses x⁽¹⁾ and x⁽²⁾ and offspring y, the deviation of an offspring value from the midparent is $\text{¦y ?}\text{1}\text{2}\text{(x}{}^{\mathrm{(1)}}\text{+ x}{}^{\mathrm{(2)}}\text{)¦}$, and those from the separate parents are $\text{¦y ? x}{}^{\mathrm{(1)}}\text{¦}$ and $\text{¦y ? x}{}^{\mathrm{(2)}}\text{¦}$. The indices called major-gene indices (MGI) investigated are functions of the deviations from midparental values compared to corresponding symmetric functions of the deviations from separate parents. Major-gene indices exceeding 1 may indicate some extent of major-gene inheritance, whereas an MGI less than 1 is suggestive of relatively more polygenic inheritance. Superposition of assortative mating and environmental effects will tend not to shift the MGI greater than 1 for polygenic inheritance, nor will they shift the MGI less than 1 for major-gene factors. The reliance on the proposed indices is reinforced on the basis of a hierarchy of representative models of monogenic and multifactorial inheritance. Extensions of the method to deal with multigenerational pedigrees are briefly discussed.     

Cytoplasmic inheritance in green algae: patterns,mechanisms and relation to sex type

Cytological and genetic investigations of two major groups of green algae, chlorophyte and streptophyte green algae, show a predominance of uniparental inheritance of the plastid and mitochondrial genomes in most species. However, in some crosses of isogamous species of Ulva compressa, these genomes are transmitted from mt⁺, mt⁻, and both parents. In species with uniparental organelle inheritance, various mechanisms can eliminate organelles and their DNA during male gametogenesis or after fertilization. Concerning plastid inheritance, two major mechanisms are widespread in green algae: (1) digestion of plastid DNA during male gametogenesis, during fertilization, or after fertilization; and (2) disintegration or fusion of the plastid in the zygote. The first mechanism also eliminates the mitochondrial DNA in anisogamous and oogamous species. These mechanisms would ensure the predominantly uniparental inheritance of organelle genomes in green algae. To trace the evolutionary history of cytoplasmic inheritance in green algae, the relations between uniparental inheritance and sex type were considered in isogamous, anisogamous, and oogamous species using sex-specific features that might be nearly universal among Chlorophyta.     

A new type of antagonistic activity of Saccharomycetes yeasts and its mode of inheritance

New type of killer activity of Saccharomyces cerevisiae was found. About 40% of this yeast strains tested formed growth inhibition zones on the lawn of the sensitive yeast Pachysolen tannophilus (Boldin et Adzet) BKM y-274. As shown by crossing these killers with non-killers and the tetrad analysis of hybrids obtained, 2 killer: 2 non-killer segregation took place, indicating the chromosomal mode of inheritance of the character. Mutants with weak expression of this killer activity were obtained after treating with 5-fluorouracil and cycloheximide.     

Adaptive dose-finding: Proof of concept with type I error control

We consider an adaptive dose‐finding study with two stages. The doses for the second stage will be chosen based on the first stage results. Instead of considering pairwise comparisons with placebo, we apply one test to show an upward trend across doses. This is a possibility according to the ICH‐guideline for dose‐finding studies (ICH‐E4). In this article, we are interested in trend tests based on a single contrast or on the maximum of multiple contrasts. We are interested in flexibly choosing the Stage 2 doses including the possibility to add doses. If certain requirements for the interim decision rules are fulfilled, the final trend test that ignores the adaptive nature of the trial (naïve test) can control the type I error. However, for the more common case that these requirements are not fulfilled, we need to take the adaptivity into account and discuss a method for type I error control. We apply the general conditional error approach to adaptive dose‐finding and discuss special issues appearing in this application. We call the test based on this approach Adaptive Multiple Contrast Test. For an example, we illustrate the theory discussed before and compare the performance of several tests for the adaptive design in a simulation study.     

Naive application of permutation testing leads to inflated type I error rates

Failure to account for family structure within populations or in complex mating designs via uninformed applications of permutation testing will lead to inflated type I error rates. Careful consideration of the design factors is essential since some situations allow several valid permutation strategies, and the choice that maximizes statistical power will not always be intuitive.     

Theoretical aspects of the mode of transmission in cultural inheritance.

This study investigates how evolutionary factors interact to determine the relative importance of vertical versus nonvertical mode of transmission in cultural inheritance. Simple mathematical models are provided to study the joint evolution of two cultural characters, one determining the viability and the fertility of individuals, and the other determining the vertical transmission rate of the first trait. Ordinary local stability analyses indicate that intrademic processes should lead to a greater reliance on vertical cultural transmission. On the other hand, when newly arisen variants are adaptive and favored in biased cultural transmission, interdemic processes may lead to a decrease in vertical transmission. This is because biased nonvertical transmission may effectively propagate the adaptive variants, further increasing the average growth rate of the population. These results are verified under several distinct sets of assumptions. It is also inferred that the degree and intensity of transmission bias may be the important determinants of cultural processes.     

Using lod-score differences to determine mode of inheritance: a simple, robust method even in the presence of heterogeneity and reduced penetrance.

Determining the mode of inheritance is often difficult under the best of circumstances, but when segregation analysis is used, the problems of ambiguous ascertainment procedures, reduced penetrance, heterogeneity, and misdiagnosis make mode-of-inheritance determinations even more unreliable. The mode of inheritance can also be determined using a linkage-based method (maximized maximum lod score or mod score) and association-based methods, which can overcome many of these problems. In this work, we determined how much information is necessary to reliably determine the mode of inheritance from linkage data when heterogeneity and reduced penetrance are present in the data set. We generated data sets under both dominant and recessive inheritance with reduced penetrance and with varying fractions of linked and unlinked families. We then analyzed those data sets, assuming reduced penetrance, both dominant and recessive inheritance, and no heterogeneity. We investigated the reliability of two methods for determining the mode of inheritance from the linkage data. The first method examined the difference (delta) between the maximum lod scores calculated under the two mode-of-inheritance assumptions. We found that if delta was > 1.5, then the higher of the two maximum lod scores reflected the correct mode of inheritance with high reliability and that a delta of 2.5 appeared to practically guarantee a correct mode-of-inheritance inference. Furthermore, this reliability appeared to be virtually independent of alpha, the fraction of linked families in the data set, although the reliability decreased slightly as alpha fell below .50.(ABSTRACT TRUNCATED AT 250 WORDS)     

西花蓟马对多杀菌素的抗性汰选和遗传方式

在室内进行了西花蓟马Frankliniella occidentalis(Pergande)种群对多杀菌素的抗性筛选和抗性遗传方式分析。经过2年多的汰选,抗性水平相比较初始种群提高了30倍,与同时测定的敏感品系相比抗性达到80.8倍。抗性遗传方式分析结果表明,正、反交后代显性度分别为0.51和0.43,二者差异不显著,说明西花蓟马对多杀菌素的抗性为常染色体、不完全显性遗传;剂量对数死亡机率值曲线分析结果显示回交后代在死亡率50%处,自交后代在死亡率25%和75%处未出现明显平坡,回交和自交后代实测值卡方检验进一步证实抗性为多基因控制。     

Models of multifactorial inheritance: I, multivariate formulations and basic convergence results

A multivariate dynamic model of a vector phenotype trait under the influence of a selective mating pattern, a hierarchy of parental-offspring transmission rules, and random environmental effects is developed. The formulation can incorporate age class effects, geographical variation, asymmetric maternal and paternal contributions, sex-differentiated offspring expression, selective family adoption procedures, and classes of family and pedigree influences. The mating, transmissible, and environmental aspects of family structure parameters can vary systematically or randomly in time. Cultural and biological variables are handled in one framework. Results on the dynamic and equilibrium behavior of these multivariate processes are set forth and interpreted.     

The effect of intraspecific sample size on type I and type II error rates in comparative studies

Comparative studies have increased greatly in number in recent years due to advances in statistical and phylogenetic methodologies. For these studies, a trade-off often exists between the number of species that can be included in any given study and the number of individuals examined per species. Here, we describe a simple simulation study examining the effect of intraspecific sample size on statistical error in comparative studies. We find that ignoring measurement error has no effect on type I error of nonphylogenetic analyses, but can lead to increased type I error under some circumstances when using independent contrasts. We suggest using ANOVA to evaluate the relative amounts of within- and between-species variation when considering a phylogenetic comparative study. If within-species variance is particularly large and intraspecific sample sizes small, then either larger sample sizes or comparative methods that account for measurement error are necessary.     

The anthocyanin pigmentation pattern in Hibiscus sabdariffa L. and its mode of inheritance,with special reference to the variation intermedius

The anthocyanin pigmentation patterns of stem, epicalyx, calyx, fading corolla, colour of anthers and petal spot character were studied in Hibiscus sabdariffa L.The stem and epicalyx pigmentation are controlled by the c and r genes. The two genes C and R are involved so far as calyx pigmentation, fading corolla colour and the anther and spot colours are concerned but an additional factor f is assumed to explain the segregation of the calyx pigmentation and fading corolla colour. Thus, a total of three genes (c, r. f) is distinguished, segregating independently.The intermedius type resembles the green-light-red rype of altissima in stem and epicalyx pigmentation but shows distinct differences in calyx pigmentation and fading corolla colour.