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PubMed2001

Genetic mapping of quantitative trait loci governing longevity of Caenorhabditis elegans in recombinant-inbred progeny of a Bergerac-BO x RC301 interstrain cross.

Recombinant-inbred populations, generated from a cross between Caenorhabditis elegans strains Bergerac-BO and RC301, were used to identify quantitative trait loci (QTL) affecting nematode longevity. Genotypes of young controls and longevity-selected worms (the last-surviving 1% from a synchronously aged population) were assessed at dimorphic transposon-specific markers by multiplex polymerase chain reaction. The power of genetic mapping was enhanced, in a novel experimental design, through map expansion by accrual of recombinations over several generations, internally controlled longevity selection from a genetically heterogeneous, homozygous population, and selective genotyping of extremely long-lived worms. Analysis of individual markers indicated seven life-span QTL, situated near markers on chromosomes I (tcbn2), III (stP127), IV (stP13), V (stP6, stP23, and stP128), and X (stP41). These loci were corroborated, and mapped with increased precision, by nonparametric interval mapping-which supported all loci implicated by single-marker analysis. In addition, a life-span QTL on chromosome II (stP100-stP196), was significant only by interval mapping. Congenic lines were constructed for the longevity QTL on chromosomes III and X, by backcrossing the Bergerac-BO QTL allele into an RC301 background with selection for flanking markers. Survival data for these lines demonstrated consistent and significant effects of each QTL on life span.

Alleles↗

PubMed2001

The genetic architecture of odor-guided behavior in Drosophila melanogaster.

Animals↗

PubMed2005

The genetic-environmental etiology of parents' perceptions and self-assessed behaviours toward their 5-month-old infants in a large twin and singleton sample.

BACKGROUND: Given the importance of parenting for the child's early socio-emotional development, parenting perceptions and behaviours, and their correlates, should be assessed as early as possible in the child's life. The goals of the present study were 1) to confirm, in two parallel population-based samples, including a large sample of twins, the factor structure of a new self-administered questionnaire assessing both parents' specific parenting perceptions and behaviours toward their 5-month-old infants (i.e., parental self-efficacy, perceived parental impact, parental hostile-reactive behaviours and parental overprotection), 2) to identify the specific risk factors associated with the negative side of these parenting dimensions, 3) to document the genetic-environmental etiology of these parenting dimensions through the twin method. METHODS: Parents (2,122 mothers and 1,829 fathers) of 5-month-old infants, and parents of 5-month-old infant twins (510 families) completed the questionnaire (28 items). The data were submitted to a series of confirmatory factor analyses. The contribution to parenting of a variety of risk factors was examined in the two samples using regression analyses. A series of quantitative genetic analyses were performed to quantify the different sources of variation in parenting. RESULTS: A consistent factor structure was found across informants and across samples. There were significant mean differences in parenting between mothers and fathers, as well as between parents of twins and parents of singletons. A differentiated pattern of association with risk factors was found for each dimension of parenting. The twin analyses revealed that shared environment accounted for each parenting dimension. Maternal hostile-reactive behaviours were also moderately related to genetic factors in the child and this association was mainly mediated by the infant difficultness. CONCLUSIONS: The overall pattern of results was consistent with Belsky's (1984) view of parenting as multiply determined. The longitudinal follow-up of these families should provide the means for testing developmental models about the determinants and outcomes of these parenting dimensions.

Adult↗

PubMed2001

Challenges implicit to gene discovery research in the control of ventilation during hypoxia.

Appointing physiological function to specific genetic determinants requires a systems physiologist to consider ways of assessing precise phenotypic mechanisms. The integration of ventilation, metabolism and thermoregulation, for example, is very complex and may differ among small and large mammalian species. This challenge is particularly applicable to the study of short- and long-term adaptation of these systems to hypoxic exposure associated with high altitude. Our laboratory has initiated a research effort to dissect the complexity of hypoxic adaptation using traditional quantitative genetic analysis and contemporary DNA genotyping techniques. Although the current evidence in murine models demonstrates that specific genes influence control of hypoxic ventilatory responses (HVR), the relevance of these determinants to human adaptation to altitude remains open to exploration. Our review discusses the progress and uncertainties associated with assigning a genetic basis to variation in acute and chronic HVR.

Adaptation, Physiological↗

PubMed2001

Functional genomics of odor-guided behavior in Drosophila melanogaster.

The avoidance response to repellent odorants in Drosophila melanogaster, a response essential for survival, provides an advantageous model for studies on the genetic architecture of olfactory behavior. Transposon tagging in a highly inbred strain of flies in combination with a rapid and simple statistical behavioral assay enables the identification of not only large phenotypic effects, but also small aberrations from wild-type avoidance behavior. The recent completion of the sequence of the Drosophila genome facilitates the molecular characterization of transposon-tagged genes and correlation between gene expression and behavior in smell-impaired (smi) mutant lines. Quantitative genetic analyses of a collection of smi lines in a co-isogenic background revealed an extensive network of epistatic interactions among genes that shape the olfactory avoidance response. Candidate genes for several of these transposon-tagged smi loci implicate genes that mediate odorant recognition, including a novel odorant binding protein; signal propagation, including a voltage-gated sodium channel; and a protein containing multiple leucine rich repeats and PDZ domains likely to be involved in postsynaptic organization in the olfactory pathway. Several novel genes of unknown function have also been implicated, including a novel tyrosine-regulated protein kinase. The discovery and characterization of novel gene products that have major, hitherto unappreciated effects on olfactory behavior will provide new insights in the generation and regulation of odor-guided behavior. The identification and functional characterization of proteins encoded by smi genes that form part of the olfactory subgenome and correlation of polymorphisms in these genes with variation in odor-guided behavior in natural populations will advance our understanding of the genetic architecture of chemosensory behavior.

Animals↗

PubMed2007

Long day plants and the response to global warming: rapid evolutionary change in day length sensitivity is possible in wild beet.

Day length is a key factor in flowering induction in many plant species in a seasonal environment with flowering induction usually happening at shorter day lengths in lower latitudes. Now, the climate changes systematically at a considerable speed due to global warming. As a consequence, earlier flowering will be selected for in long day plants by favouring a lower threshold for day length sensitivity, on the condition of available genetic variability. Here, we show that there is considerable genetic variation for day length sensitivity in our study species, the seabeet Beta vulgaris subsp. maritima. In the northernmost natural populations without vernalization requirement, in southwest France, the necessary day length for flowering induction could be reduced by artificial selection in <10 generations from >13 h to <11 h, the latter value corresponding to populations in the Beta-species complex from Northern Africa and the eastern part of the Mediterranean tested under the same conditions. A quantitative genetic analysis provided evidence of a gradual change without detectable major genes. Additional experiments were carried out to separate the response to photoperiod from age and energy effects. A certain effect of energy availability has been found, whereas age effects could be excluded. These results indicate a considerable potential for evolutionary change in adjusting flowering time in a changing climate.

Adaptation, Physiological↗

PubMed1976

A genetic study on the length of tibia.

The length of tibia was studied in 1364 males and 1791 females over 10 years of age in an agricultural district of Wakayama Prefecture, Japan. (1) The length markedly increased from 10 to 17 years of age in males, and 10 to 15 in females, but it remained comparatively unchanged from 20 to 79 years in both sexes. The following regressions of tibial length covering 20 to 79 years were obtained: Y male = 0-0183x+34-7892, Y female = -0-0269x + 32-5329. The modified data proved to be a normal distribution on skewness and kurtosis test; they were analysed on a quantitative genetic basis. (2) No significant contribution of X-linked and Y-linked genes to tibial length was found in an analysis of parent-child combinations. (3) There was no indication of maternal effect, since the difference between father-child (r = 0-36 +/- 0-05) and mother-child (r = 0-42 +/- 0-04) correlations was not significant. (4) Correlation coefficients between sibs were significant, the values being 0-57 +/- 0-09 for brother-brother, 0-32 +/- 0-22 for sister-sister, and 0-27 +/- 0-13 for brother-sister. Correlation coeffiecients between parent and child were also significant, the values being 0-36 +/- 0-06 for father-son, 0-35 +/- 0-09 for father-daughter, 0-44 +/- 0-04 for mother-son, 0-35 +/- 0-07 for mother-daughter. The regression coefficients of child on midparent were calculated to be 0-77 +/- 0-12. Thus, the heritability for the length of tibia may be estimated to be 0-77 approximately 0-80. Contribution of dominance variance to total variance was very small (VD = 0-01), in contrast to a far greater additive genetic variance (VA = 0-80).

Adolescent↗

PubMed2006

Quantitative trait locus on Chromosome 19 for circulating levels of intercellular adhesion molecule-1 in Mexican Americans.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) is a biochemical marker of inflammation. We performed variance-components-based quantitative genetic analyses in SOLAR of sICAM-1 in 1170 individuals from Mexican American families in the San Antonio Family Heart Study. The trait is heritable (h(2)=0.50+/-0.06, P<10(-6)). Multipoint linkage analysis using a approximately 10-cM microsatellite map revealed a region on Chromosome 19p near marker D19S586 showing strong evidence of linkage for sICAM-1 (empirically adjusted univariate-equivalent LOD=4.95), coincident with the structural gene ICAM1. This region has been identified previously as a QTL for inflammatory, autoimmune, and metabolic syndrome traits. There is significant evidence (P=0.0023) of locus heterogeneity for sICAM-1 in this sample: a subset of pedigrees contributes most of the linkage signal for sICAM-1 on Chromosome 19, suggesting a logical focus for future genetic dissection of the trait.

Adult↗

PubMed1985

Biochemical and genetic properties of oligomeric structures: a general approach.

The oligomers constituted by association of different subunits can exist under multiple forms. In the case of the genetically variable proteins, such a multiplicity leads to numerous questions (i) on the enumerations: what is the number of active forms when a given subunit can make the oligomer inactive, or when the subunits are encoded by s alleles; (ii) on the subunit effects on biochemical properties: how to estimate these effects, are they equal, are there interactions between subunits, etc. Theoretical methods for the study of such oligomeric structures are developed, which mainly rely on linear model techniques. Peculiar properties examined are Vmax and Km, but also the quantities of the various oligomers, which depend on their association law. This approach is extended to the oligomers composed of different sets of subunits, as are for example some enzymes. These aspects are discussed from numerous bibliographic examples, with special reference to molecular interactions (protein complementation or molecular heterosis). Otherwise the genetic application of this theoretical approach is presented: it is possible to consider a genotype as an oligomer of alleles, and thus to study their effects and their interactions, in the one-locus case as well as in the several-loci case. The relevance of this generalization is discussed in connection with two other concepts, the "sequence space" used in molecular evolution and the regression of the genotypic values on the number of alleles used in quantitative genetics.

Enzymes↗

PubMedDate not supplied

[Regression methods and causal inference: structural equations models].

The estimate of correlations among observed outcomes is crucial in biomedical research, especially when the aim of the study is to infer, from the magnitude of these correlations, the causal influence of certain, sometimes latent, factors. In such situations, a typical regression approach, known as "structural equation models" (SEM), which was introduced in the 1970s, becomes significant. These models allow hypotheses to be formulated quite clearly, thanks to some explicit and rigorous graphical representations, on which the "path analysis" is based. SEM, which were initially used in economics, have in the past decade been applied in a wide variety of fields, especially in genetic epidemiology. It's in this field that SEM are extraordinarily effective, representing a simple yet powerful means of estimating the contribution of genes and the environment to the phenotypic expression of a given disease. To this end, data on twins are particularly useful, and in this case the correlation between the outcomes describes the extent of similarity of the twin phenotypes. From this standpoint, SEM undoubtedly constitute one of the most promising statistical tools for family studies and quantitative genetic research. The method can be easily extended to traditional epidemiology, and some interesting applications have already been developed in occupational and social epidemiology. In this paper, we describe in detail the SEM approach and discuss the use of these models in genetic epidemiology, using twin studies as an example. We also discuss the application of SEM in fields other than genetic research.

Causality↗

PubMed1997

Immunogenetics and the cause of autoimmune disease.

Autoimmune disease results from the action of environmental factors on a predisposed genotype. In this review, the role of genetic susceptibility in the aetiology of autoimmune disease is examined. As the genetics of autoimmune diabetes has been studied more intensively than that of other autoimmune diseases, supporting evidence is drawn principally from that example. Autoimmune diseases are not inherited as entities but as constitutions which confer an increased probability of developing disease. It is proposed that there are two components to autoimmune disease susceptibility. One confers susceptibility to autoimmunity per se, while the other determines tissue specificity. In this review, the concept of liability is introduced as a tool used in quantitative genetics and is applied to the analysis of autoimmune diabetes by considering a threshold model. In this example, empirically derived incidence figures are used to calculate heritability which is a relative measure of the influence of genetics and environmental factors. The validity of applying the concept of liability to diabetes is confirmed by examining the values of heritability calculated from empirical data obtained from different kindred relationships, and by confirming that the assumptions on which liability is based are supported by recent gene mapping data. Finally, the physiological significance of liability is considered and its significance to the cause of autoimmunity discussed.

Animals↗

PubMed1999

Percent of oxygen saturation of arterial hemoglobin among Bolivian Aymara at 3,900-4,000 m.

A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO2) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO2. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO2 among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO2 of 381 Aymara at 3,900-4,000 m was 92+/-0.15% (SEM) with a range of 84-99%. The average was 2.6% higher than the average SaO2 of a sample of Tibetans at 3,800-4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO2 in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population.

Adaptation, Physiological↗

PubMed2003

Heritability of fearful-anxious endophenotypes in infant rhesus macaques: a preliminary report.

BACKGROUND: Research efforts to discover the genetic underpinnings of anxiety and depression is challenging because of the etiologic heterogeneity inherent to these disorders. These efforts might be aided by the study of related behavioral phenotypes in model organisms, such as monkeys. METHODS: Eighty-five rhesus monkeys (Macaca mulatta) from the Oregon National Primate Research Center were drawn from a standard matriarchal colony and tested for behavioral response in four testing paradigms designed to elicit fearful-anxious reactions. Heritabilities were estimated using variance component-based quantitative genetic analyses with much of the genetic information arising from paternal half-sibs. RESULTS: Individual behaviors reflecting increased distress responses (e.g., vocalizations and teeth grinding) and behavioral inhibition (e.g., latency to leave mother, latency to inspect novel fruit) showed significant heritability, even though a small number of monkeys were assessed. Exploratory factor analyses identified seven clusters of behaviors across tests, some of which were found to be heritable. CONCLUSIONS: These results indicate that several specific fearful-anxious behaviors in infant rhesus monkeys are heritable within this colony. Accordingly, these phenotypes, which are believed to represent the genetic liability for anxiety and depression, are good candidates for further genetic investigation in this population.

Animals↗

PubMed2005

The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: a study of healthy Danish twins.

BACKGROUND: A large proportion of healthy, euthyroid, nongoitrous individuals have thyroid nodules. The aetiology of these ultrasonographically detected morphological abnormalities is largely unknown. Factors such as age, gender, iodine intake, smoking and parity are associated with nodularity of the thyroid. Whether there is a genetic susceptibility is unclear. AIM: To gain insight into the aetiology of thyroid nodularity by investigating a large cohort of healthy euthyroid monozygotic and dizygotic twins. DESIGN: A cross-sectional twin study. PARTICIPANTS: A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ) and 49 opposite sex (OS) twin pairs were investigated. MEASUREMENTS: Probandwise concordance and tetrachoric correlations. Quantitative genetic modelling was used to elucidate the relative importance of genetic and environmental effects for the variation in the liability of nodularity. RESULTS: A higher concordance rate for thyroid nodularity was found in MZ twins [0.57 (95% CI 0.36-0.76)] than in DZ twins [0.36 (95% CI 0.17-0.56, P = 0.074)]. The same was true for tetrachoric correlations: 0.67 (95% CI 0.34-0.87) in MZ twins and 0.17 (CI - 0.28-0.56, P = 0.053) in DZ twins. The difference, although not significant, was more pronounced for multiple nodules than for solitary nodules. Controlling for covariates (age, gender and smoking habits), it was calculated that genetic factors accounted for 67% (95% CI 35-87%) and environmental factors for 33% (95% CI 13-65%) of the individual differences in the liability to thyroid nodularity. CONCLUSIONS: This study suggests that genetic factors are of aetiological importance for thyroid nodularity in clinically healthy and euthyroid individuals, and indicates a difference in the aetiology of solitary and multiple thyroid nodules.

Adult↗

PubMedDate not supplied

Genetic and environmental influences on forced expiratory volume in midlife: a cross-cultural replication.

Previous research has shown that forced expiratory volume (FEV) is a useful predictor of remaining life in older adults. The present analyses are an attempt to replicate results from a study of Swedish twins which demonstrated substantial heritability of FEV with a sample of middle-aged Russian adult twins. Data were collected from 116 pairs of Russian twins (monozygote = 71, dizygotic = 45, mean age = 40.9 years). Phenotypic correlations between FEV, age, gender, height, and cigarette consumption (in pack years) were all significant, ranging from -.72 to .31. After the effects of age, gender, height, and smoking were partialled out of FEV, quantitative genetic analyses were conducted. Shared environmental effects were significant, accounting for 47% of the variance in FEV. Genetic effects, which accounted for about 28% of the variance, could be dropped from the model without a significant decrease in the fit. These results are discussed in relation to previous research conducted in other countries.

Adult↗

PubMed2006

Genetic and environmental correlations between obesity phenotypes and age at menarche.

OBJECTIVE: To assess the extent that the genetic and environmental factors contribute to the phenotypic correlations between obesity traits and age at menarche (AAM), and also to examine the influence of AAM on obesity in both pre- and postmenopausal women. METHODS: F ive hundred and twelve pedigrees with 2667 Caucasian female subjects from two to four generations were recruited. Fat mass and lean mass (both in kg) were measured by dual-energy X-ray absorptiometry scanner. Body mass index (BMI) (kg/m(2)) was calculated. We performed bivariate quantitative genetic analyses in the total sample containing 2667 Caucasian women. We also selected 206 unrelated premenopausal women and 140 unrelated postmenopausal women from the total sample, and computed the respective phenotypic correlation between obesity and AAM in these two subgroups. RESULTS: For fat mass, lean mass and BMI, we detected their significant negative genetic correlations with AAM after adjustment for significant covariates, which were -0.3170 (P<0.001), -0.1721 (P<0.05) and -0.3665 (P<0.001), respectively. However, their environmental correlations with AAM were all nonsignificant (P>0.05), ranging from -0.0016 to 0.0192. In the premenopausal subgroup, significant associations were observed between fat mass and AAM (rho=-0.231, P<0.01) as well as between BMI and AAM (rho=-0.257, P<0.01). In the postmenopausal subgroup, no such associations were observed. CONCLUSION: Our results for the first time suggested that significant phenotypic association between obesity phenotypes and AAM is mainly attributable to shared genetic rather than environmental factors, and AAM may have stronger effects on obesity phenotypes in pre- than in postmenopausal women.

Adipose Tissue↗

PubMed2005

Epistasis in the expression of relevant traits in cassava (Manihot esculenta Crantz) for subhumid conditions.

There is limited knowledge on the inheritance of agronomic traits in cassava and the importance of epistasis for most crops. A nine-parent diallel study was conducted in subhumid environments. Thirty clones were obtained from each F1 cross. Each clone was represented by six plants, which were distributed in three replications at two locations. Therefore the same 30 genotypes of each F1 cross were planted in the three replications at the two locations. Analysis of variance suggested significant genetic effects for all variables analyzed (reaction to thrips, fresh root and foliage yields, harvest index, dry matter content, and root dry matter yield). Significant epistatic effects were observed for all variables, except harvest index. Dominance variance was always significant, except for dry matter content and dry matter yield. Additive variance was significant only for reaction to thrips. Results suggested that dominance plays an important role in complex traits such as root yield. The significance of epistasis can help us understand the difficulties of quantitative genetics models and QTLs in satisfactorily explaining phenotypic variation in traits with complex inheritance. Significant epistasis would justify the production of inbred parental lines to fix favorable allele combinations in the production of hybrid cassava cultivars.

Analysis of Variance↗

PubMed2006

Evidence for independent heritability of the glycation gap (glycosylation gap) fraction of HbA1c in nondiabetic twins.

OBJECTIVE: HbA(1c) (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C - A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C. RESEARCH DESIGN AND METHODS: We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range. RESULTS: GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C. CONCLUSIONS: Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment.

Adult↗