Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade island.

To determine the nature of the genetic component controlling susceptibility to leprosy and its subtypes, complex segregation analysis, by means of the POINTER strategy, was performed on 27 multigenerational pedigrees from Desirade, a Caribbean island where leprosy is highly prevalent. The results are consistent with the presence of a recessive or codominant major gene controlling susceptibility to leprosy per se and nonlepromatous leprosy, respectively. Under the major-gene model, tests of homogeneity to check for internal consistency of the sample and to compare subsamples according to an epidemiological criterion, the place of residence of the probands, were conducted; results of none of these tests were significant. However, we have noted that information on 3 generations (nuclear families with a pointer to the sibship) is of major importance for detecting major gene(s). Besides, the discrepancy in the results obtained in separate analyses of the family subsamples defined by the place of residence of the probands is discussed in terms of possible genetic and/or environmental differences. Referring to experimental data and previous studies, we suggest that the gene for susceptibility to leprosy per se and that for susceptibility to nonlepromatous leprosy might be different, acting at successive stages of the immune response to infection with Mycobacterium leprae.     

On the evolution of fluctuating segregation distortion

Previous mathematical models of the genetic control by one locus of the segregation at another have all concluded that alleles causing departures from Mendelian segregation should succeed. In this study the segregation ratios induced at the major locus by the modifier locus fluctuate cyclically. It is shown that if initially there is Mendelian segregation and if the rare modifying allele induces symmetric fluctuation about the Mendelian ratios it cannot succeed. It is further proven that if initially there are symmetric fluctuations about Mendelian segregation then an allele reducing the amplitude of the fluctuation will succeed.     

Inheritance of dermatoglyphic asymmetry in 500 Indian pedigrees: complex segregation analysis

The major aim of this study is to determine the mode of inheritance of asymmetry of quantitative dermatoglyphic traits based on principal factors through the application of complex segregation (genetic model fitting) analyses on a large ethnically homogeneous sample of 500 Indian pedigrees (2435 individuals) of two generations. By segregation analysis of the traits- PC1_FA both Mendelian and Environmental models were rejected (< 0.001) with the General model, i.e. that despite presence of significant inheritance (rejection of Environmental model), the nature of inheritance is more complex, than Mendelian one. Although a little genetic effect was observed due to familial correlations on asymmetry traits, no evidence was found of major gene contribution to be involved, but this does not contradict the notion postulated by several earlier authors that asymmetry (fluctuating) provides a measure of developmental instability in human.     

Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics.

To determine the nature of the genetic component controlling liability to alcoholism, complex segregation analysis was performed on 35 multigenerational families each ascertained through a pair of male alcoholics. The results suggest that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. Mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus. Absence of this major effect, leaving only multifactorial effects, was also rejected. Some sources for the non-Mendelian character of the major effect are suggested, such as a combination of two or more Mendelian loci, the presence of phenocopies, sex-dependent differences in the underlying liability model, or heterogeneity in the alcoholism phenotype. Evidence for and against each is discussed.     

Heterogeneity of genetic control of blood pressure in ethnically different populations.

We review the literature on statistical genetic analyses of blood pressure in samples from various ethnic backgrounds using different statistical methods and packages. We then provide the results of a complex segregation analysis performed on familial data on systolic and diastolic blood pressure in 2 ethnically different populations, Chuvashans and Turkmenians. Two types of major gene models were tested in the segregation analysis: Model type 1 tests for a Mendelian mode of transmission and estimates genotype-specific averages regardless of age and sex effect, and model type 2 estimates age and sex effects on each of 3 genotypes within the putative major genotype. In both total samples, by both types of segregation analysis, familial aggregation of both systolic and diastolic blood pressure was inconsistent with the Mendelian mode of inheritance. In the next step of analysis the pedigrees in both samples were sorted into 2 groups on the basis of 2 likelihoods as obtained under Mendelian and nontransmission models for each entire sample. This procedure resulted in the appearance of 2 subsamples (large and small) in each ethnic sample. The segregation analysis that was carried out then on the larger subsample provided consistent evidence to support the major gene effect on systolic and diastolic blood pressure in 2 ethnic groups. Interestingly, model type 2 showed that in both ethnically different large subsamples, for each sex the genotype predisposing to a larger mean value of systolic (or diastolic) blood pressure also displayed the highest rate of blood pressure increase with age. We discuss in detail possible sources of heterogeneity in familial transmission of blood pressure observed in our 2 samples, and we suggest a method to improve the analysis of heterogeneity for trait inheritance.     

Nonrandom segregation during meiosis: the unfairness of females

Most geneticists assume that chromosome segregation during meiosis is Mendelian (i.e., each allele at each locus is represented equally in the gametes). The great majority of reports that discuss non-Mendelian transmission have focused on systems of gametic selection, such as the mouse t-haplotype and Segregation distorter in Drosophila, or on systems in which post-fertilization selection takes place. Because the segregation of chromosomes in such systems is Mendelian and unequal representation of alleles among offspring is achieved through gamete dysfunction or embryonic death, there is a common perception that true disturbances in the randomness of chromosome segregation are rare and of limited biological significance. In this review we summarize data on nonrandom segregation in a wide variety of genetic systems. Despite apparent differences between some systems, the basic requirements for nonrandom segregation can be deduced from their shared characteristics: i) asymmetrical meiotic division(s); ii) functional asymmetry of the meiotic spindle poles; and iii) functional heterozygosity at a locus that mediates attachment of a chromosome to the spindle. The frequency with which all three of these requirements are fulfilled in natural populations is unknown, but our analyses indicate that nonrandom segregation occurs with sufficient frequency during female meiosis, and in exceptional cases of male meiosis, that it has important biological, clinical, and evolutionary consequences. Received: 28 December 2000 / Accepted: 23 January 2001     

病理性近视的家系研究

为了探讨我国病理性近视的遗传模式,对90个病理性近视大家系进行了分离分析。简单分离分析采用先验法和SEGRAN-B软件,进行拟合优度卡方检验,比较实际分离比与理论分离比的符合程度;复合分离分析运用SAGE-REGD软件进行孟德尔遗传模型(主基因、显性、隐性、共显性)和非孟德尔遗传模型(非传递、环境、一般)的拟合。结果显示,婚配类型为A*N的家系符合常染色体显性遗传,散发概率为13．8％,婚配类型为N*N的家系符合常染色体隐性遗传,散发概率为16．3％,但常染色体显性遗传不能除外,复合分离分析接受孟德尔遗传的显性、隐性、共显性和主基因模型,共显性模型的可能性最大,基因频率为0．21442999。因此,我国病理性近视存在常染色体显性和隐性遗传模式,并有一定比例的散发病例,具有遗传异质性。     

Components of Selection in X Chromosome Lines of DROSOPHILA MELANOGASTER: Sex Ratio Modification by Meiotic Drive and Viability Selection

Selection coefficients and segregation parameters have been estimated in 18 randomly chosen lines carrying wild X chromosomes on the cn bw genetic background. Each line was studied in replicated crosses of four types, with approximately 100 replications per line per cross. Crosses in which male X chromosomes differed exhibited significant sex ratio heterogeneity. Maximum likelihood estimation of segregation parameters revealed two lines in which the proportion of X-bearing gametes produced by males was significantly different from Mendelian expectations. These observations suggest that segregation distortion is a common feature of naturally occurring genetic variation. Non-Mendelian segregation has important evolutionary implications.     

VARIATION IN ENVIRONMENTAL AND GENOTYPIC SEX-DETERMINING MECHANISMS ACROSS A LATITUDINAL GRADIENT IN THE FISH,MENIDIA MENIDIA

Models of environmental sex determination (ESD) usually assume that genetic influences on sex are polygenic, but the validity of this (or any other) form of genotype-environment interaction is virtually unknown. In the Atlantic silverside, Menidia menidia, sex is determined by an interaction between temperature and genotype and the response of sex ratio to temperature differs among populations from different latitudes. We examined the genetic basis of this pattern by measuring among family variation in the proportion of females, F/(F + M), within and among high (21°C) and low (15°C) temperatures for two populations: one from Nova Scotia (NS) where the level of ESD is low, and another from South Carolina (SC) where the level of ESD is high. In NS fish, temperature had a significant influence on sex ratio in only 1 of 23 families. The distribution of the fraction of females within temperatures for families from NS was highly heterogeneous and tended to fall into distinct classes (0.0, 0.25, 0.5, 1.0) like that expected from Mendelian segregation of a major sex factor(s). In contrast, temperature had a highly significant influence on sex ratio in all SC families examined (N = 24). Family sex ratios within temperatures were highly heterogeneous and, at least at 15°C, did not conform to simple Mendelian ratios. At 21°C, the proportion of females in most SC families was near zero and so the underlying sex tendencies of different families could not be discerned. Based on a previous study, mid-latitude fish appear to have an intermediate form of sex determination: simple Mendelian sex-ratio patterns exist and there is a moderate thermal influence on sex ratio in most but not all families. We suggest that sex determination in M. menidia is controlled by an interaction between major genetic factors, polygenic factors, and temperature and that the relative importance of each component differs with latitude. High latitude populations appear to have evolved a major sex-determining factor(s) that overrides the effect of temperature, and this factor(s) is lacking in low latitude populations.     

Leprosy: a paradigm for the study of human genetic susceptibility to infectious diseases

Fifty years ago, the first identification of a non Mendelian genetic contribution to the development of a common infectious disease, i.e. the association between malaria and sickle-cell trait, was shown using a supervised approach which tests a limited number of candidate genes selected by hypothesis. Since then, the few genes that were convincingly associated with susceptibility to human infectious diseases were identified following the same strategy. The study of leprosy has contributed to modifying this way of thinking. In the absence of a satisfying experimental model and because of the impossibility to grow the causative agent in vitro, the candidate gene approach has turned out to be of limited interest. Conversely, positional cloning led to the identification of two major genes involved in the control of the disease, establishing for the first time the oligogenic nature of a human genetic contribution to an infectious disease. It is likely that these major results obtained in leprosy and the recent burst of genomic tools will make the genome-wide screening (functional or positional) the main strategy of dissection of the genetic susceptibility to many common infectious diseases.     

Evidence of Pleiotropic Loci for Fasting Insulin,Total Fat Mass,and Abdominal Visceral Fat in a Sedentary Population: The HERITAGE Family Study

Objective: To examine whether there is a major gene effect on fasting insulin and pleiotropic loci for fasting insulin, total fat mass (FM), and abdominal visceral fat (AVF). Research Methods and Procedures: A major gene hypothesis for fasting plasma insulin levels was assessed using segregation analyses of data on 495 members in 98 normolipidemic sedentary families of white descent who participated in the HERITAGE Family Study. Results: Segregation analyses were performed on insulin adjusted for age, on insulin adjusted for age and FM, and on insulin adjusted for age and AVF. Before adjustment for AVF and FM, a major gene effect on fasting insulin levels was indicated. The putative locus accounted for 54% of the variance under a recessive inheritance pattern, affecting 11% of the sample (i.e., allele frequency = 0.33). However, after adjusting for the effects of AVF or FM, neither a major effect alone nor a multifactorial component alone could be rejected, and support for a major gene was equivocal, i.e., neither the hypothesis of Mendelian τ values or that of the equal τs were rejected and the equal τ model fit the data better than the Mendelian τ model. This pattern (i.e., major gene evidence for insulin before but not after adjustment for AVF or FM) suggests that there is a putative locus with pleiotropic effects on both insulin and FM and another pleiotropic locus for both insulin and AVF. Discussion: Although these data do not directly support an additional major gene for insulin independent of AVF and FM, such support cannot be ruled out because there is still a significant major effect on FM‐ or AVF‐adjusted insulin (albeit the Mendelian nature of this effect is ambiguous).     

Segregation analysis of random amplified polymorphic DNA (RAPD) markers in Picea abies Karst.

The reliability of arbitrarily primed amplification products was tested. The segregation analysis of 266 amplification products obtained using 17 different 10-mer oligonucleotides in 34 megagametophytes from a single tree of Picea abies was carried out. Fifty-four out of the 165 variable bands fit the 1:1 segregation ratio expected for Mendelian traits. The segregation ratio of a subset of six RAPD markers in five other individuals from the same population confirmed their genetic nature. Our results strengthen the evidence previously reported that RAPDs markers can be considered Mendelian traits useful in the detection of genetic variability among both different individuals and populations.     

Segregation analysis reveals a major gene effect in compact and cancellous bone mineral density in 2 populations

Involvement of genetic factors in determining bone mineral density (BMD) is doubtless. However, the exact nature of the genes governing BMD variation and sources for genetic determination of BMD of different parts of bone (compact and cancellous) have not been completely studied. The results of the complex segregation analyses performed in our previous study (Livshits et al. 1996) on a Turkmenian sample strongly support the hypothesis that a single Mendelian locus has a large effect on BMD. The parameter estimates for both types of bone tissue were so similar that we could assume a common gene effect for BMD variation of cancellous and compact bone. The objectives of the present study are to test again the possibility of major gene control of BMD in a different ethnic sample of pedigrees, namely, the Chuvasha. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both the Turkemenian and the Chuvasha samples of pedigrees. The results of the present study closely resemble the results obtained on the Turkmenian pedigrees. Likewise, the major finding of the present study is that there is a significant major gene effect on both compact and cancellous BMD; polygenic hypotheses were clearly rejected. Moreover, the results of the bivariate segregation analysis in both the Chuvasha and Turkmenian samples were similar. They lead to acceptance of the hypothesis that there is a single major locus with pleiotropy to both compact and cancellous bone.     

Leprosy as a genetic disease

Leprosy (Hansen??s disease) is a human infectious disease whose etiological agent, Mycobacterium leprae, was identified by G. H. A. Hansen in the 19th century. Despite the high efficacy of multidrug therapy (<0.1% annual relapse rate), transmission is persistent. In 2008, approximately 250,000 new cases were reported to the World Health Organization. Clinically, leprosy presents as either the paucibacillary (1?C5 lesions) or the multibacillary (>5 lesions) subtype, highly reflective of a Th1 (cell-mediated) or Th2 (humoral) host immune response, respectively. Subsequent to Mycobacterium leprae exposure, epidemiological studies (e.g., twin studies and complex segregation analyses) maintain the importance of host genetics in susceptibility to leprosy. The results of genome-wide analyses (linkage and association) and candidate gene studies suggest an independent genetic control over both susceptibility to leprosy per se and development of clinical subtype. Moreover, the emergence of a shared genetic background between leprosy and several inflammatory/autoimmune diseases suggests that leprosy is a suitable model for studying the genetic architecture and subsequent pathogenesis of both infectious and inflammatory/autoimmune diseases. We provide the example of NOD2 (Crohn??s disease gene) and LTA (myocardial infarction gene) and the implication of a common genetic risk factor between these two diseases and leprosy. The value of leprosy as a model disease therefore extends far beyond this ancient disease to common afflictions of the 21st century.     

Testing Mendelian inheritance from field-collected parasites: Revealing duplicated loci enables correct inference of reproductive mode and mating system

Cryptic aspects of parasite population biology, e.g., mating systems, are increasingly being inferred from polymorphic and co-dominant genetic markers such as microsatellite loci. Underlying the use of such co-dominant markers is the assumption of Mendelian inheritance. The failure to meet this assumption can lead to artifactual statistics and erroneous population inferences. Here, we illustrate the importance of testing the Mendelian segregation and assortment of genetic markers and demonstrate how field-collected samples can be utilised for this purpose. To examine the reproductive mode and mating system of hermaphroditic parasites, we developed microsatellites for the cestode, Oochoristica javaensis. Among loci, we found a bimodal distribution of F_IS (a fixation index that quantifies the deviation from Hardy–Weinberg equilibrium within subpopulations) values where loci were either highly negative (close to −1) or highly positive (∼0.8). By conducting tests of Mendelian segregation from natural crosses, we determined that loci with negative F_IS values were in fact duplicated loci that were amplified by a single primer pair. Genetic crosses also provided linkage data and indicated that the duplicated loci most likely arose via tandem duplications rather than whole genome/chromosome duplications. By correcting for the duplicated loci, we were able to correctly infer that O. javaensis has sexual reproduction, but the mating system is highly inbred. To assist others in testing Mendelian segregation and independent assortment from natural samples, we discuss the benefits and limitations, and provide guidelines for particular parasite systems amenable to the methods employed here.     

Selective Embryo Abortion Hypothesis Revisited - A Molecular Approach

Abstract: Many plant species abort a large fraction of their embryos. It has often been suggested that embryos of genotypes that would perform worse later in life are preferentially aborted. Such selective embryo abortion would lead to investment of resources only in the offspring with the highest potential fitness. Many studies have shown that otherwise viable embryos are aborted. However, only few manipulative studies have indeed shown a correlation between the level of abortion and offspring quality and these studies have been challenged for their experimental design. Molecular techniques open new opportunities to study selective embryo abortion. Non-random abortion at the level of molecular markers can be observed as a deviation from Mendelian segregation: over- or under-representation of markers in the offspring. Subsequently, the over- or under-represented markers can be related to offspring quality later in life. We reviewed the literature on the genetic maps of intraspecific crosses of wild plant species and the selection of cultivated species. The level of non-Mendelian segregation we found in these maps is high. On average, 11.5 % of the tested markers in the genetic maps of wild species and 14.6 % in the cultivated ones, show a departure from Mendelian segregation. From six studies, providing sufficient data, it was calculated that in 68 % of loci segregating in non-Mendelian fashion post-fertilization selection is involved. We propose that the deviation from Mendelian segregation can be partly explained by selective embryo abortion. We describe an experimental design that allows for attributing selective embryo abortion to the non-Mendelian segregation that is found in a genetic map.     

Segregation,linkage, and diversity of allozymes in knobcone pine

Summary Female gametophytes of knobcone pine were used to study genetic variation at 58 loci in 26 enzyme systems. Mendelian segregation and linkage were tested at 21 loci. Got1, Pgi2, Mnr3, Adh2, and Lap2 were linearly arrayed in a single linkage group. Est and Acp3, and Flest and Lap1, formed two independent linkage groups. Although Mendelian segregation was the rule, several cases of segregation distortion were observed. Pooled over trees, Lap1 and Aap1 showed significant distortion. Of 11 cases of distortion observed for individual trees, 10 showed an excess of common alleles. Pooled over both loci and trees, giving a total sample of 17,183 gametes, the common alleles were significantly overrepresented by 1.1%, and heterogeneity was highly significant. Our results, and others in the literature, suggest that segregation distortion may affect the genetic structure of conifer populations.     

送春与多花兰种间杂交后代的ISSR分析

该文使用简单重复序列间( ISSR)分子标记,对送春与多花兰种间杂交后代进行了研究。结果表明：从80个ISSR引物中筛选出14个扩增效果稳定的ISSR引物,对两亲本和59个F1代个体进行了ISSR扩增,得到107个扩增位点,扩增的片段大小位于90~2100 bp之间,平均每个引物扩增7.64条条带,得到11种类型的带。 ISSR标记在送春×多花兰的F1代中表现出一定的多态性,分离频率为44.86％,分离位点有83.33％符合孟德尔1︰1或3︰1的分离规律,产生偏孟德尔分离的位点占12.50％,余下的4.17％属于特殊分离带型。可能导致后代变异的位点为偏孟德尔分离的6条带、缺失的8条带或新生成的2条带。聚类图中父本和母本与F1代个体间的遗传距离较远,59个杂交后代先聚集成一组,再同母本相聚为一组,最后才同父本聚在一起,59个杂种均偏母本型。送春与多花兰的杂交后代在植株形态、染色体、遗传物质方面都具备双亲特点,61个个体间的ISSR分子量标记结果和植株形态学特征都说明,59个F1代杂种包含送春和多花兰的遗传特性是真杂种;F1代杂种既有双亲的互补特征带,又有双亲的重组片断即产生新的特异带,这说明送春与多花兰的杂交后代具有遗传变异的特点。该研究结果可以有效地对杂交后代进行定向选择,为兰花的杂交育种提供了分子依据。     

TRANSMISSION GENETICS OF ISOZYME LOCI IN RAPHANUS SATIVUS (BRASSICACEAE): STRESS-DEPENDENT NON-MENDELIAN SEGREGATION

Deviations from Mendelian ratios are frequently treated as an intrinsic property of individuals, independent of the environment. We tested whether the environment of the parents could alter patterns of inheritance in the wild radish, Raphanus sativus. We demonstrated the genetic basis of 12 isozyme loci by controlled pollinations of unstressed plants. The frequency of deviant segregation detected was not different than that expected by chance. Controlled pollinations among stressed plants showed over 3 times as much deviant segregation as the unstressed controls. No genetic correlates of segregation bias were detected. Linkage was assessed for 64 of the 66 pairs of loci. Two linkage groups were detected, one involving four loci (PGM2–ACO–ACP–LAP), the other involving a single pair (EST-PRX). The second linkage group is apparently associated with a locus or tightly linked loci which may segregate for “balanced” lethals on the same chromosome. Deviant segregation did not appear to act primarily by selection on a particular gamete. Postzygotic selection was the probable source of at least some of the aberrant segregation. Because no particular allele was favored in such situations, selection is apparently operating on alleles at linked loci rather than on the allozyme loci per se. Data from other studies on wild radish support the suggestion that postzygotic selection might be an important influence on progeny segregation ratios. Because wild radishes often encounter a variety of stresses in the field, in this species, aberrant segregation may be common under natural conditions.     

Common features of segregation distortion in plants and animals

Segregation distortion is increasingly recognized as a potentially powerful evolutionary force. This runs counter to the perception that non-Mendelian genes are rare genetic curiosities, a view that seems to be supported by the near ubiquity of the Mendelian system of inheritance. There are several reasons why segregation distortion may be more important than is evidenced by known empirical examples. One possibility is that the types of segregation distorters we have found are only a subset of a broader range of non-Mendelian systems, many of which go undetected. In this paper, we review what is known about the sex-linked meiotic drive system in the plant, Silene latifolia, and present some data on the mechanism of segregation distortion. We outline the general features that segregation distorters in plants and animals have in common. In some cases, such as the paucity of systems that directly alter meiotic segregation, there are likely to be inherent constraints on the range of systems that can possibly occur. Other generalities, however, support the notion that many forms of meiotic drive are possible, and that the known examples of segregation distortion are likely to be only subset of those that can possibly occur. Non-Mendelian genes may therefore have greater evolutionary importance than their current abundance in nature would suggest.