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PubMed1996

Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness.

To investigate genetic factors in asthma and atopy, we sought allelic associations for 12 markers near candidate loci for serum total, immunoglobulin E (IgE), and bronchial hyperresponsiveness (BHR) to inhaled histamine in 131 families comprising 685 individuals, selected randomly without regard to atopy or asthma. Nonparametric linkage and association analyses were performed with the Nonparametric Analysis of Lineage and Association (NOPAR) program, and parametric analyses were performed with the Complex Inheritance with Diathesis and Severity (COMDS) program on an ordered polychotomy of ranked scores. On chromosome 11q, allele 168 at the D11S527 locus was significantly associated with BHR (p<0.0003) but not with log IgE. At the D11S534 locus, allele 235 was significantly associated with log IgE (p = 0.007) but not with BHR. Both D11S527 and D11S534 were too distant from the gene encoding the high-affinity IgE receptor FcepsilonRIbeta to account for the association. At the interleukin-9 (IL-9) locus, the 118 allele showed significant association with serum total IgE (p<0.003) but not with histamine BHR. Parametric tests are more conservative, perhaps because they demand consistency with mendelian inheritance and tight linkage. These findings provide support for the view that both chromosomes 5 and 11 may contain genes relevant to asthma and atopy, a possible candidate being the interleukin-4 (IL-4) gene cluster. Because these associations are extremes in a large number of tests, they require confirmation in other samples.

Adolescent↗

PubMed2006

Discrete polymorphisms due to disruptive selection on a continuous trait--I: the one-locus case.

We have investigated, numerically and analytically, long-term evolution under frequency-dependent disruptive selection of a continuous trait varying in a finite range and controlled by one diploid mendelian locus. We found that evolution converges towards a unique long-term equilibrium where only two extreme phenotypes are present with frequencies identical to those of the mixed strategy that would be the unique ESS of the game defined by the basic fitness function of the model. As long as this precise phenotypic composition is preserved, any genetic configuration of the polymorphism is equally acceptable (selectively neutral) at the equilibrium. Thus the number of alleles and their dominance pattern may vary considerably among different equilibrium populations. If genetic expression of the trait is variable but the amount of variability is genetically modifiable, disruptive selection, acting on such modifiers, produces a steady increase of expression variability before the equilibrium is attained. In this case a population at the long-term equilibrium might even be genetically monomorphic, with the phenotypic dimorphism resulting from purely random individual variation.

Alleles↗

PubMed2005

[Identification and mapping of polymorphic RAPD markers of pea (Pisum sativum L.) genome].

Various pea cultivars, lines, and mutants were studied by the RAPD method. Polymorphic fragments characteristic of certain pea genotypes and which can be used for identifying genotypes were detected. Inheritance of some polymorphic RAPD fragments was studied. Mendelian inheritance of these fragments was shown. By analyzing the data obtained in studies of RAPD polymorphism, genetic distances between different pea cultivars, lines, and mutants were calculated and a genealogic dendogram showing a varying extent of differences between RAPD patterns was constructed. Ten new RAPD markers linked to various pea genes were detected. Genetic distances between RAPD markers and genes to which they are linked were calculated, and the respective disposition of RAPD markers on chromosomes was established.

Chromosome Mapping↗

PubMed2000

Evidence for major genes influencing pulmonary function in the NHLBI family heart study.

Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0. 515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function.

Anthropometry↗

PubMed2003

The heritability theory of heterosis and its meaning for global agriculture.

This paper begins with the overthrow of the concept of combining ability in crossbreeding by the concept of heritability. The reason is that general combining ability changes with the number and kind of pure strains in the foundation stock and hence special combining ability changes also, so that work with different kinds of pure strains in the foundation stock cannot be compared. Hence combining ability is useless as a parameter to predict the amount of heterosis expected in the next generation. On the other hand, since each cross has a separate heritability, it can be applied to a cross population just as successfully as in purebreeding. Since the same concept holds in both cases, resort to any other concept would be superfluous. That's why combining ability must be rejected. Another reason (not given in the full text) is, an infinite number of pure strains would be required in the foundation stock for its results to be comparable with those of the heritability theory, which disposes of its utility altogether. The main content of the thesis is then the centennial enigma of heterosis can be resolved by Descarte's theoretic method of deduction. Accordingly we start from the definition of heterosis. [formula: see text] where H is heterosis, F1 is the first generation offspring, MP is the mean of the parents or midparent, and from the use of a binomial random variable and its extension to the multinomial case derive the basic relations of heterosis with its components. Starting with second degree statistics, we obtain [formula: see text] where V and cov stand for variance and covariance. The equations of heterosis are [formula: see text] where N is number of genes controlling a trait, a = (Pi - Pj)/2, d is deviation from midparent, while the variance components are all indicated by their names under the respective terms. It turns out that all these can be easily computed from the data so that the problem becomes a simple one which any college student may solve. In other words, the right answers are found when the right questions are asked. Who had ever shown that the heritability principle is inapplicable in crossbreeding, e.g., in a crossing of two pure strains? From this cue arose the realization that the F1 of a cross of two pure strains must also be a Mendelian population, with p and q both equal to 1/2 which simplifies the algebra outright. This Heritability Theory of Heterosis, or HTH in capital letters, rests on 2 initial arguments: 1) Since 0.5 + 0.5 = 1, crossing two pure strains gives a population which is only a special case of pure-breeding, therefore a heritability coefficient must exist for the F1; 2) Our problem reduces to that of finding that coefficient; the answer is given by the additive component divided by VF1, i.e., (1/2) Na2/VF1. which is readily found from the solution of the heterosis equations. Thus the eternal enigma of heterosis is resolved! This happened at the end of the 20th century. We now come to the second point of the discovery, the new genetic parameter crossheritability which will rise in size with the increase of the number of times it's used and form the link between breeding and evolution. The advent of the Age of Evolution Engineering in the 21st century marks a totally new era, showing that artificial will ultimately supercede natural selection, with the long span of time element eliminated. For agriculture at least, it means there is no limit to the increase of food supply by the new method, with the concentration of desirable genes by hybridization in place of the old theory of their fixation. Genetic gain is achieved through artificial selection, with an 80% saving of time, labor and cost by adoption of the new method. Applied to a further increase in all kinds of agricultural products including hybrid rice, it means that a huge escalation, in fact a New Green Revolution, on a much larger scale than that of any such before, is in view, provided it is adopted in our research and educational institutions as early as possible, ere its spread elsewhere. The possibilities from the evolution point of view can only be pictured by science fiction.

Agriculture↗

PubMed2003

Indexing anatomical concepts to OMIM Clinical Synopsis using the UMLS Metathesaurus.

As a first step toward the quantitative comparison of clinical features of diseases, we indexed the text descriptions in the Clinical Synopsis section of the Online Mendelian Inheritance in Man (OMIM) with concepts for the body parts, organs, and tissues contained in the Metathesaurus of the Unified Medical Language System (UMLS). We also indexed the text with the diseases and disorders having links to body parts specified in the thesaurus. The vocabulary size was approximately 177,540 representations for 81,435 concepts, and 2,161 concepts were indexed to 3,779 OMIM entries. The indexed concepts included 134 concepts for the noun forms of anatomical concepts and 985 indexed concepts for diseases and disorders that were linked to 132 and 408 anatomical concepts, respectively. We report herein that the retrieval of OMIM entries for diseases affecting specific organs can be made more comprehensive through the anatomical concepts indexed to the Clinical Synopsis or linked to the indexed concepts, as compared to simply matching organ names to the Clinical Synopsis text. The recall and precision of identifying relevant body parts in the Clinical Synopsis were calculated as 78% and 92.5%, respectively, based on random sampling. The examination of the unidentified body parts due to lack of indexed diseases and disorders showed that although most of the concepts for diseases and disorders were contained in the Metathesaurus, their relations to body parts were not. The indexing result proved the effectiveness of the Metathesaurus as a resource for the identification of concepts indicating body parts, diseases, and disorders.

Abstracting and Indexing↗

PubMed1996

Overall informativity, OI, in DNA polymorphisms revealed by inter-Alu PCR: detection of genomic rearrangements.

We studied two systems of multilocus markers revealed by PCR using primers directing amplification between Alu repeats in a tail-to-tail orientation. Genomic polymorphisms were detected as the presence or absence of the electrophoretic bands representing DNA fragments of a given length. A total of 104 such fragments segregating as Mendelian markers in a panel of eight CEPH families were analyzed by two-point linkage analysis. Fifty-one of these fragments were localized with respect to CEPH markers; they represented 33 loci, 7 of which were multiallelic. Locus-specific oligonucleotides were developed and used as hybridization probes to identify the mapped loci within a complex pattern of inter-Alu PCR products. A great proportion of inter-Alu PCR polymorphisms represented length variants within amplified DNA segments, while others were presumably due to mutations within the priming sites. To describe the expected number of informative loci per typing experiment we introduced a parameter called overall informativity (OI), which provides a single measure of the multiplex ratio and the informativity of markers contributing to a multilocus system (OI of a single locus is equivalent to its heterozygosity and cannot exceed 0.5 for a biallelic codominant marker). High OI values (5.8 and 11.5) of the two presented systems of inter-Alu PCR markers of random chromosomal distribution render them suitable for mapping genomic rearrangements such as genomic deletions in tumoral tissues. This was illustrated by the detection of loss of heterozygosity in the 9q22-qter region in sporadic colon cancer.

Animals↗

PubMed1977

The specific antigen-binding cell populations of individual fetal mouse spleens: repertoire composition, size, and genetic control.

In order to analyze the genetic and physiological basis of controls affecting the generation of the repertoire of antigen-binding cells in fetal mice, we have measured the numbers of spleen cells specific for each of four antigens as a function of the total numbers of nucleated and Ig-bearing cells in inbred, hybrid, and random bred fetuses. For each of the two inbred strains BALB/c and CBA/J, the proportion of nucleated cells specific for a given antigen was the same for all individuals of the strain at the 18th day of gestation. The proportion did vary from antigen to antigen, however, and for each antigen the proportion of specific cells observed in CBA/J fetuses was approximately four times that observed in BALB/c fetuses. This difference appeared to be due to a difference between the two strains in the relative size of the repertoire of antigen-binding spleen cells at this stage of development, inasmuch as the frequency of Ig-bearing spleen cells in CBA/J fetuses was likewise approximately four times that observed in BALB/c fetuses. In random bred Swiss-L fetal mice at the 18th day of gestation, the proportion of cells specific for a given antigen varied significantly from one individual to the next. The ratio of proportions of the two antigens observed was constant from individual to individual, however, and this constant ratio differed significantly from the ratio observed for the same two antigens in fetal BALB/c and CBA/J inbred mice. These data suggest that the ontogeny of the repertoire of antigen-binding cells in fetal mice is subject to at least two independent sets of controls, one affecting the relative size of the repertoire in the spleen, and the other affecting the distribution of antigen-binding specificities within that repertoire. Analysis of repertoire size and composition in the spleens of hybrid fetuses confirmed the observation that the two parameters are controlled independently, and suggested further that the control of repertoire size in these fetuses is due to the action of one or a few closely-linked autosomal Mendelian genes. These data are consistent with models for the origin of antibody diversity in which the genes coding for the full repertoire of antibodies are generated somatically from a small number of germ-line genes early in development and in the absence of any strong positive or negative selection with respect to antigenic specificity.

Animals↗

PubMed1996

Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study.

The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in 1993. Familial correlations and segregation analyses of lung function were carried out in 799 individuals in 214 nuclear families that included 214 fathers, 214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and maximal mid-expiratory flow rate (MMFR) were first regressed on age, height, weight, and their quadratic and cubic terms as well as on smoking status in four groups separately (mothers, fathers, daughters, and sons), with terms significant at the 0.10 level being retained. Residual phenotypes were standardized within the four groups. Class D regressive models were used to perform familial correlations and segregation analyses. For both FEV1 and MMFR, father-mother correlations were not significantly different from zero, and mother-offspring, father-offspring, and sibling-sibling correlations showed no statistically significant difference from each other. Based on the "polygenic" models, the estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/- 0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342 for MMFR. Segregation analysis shows that the "mixed" model with both single locus and polygenic components had a better fit for FEV1 than single-locus or polygenic only models. However, the model which included a nontransmitted environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0] [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood compared to the simple polygenic model. Comparison of the single-locus model and Mendelian "mixed" model shows no difference in fitting the data. This study suggests that FEV1 and MMFR are controlled by many loci with no major effects and/or common environmental factors.

Adolescent↗

PubMed1991

Characterization of the level, target sites and inheritance of cytosine methylation in tomato nuclear DNA.

The tomato nuclear genome was determined to have a G + C content of 37% which is among the lowest reported for any plant species. Non-coding regions have a G + C content even lower (32% average) whereas coding regions are considerably richer in G + C (46%). 5-methyl cytosine was the only modified base detected and on average 23% of the cytosine residues are methylated. Immature tissues and protoplasts have significantly lower levels of cytosine methylation (average 20%) than mature tissues (average 25%). Mature pollen has an intermediate level of methylation (22%). Seeds gave the highest value (27%), suggesting de novo methylation after pollination and during seed development. Based on isoschizomer studies we estimate 55% of the CpG target sites (detected by Msp I/Hpa II) and 85% of the CpNpG target sites (detected by Bst NI/Eco RI) are methylated. Unmethylated target sites (both CpG and CpNpG) are not randomly distributed throughout the genome, but frequently occur in clusters. These clusters resemble CpG islands recently reported in maize and tobacco. The low G + C content and high levels of cytosine methylation in tomato may be due to previous transitions of 5mC----T. This is supported by the fact that G + C levels are lowest in non-coding portions of the genome in which selection is relaxed and thus transitions are more likely to be tolerated. This hypothesis is also supported by the general deficiency of methylation target sites in the tomato genome, especially in non-coding regions. Using methylation isoschizomers and RFLP analysis we have also determined that polymorphism between plants, for cytosine methylation at allelic sites, is common in tomato. Comparing DNA from two tomato species, 20% of the polymorphisms detected by Bst NI/Eco RII could be attributed to differential methylation at the CpNpG target sites. With Msp I/Hpa II, 50% of the polymorphisms were attributable to methylation (CpG and CpNpG sites). Moreover, these polymorphisms were demonstrated to be inherited in a mendelian fashion and to co-segregate with the methylation target site and thus do not represent variation for transacting factors that might be involved in methylation of DNA. The potential role of heritable methylation polymorphism in evolution of gene regulation and in RFLP studies is discussed.

Base Composition↗

PubMed2003

Estimation of variances for gametic effects on litter size in Yorkshire and Landrace swine.

The objective of this study was to test for effects of gametic imprinting on litter size in swine by estimating variances for parent-specific gametic effects. Data were 64,047 and 137,009 multiparous records of number born alive for the U.S. Landrace and Yorkshire breeds, respectively. The statistical model included fixed effects of parity number and herd, and random effects of herd-year-season, mate, permanent environment, animal (additive genetic), and either maternal or paternal gametes. A Bayesian approach that used Gibbs sampling to obtain posterior distributions was employed. To aid in the interpretation of results, the Landrace data structure was used to simulate data with and without effects of imprinting. Analyses of the simulated records indicated that the model applied was capable of detecting effects of imprinting when such effects were present. Small, but non-zero, estimates of gametic variances were obtained when no imprinting was simulated. Estimates of the proportion of total variance accounted for by paternally transmitted gametes were 0.8 and 0.9% for Landrace and Yorkshires, respectively. These estimates were different from zero, but were similar to the results observed for data simulated without an imprinting effect. Corresponding results for maternally transmitted gametes were 1.6% for Landrace and 0.8% for Yorkshires. The estimate for Landrace was significantly greater than that observed for Yorkshires and for the simulations without a true effect and suggested the presence of a non-Mendelian genetic influence on litter size. Paternally imprinted genes are a plausible reason for the observed results. Assuming that the effect observed was due to paternal imprinting at a single biallelic locus, the substitution effect of the superior allele could be greater than 0.7 piglets per litter. Identification of a genetic marker for such an allele would be useful in marker-assisted selection of females. Other possible explanations exist for the increased gametic variance in the Landrace breed, but these explanations (such as maternal or cytoplasmic effects) may be less likely than paternal imprinting.

Animals↗

PubMed1986

A DNA probe detecting multiple haplotypes of the human Y chromosome.

We have characterized a DNA probe (49f) that detects about 15 Y-specific TaqI bands corresponding to a low-copy number sequence. Five of these bands, each representing a single DNA fragment, can either be present, absent, or variable in length. Familial segregation studies have shown that the variations of these fragments are inherited in a Mendelian fashion and strictly Y-linked. A survey of 44 male individuals indicated that the five variable TaqI fragments detected by probe 49f can be considered as five independent allelic series. Each series represents the different and mutually exclusive allelic forms observed for a single DNA fragment. A total of 16 haplotypes, each defined by a different combination of the various forms of each of these five restriction fragment length polymorphisms, were observed among the 44 scored individuals. These TaqI restriction polymorphisms are not observed with other restriction digests and have therefore been attributed to point mutations. The five polymorphic fragments map to Yq11, a region that does not recombine with the X chromosome and are therefore not redistributed. This implies that an apparently independent reassortment of one of these series with respect to the others can be explained only on the basis of mutations that occurred several times (or reverted) during evolution of the Y chromosome. However, an examination of the different combinations of two or more allelic series suggests that some alleles are not randomly distributed and raises the possibility of establishing a genealogy of the human Y chromosome.

Alleles↗

PubMed2003

Detection of universal variable fragments as markers for genetic studies. A novel technology for DNA fingerprinting.

A novel DNA technology enables the detection of universal variable fragments (UVF), thus revealing genetic variation without a priori sequence information. The detection of UVF markers is based on two amplifications of genomic DNA with the polymerase chain reaction. In the first amplification, two short oligonucleotide primers produce a large number of fragments. One primer is based on a microsatellite sequence, whereas the second primer can have any sequence. In the second amplification, the length of the primers is increased in order to decrease the number of amplicons. This enables the selection of polymorphic fragments. Restriction digestion can be used to further increase the number of polymorphisms. Until now, we have demonstrated UVF in several different species. In addition, with the present study we have contributed to the linkage map of the rabbit by localizing 11 UVF markers on different linkage groups. Mendelian inheritance was shown in this linkage study through a backcross of two inbred rabbit strains. The power of the UVF technique is based on the selection for microsatellite variation in combination with the detection of single-nucleotide polymorphisms. UVF thus offers the possibility of increasing the clustering of markers and localizing genes in species for which sequence information is either not present or only scarcely present.

Animals↗

PubMed2004

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (beta-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 ( approximately 12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas.

Adenoma↗

PubMed2001

Meiotic pairing of sex chromosome fragments and its relation to atypical transmission of a sex-linked marker in Ephestia kuehniella (Insecta: Lepidoptera).

The physical basis of non-Mendelian segregation of a sex-linked marker was studied in sex- chromosome mutant females of eight ASF ('abnormal segregating females') lines in the flour moth, Ephestia kuehniella. Electron microscopical analysis of microspread synaptonemal complexes revealed that in one line, the Z chromosome segment that contained the dz+ allele was translocated onto an autosome. The resulting quadrivalent visible in early female meiosis was 'corrected' into two bivalents in later stages. This explains autosomal inheritance of the sex chromosome marker in this strain. In the other seven ASF lines, the type of meiotic pairing of an additional fragment (Zdz+) of the Z chromosome was responsible for abnormal segregation of the marker gene. In several of these lines, Zdz+ contained a piece of the W chromosome in addition to the Z segment, as was confirmed by comparative genomic hybridization (CGH). Zdz+ formed three alternative pairing configurations with the original sex chromosomes: (i) a WZZdz+ trivalent, (ii) a WZ bivalent and a Zdz+ univalent or (iii) a ZZdz+ bivalent and a W univalent. In the most frequent WZZdz+ configuration, Zdz+ synapsed with Z and, consequently, segregated with W, simulating W linkage. This explains the predominant occurrence of the parental phenotypes in the progeny. Zdz+ univalents or W univalents, on the other hand, segregated randomly, resulting in both parental and nonparental phenotypes. In two of these lines, the Zdz+ was transmitted only to females. The results suggest that the W chromosome segment in Zdz+ of these lines contains a male-killing factor which makes it incompatible with male development. Our data provide direct evidence for the regular transmission of radiation-induced fragments from lepidopteran chromosomes through more than 50 generations. This is facilitated by the holokinetic nature of lepidopteran chromosomes. We conclude that Zdz+ fragments may persist as long as they possess active kinetochore elements.

Animals↗

PubMed1992

Allele frequency distribution of the (TG)n(AG)m microsatellite in the apolipoprotein C-II gene.

The dinucleotide (TG)n interspersed repetitive sequences are the most abundant microsatellites in the human genome. Using the polymerase chain reaction to amplify a (TG)n(AG)m microsatellite in the first intron of the apo C-II gene, we have detected 15 different alleles in 242 unrelated individuals of French ancestry. The heterozygosity index was 0.85 and codominant Mendelian inheritance of the alleles was observed in individuals from 121 nuclear families. We report that polymorphism at this locus is attributable to length variation at both (TG)n and (AG)m motifs, although the (AG)m motif contains only two alleles differing by one repeat unit. A quadrimodal allele frequency distribution was observed at the (TG)n(AG)m locus. Each of the first three modes comprises one frequent allele and one very rare allele adjacent in size. No alleles of intermediate size were found between the three first modes. The fourth mode encompasses nine alleles that span from 27 to 35 repeat units. We suggest that this distribution reflects the molecular mechanisms by which alleles give rise to one another.

Alleles↗

PubMed1998

[Population dynamics of the response of the genomic pattern of the mobile genetic element Dm412 in Drosophila on selection for a quantitative trait].

In an isogenic line of Drosophila melanogaster carrying the Mendelian mutation radius incompletus, selection for the total length of two segments of the disrupted longitudinal wing vein was conducted. After gamma-irradiation at a dose of 13 Gy, positive and negative truncation selection became highly effective and was completed in 50 generations. The pattern of mobile genetic element Dm412 was almost completely fixed in the course of selection. In the positive direction of selection, fixations of mobile genetic element (MGE) sites exceeded losses; in the negative direction, this relationship was reversed. The number of MGE sites in the pattern increased from 23 to 33 and to 26 in the positive and negative directions, respectively. The mean heterozygosity of MGE sites decreased respectively ten and six times. The dynamics of some sites (6F, 43B, 66A, 69E, and others) corresponded to that expected with an adaptive response to selection. Two out of these sites (43B and 66A) were previously assigned to hot sites of Dm412 transposition induced by heat shock. Fixation and loss of sites continued on average for tens of generations. Four hypotheses describe the relationship between patterns of polygenes and MGE in the context of explanation of the above facts: (1) genetic drift; (2) the linkage of MGE and polygenes without modification of the latter (hitchhiking); (3) the linkage and modifying effect of MGE on polygenes linked with them; (4) the selection of the "champion" pattern of polygenes and a random or adaptive MGE pattern linked with it. Hypotheses 1 and 2 are unlikely, hypothesis 3 is possible in the case of other selection modes, whereas hypothesis 4 seems to be most plausible.

Animals↗

PubMed1984

The bingo model of survivorship. II: statistical aspects of the bingo model of multiplicity 1 with application to hereditary polyposis of the colon.

Some Mendelian disorders (Huntington chorea, hereditary polyposis coli) are not manifest at birth but show a distribution in the age of onset. Patients at risk fall into three groups. In type I, they are affected when first examined. In type II, they are not affected at one visit, but are at a later visit. Those of type III (who comprise an indistinguishable mixture of those who have, and those who have not, inherited the gene) are never found to be affected. This paper posits a model that the age of onset is logistic. (It is a degenerate bingo model in which competing causes of death may be ignored.) The statistical properties of maximum likelihood estimation (MLE) are explored by Monte Carlo simulation of this logistic function with known arbitrary parameters. Two schemes are used: point-prevalence (or synchronic) data of types I and III, and piecewise longitudinal (diachronic) data; this allows all three types to be included. Samples of various sizes between 25 and 100 are used. While estimates of the parameters are positively biased (especially with small samples), the estimate of the mean appears to be consistent, almost unbiased, and fairly precise, though somewhat larger than the estimates from the lower bound (a fact that calls for some caution in interpreting actual data). The MLE was applied to 109 patients with the Gardner syndrome (GS); measures of variability found by applying MLE to four random subsets of 25 each were compared against the asymptotic estimates. The analysis was also applied to 36 persons with familial polyposis coli (FPC). The mean age of onset in GS and FPC was similar, and since they are rather earlier than is currently believed, it is recommended that regular supervision be started at not later than 10 years of age.

Adolescent↗