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PubMed2004

Did natural selection or genetic drift produce the cranial diversification of neotropical monkeys?

A central controversy among biologists is the relative importance of natural selection and genetic drift as creative forces shaping biological diversification (Fisher 1930; Wright 1931). Historically, this controversy has been an effective engine powering several evolutionary research programs during the last century (Provine 1989). While all biologists agree that both processes operate in nature to produce evolutionary change, there is a diversity of opinion about which process dominates at any particular organizational level (from DNA and proteins to complex morphologies). To address this last level, we did a broadscale analysis of cranial diversification among all living New World monkeys. Quantitative genetic models yield specific predictions about the relationship between variation patterns within and between populations that may be used to test the hypothesis that genetic drift is a sufficient explanation for morphological diversification. Diversity at several levels in a hierarchy of taxonomic/phylogenetics relationship was examined from species within genera to families within superfamilies. The major conclusion is that genetic drift can be ruled out as the primary source of evolutionary diversification in cranial morphology among taxa at the level of the genus and above as well as for diversification of most genera. However, drift may account for diversification among species within some Neotropical primate genera, implying that morphological diversification associated with speciation need not be adaptive in some radiations.

Adaptation, Physiological↗
PubMed2005

Genetic component of noise sensitivity.

We investigated the genetic component of noise sensitivity using a twin-study design. The study sample consisted of 573 same-sexed twin pairs from the Finnish Twin Cohort. The 131 monozygotic (MZ) and 442 dizygotic (DZ) twin pairs with an age range of 31 to 88 years replied to a questionnaire on noise and health-related items in 1988. The noise sensitivity of respondents was defined as high, quite high, quite low or low. MZ pairs were more similar with regards noise sensitivity than DZ pairs, and quantitative genetic modeling indicated significant familiality. The best z-fitting genetic model provided an estimate of heritability of 36% (95% CI = .20-.50) and when hearing impaired subjects were excluded this rose to 40% (95% CI = .24-.54). In conclusion, noise sensitivity does aggregate in families and probably has a genetic component.

Adult↗
PubMed2000

The interaction of prematurity with genetic and environmental influences on cognitive development in twins.

OBJECTIVE: To investigate how the degree of prematurity interacts with genetic and environmental influences in their effect on verbal and nonverbal cognitive development. STUDY DESIGN: The target sample consisted of more than 2000 pairs of twins born in England and Wales in 1994. At 24 months, measures of verbal and non-verbal cognitive development were obtained from the twins' parents. The sample was divided into 3 groups according to degree of prematurity: very preterm or high-risk (<32 weeks), moderately preterm or medium-risk (32-33 weeks), and mildly preterm/term or low-risk (>34 weeks). Quantitative genetic analyses were used to assess the contributions of genetic and environmental influences on vocabulary and cognitive development. RESULTS: The results indicated gene-environment interactions. For the high-risk group, genetic effects on both verbal and non-verbal cognitive ability were completely overshadowed by shared environmental factors, whereas for both medium- and low-risk groups, additive genetic effects explained 18% to 33% of the variance. CONCLUSIONS: Our findings indicate that genetic factors are not responsible for cognitive outcomes of very preterm infants and suggest that early environmental influences appear to affect verbal and non-verbal cognitive development at 2 years of age.

Child Development↗
PubMed2002

Genetic and environmental influences on body-fat measures among African-American twins.

OBJECTIVE: To investigate the genetic and environmental influences on body-fat measures including waist circumference (WC), waist-to-hip ratio (WHR), and body mass index (BMI) among African-American men and women. RESEARCH METHODS AND PROCEDURES: Measurements were taken as part of the Carolina African American Twin Study of Aging. This sample currently comprises 146 same-sex African-American twins with an average age of 50 years (range, 22 to 88 years). This analysis included 26 monozygotic and 29 dizygotic men and 45 monozygotic and 46 dizygotic women. Maximum likelihood quantitative genetic analysis was used. RESULTS: In men, additive genetic effects accounted for 77% of the variance in WC, 59% in WHR, and 89% in BMI. In women, additive genetic effects accounted for 76% of the variance in WC, 56% in WHR, and 73% in BMI. The remaining variance in both men and women was attributed to unique environmental effects (WC, 21%; WHR, 36%; BMI, 11% in men and WC, 22%; WHR, 38%; BMI, 27% in women) and age (WC, 2%; WHR, 5% in men and WC, 2%; WHR, 6% in women). When BMI was controlled in the analysis of WC and WHR, it accounted for a portion of the genetic and environmental variance in WHR and over one-half of the genetic and environmental variance in WC. DISCUSSION: There are both genetic and environmental influences on WC, WHR, and BMI, and independent of BMI, there are genetic and environmental effects on WC and WHR among both genders. The results from this African-American twin sample are similar to findings among white twin samples.

Adult↗
PubMed2003

Genetic characterization of stress responsiveness in Japanese quail. 2. Analyses of maternal effects, additive sex linkage effects, heterosis, and heritability by diallel crosses.

Diallel crosses were used to investigate the genetic inheritance of stress responsiveness through examination of population effects in progeny of randombred (RB) quail and quail selected for reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone (CS) response to brief immobilization. The three genotypes were crossed in a 3 x 3 factorial arrangement of treatments that allowed all possible crosses between RB, LS, and HS males with RB, LS, and HS females. The nine crosses produced 479 progeny that were, at 28 d of age, stressed by immobilization, and a sample of blood was collected. The following quantitative genetic parameters were estimated for plasma CS: heritability, heterosis, maternal effects, sex-linkage effects, and heterosis due to the sex chromosomes. Genotypic-phenotypic correlations within RB quail and quail of the two selected lines were also obtained. Maternal effects were different (P < 0.05) from zero for the plasma CS responses of all three genotypes. Additive sex linkage effects on plasma CS responses were variable and of much less importance than maternal effects. The correlations between plasma CS response and genotype were: 0.22 for RB quail and 0.37 and 0.55 for quail of the LS and HS lines, respectively. Heterosis effects were low and most likely due to either an increase in homozygozity of genes on the sex chromosomes or an increase of maternal effects within reciprocal crosses. Heritability, estimated for the post-immobilization plasma CS response, was 0.05 for RB quail and 0.14 and 0.30 for quail of the LS and HS lines, respectively.

Alleles↗
PubMed2001

Evidence for Dobzhansky-Muller incompatibilites contributing to the sterility of hybrids between Mimulus guttatus and M. nasutus.

Both chromosomal rearrangements and negative interactions among loci (Dobzhansky-Muller incompatibilities) have been advanced as the genetic mechanism underlying the sterility of interspecific hybrids. These alternatives invoke very different evolutionary histories during speciation and also predict different patterns of sterility in artificial hybrids. Chromosomal rearrangements require drift, inbreeding, or other special conditions for initial fixation and, because heterozygosity per se generates any problems with gamete formation, F1 hybrids will be most infertile. In contrast, Dobzhansky-Muller incompatibilities may arise as byproducts of adaptive evolution and often affect the segregating F2 generation most severely. To distinguish the effects of these two mechanisms early in divergence, we investigated the quantitative genetics of hybrid sterility in a line cross between two members of the Mimulus guttatus species complex (M. guttatus and M. nasutus). Hybrids showed partial male and female sterility, and the patterns of infertility were not consistent with the action of chromosomal rearrangements alone. F2 and F1 hybrids exhibited equal decreases in pollen viability (> 40%) relative to the highly fertile parental lines. A large excess of completely pollen-sterile F2 genotypes also pointed to the segregation of Dobzhansky-Muller incompatibility factors affecting male fertility. Female fertility showed a pattern similarly consistent with epistatic interactions: F2 hybrids produced far fewer seeds per flower than F1 hybrids (88.0 +/- 2.8 vs. 162.9 +/- 8.5 SE, respectively) and either parental line, and many F2 genotypes were completely female sterile. Dobzhansky-Muller interactions also resulted in the breakdown of several nonreproductive characters and appear to contribute to correlations between male and female fertility in the F2 generation. These results parallel and contrast with the genetics of postzygotic isolation in model animal systems and are a first step toward understanding the process of speciation in this well-studied group of flowering plants.

Asteraceae↗
PubMed2007

Technical note: how to use Winbugs to draw inferences in animal models.

This paper deals with Bayesian inferences of animal models using Gibbs sampling. First, we suggest a general and efficient method for updating additive genetic effects, in which the computational cost is independent of the pedigree depth and increases linearly only with the size of the pedigree. Second, we show how this approach can be used to draw inferences from a wide range of animal models using the computer package Winbugs. Finally, we illustrate the approach in a simulation study, in which the data are generated and analyzed using Winbugs according to a linear model with i.i.d errors having Student's t distributions. In conclusion, Winbugs can be used to make inferences in small-sized, quantitative, genetic data sets applying a wide range of animal models that are not yet standard in the animal breeding literature.

Animals↗
PubMed1988

A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations.

Genes that code for products involved in the physiology of a phenotype are logical candidates for explaining interindividual variation in that phenotype. We present a methodology for discovering associations between genetic variation at such candidate loci (assayed through restriction endonuclease mapping) with phenotypic variation at the population level. We confine our analyses to DNA regions in which recombination is very rare. In this case, the genetic variation at the candidate locus can be organized into a cladogram that represents the evolutionary relationships between the observed haplotypes. Any mutation causing a significant phenotypic effect should be imbedded within the same historical structure defined by the cladogram. We showed, in the first paper of this series, how to use the cladogram to define a nested analysis of variance (NANOVA) that was very efficient at detecting and localizing phenotypically important mutations. However, the NANOVA of haplotype effects could only be applied to populations of homozygous genotypes. In this paper, we apply the quantitative genetic concept of average excess to evaluate the phenotypic effect of a haplotype or group of haplotypes stratified and contrasted according to the nested design defined by the cladogram. We also show how a permutational procedure can be used to make statistical inferences about the nested average excess values in populations containing heterozygous as well as homozygous genotypes. We provide two worked examples that investigate associations between genetic variation at or near the Alcohol dehydrogenase (Adh) locus and Adh activity in Drosophila melanogaster, and associations between genetic variation at or near some apolipoprotein loci and various lipid phenotypes in a human population.

Alcohol Dehydrogenase↗
PubMed2006

Characterization of mycobacterial virulence genes through genetic interaction mapping.

We have previously shown that approximately 5% of the genes encoded by the genome of Mycobacterium tuberculosis are specifically required for the growth or survival of this bacterium during infection. This corresponds to hundreds of genes, most of which have no identifiable function. As a unique approach to characterize these genes, we developed a method to rapidly delineate functional pathways by identifying mutations that modify each other's phenotype, i.e., "genetic interactions". Using this method, we have defined a complex set of interactions between virulence genes in this pathogen, and find that the products of unlinked genes associate to form multisubunit transporters that are required for bacterial survival in the host. These findings implicate a previously undescribed family of transport systems in the pathogenesis of tuberculosis, and identify genes that are likely to function in the metabolism of their substrates. This method can be readily applied to other organisms at either the single pathway level, as described here, or at the system level to define quantitative genetic interaction networks.

Animals↗
PubMed1996

Metabolic models of selection response.

Consequences of directional selection on metabolic flux are explored in models for which variation in flux among individuals is generated by segregation of allelic variants at enzyme activity loci. The pattern of selection response is strongly affected by the presence of genetic dominance and epistasis, which are automatically generated in metabolic systems. The expected magnitudes of dominance and epistasis effects on flux are evaluated. Small differences in enzyme activity generate little dominance, but a null allele will tend to be recessive for the pathway in which it occurs and for metabolically distant pathways. Epistasis is found to be greatest in short pathways in which large differences in enzyme activity occur. Under divergent artificial selection asymmetrical responses can occur due to the presence of directional dominance and epistasis, and lead to departures from the classic infinitesimal model of quantitative genetic variation. The effects of epistasis and dominance are in opposite directions, however, and partially cancel each other out in a diploid population.

Alleles↗
PubMed2006

Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in the Hispanic population.

BACKGROUND: Genetic and environmental contributions to childhood obesity are poorly delineated. OBJECTIVE: The Viva la Familia Study was designed to genetically map childhood obesity and its comorbidities in the Hispanic population. The objectives of this report were to describe the study design and to summarize genetic and environmental contributions to the phenotypic variation in obesity and risk factors for metabolic diseases in Hispanic children. DESIGN: The Viva la Familia cohort consisted of 1030 children from 319 families selected based on an overweight proband between the ages of 4 and 19 y. In-depth phenotyping to characterize the overweight children and their siblings included anthropometric and body-composition traits by dual-energy X-ray absorptiometry and assessments of diet by 24-h recalls, physical activity by accelerometry, and risk factors for metabolic diseases by standard biochemical methods. Univariate quantitative genetic analysis was used to partition phenotypic variance into additive genetic and environmental components by using the computer program SOLAR. RESULTS: Sex, age, and environmental covariates explained 1-91% of the phenotypic variance. Heritabilities of anthropometric indexes ranged from 0.24 to 0.75. Heritability coefficients for the body-composition traits ranged from 0.18 to 0.35. Diet and physical activity presented heritabilities of 0.32 to 0.69. Risk factors for metabolic diseases were heritable with coefficients ranging from 0.25 to 0.73. Significant genetic correlations between obesity traits and risk factors for metabolic diseases substantiated pleiotropy between traits. CONCLUSION: The Viva la Familia Study provides evidence of a strong genetic contribution to the high prevalence of obesity and its comorbidities in Hispanic children.

Adolescent↗
PubMed2006

Genetic and environmental influences on body fat and blood pressure in African-American adult twins.

OBJECTIVE: African Americans have a particularly high prevalence of excessive body fat and high blood pressure. Genetic and environmental influences may be implicated for both of these risk factors. We investigated the potential for common genetic and environmental influences on body fat (waist circumference (WC), body mass index (BMI)) and blood pressure measures (systolic and diastolic pressure (SBP, DBP)) among African-American male and female subjects. RESEARCH METHODS AND PROCEDURES: Measurements were taken as part of the Carolina African-American Twin Study of Aging (CAATSA). The CAATSA sample contains 217 same-sex African-American male and female twins with average age of 47 years. This analysis included 39 monozygotic male pairs (MZ), 43 dizygotic male pairs (DZ); 63 MZ female pairs, and 72 DZ female pairs. Maximum likelihood quantitative genetic analyses were used. RESULTS: The total genetic variance for SBP was 22% in male subjects and 40.1% in female subjects. Of this total variance, 3.1% was in common with BMI in male subjects and 6% was in common with BMI in female subjects. After controlling for the effects of BMI, WC had less than 1% of its variance in common with SBP in male and female subjects. For DBP, the total genetic variance was 16.9% in male and 38.7% in female subjects. Of this total variance 6.1% was in common with BMI in male subjects and 3.7% was in common in female subjects. Again, WC had less than 1% of its genetic variance in common with DBP in both male and female subjects. The environmental variance common among these measures was also very small. The remaining variance was primarily accounted for by genetic and environmental effects unique to each measure as well as age. DISCUSSION: Based on the very small common genetic variance for BMI, SBP, and DBP as well as WC and the blood pressure measures, our results suggest that searching for common genes among these measures may be inconclusive.

Adult↗
PubMed2002

[Pathophysiology and genetics of obesity].

Obesity has become the most prevalent nutritional disorder in post-industrialised societies and it is associated with the development of severe and costly complications such as type 2 diabetes mellitus and coronary heart disease or cancer. A large proportion of the risk of obesity is determined by the genetic susceptibility of an individual, but environmental factors conducive for the disorder play an important role in its phenotypic expression. Several candidate genes emerged from studies in animal models of obesity, but human pathophysiology is likely to be more complex. Thus, most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favouring deposition of excess calories as fat. The recent surge of obesity may relate to past evolutionary pressure which favoured selection of mechanisms defending body-weight against caloric restriction rather than against caloric excess. Rapidly developing new techniques in quantitative genetics and growing information from functional genomics will help to understand the interaction of environmental factors with signalling networks that regulate energy metabolism. The role of previously unknown pathways in the aetiology of obesity will be uncovered. The typing of numerous genetic variants will become possible and allow individual risk assessment for obesity and/or its associated disorders. Thus, rational and individually tailored therapies may be developed to combat obesity and its associated disorders.

Adult↗
PubMed2000

Higher arterial oxygen saturation during submaximal exercise in Bolivian Aymara compared to European sojourners and Europeans born and raised at high altitude.

Arterial oxygen saturation (SaO(2)) was measured at 3,600-3,850 m by pulse oximetry at rest and during submaximal exercise in three study groups: 1) highland Aymara natives of the Bolivian altiplano (n = 25); 2) lowland European/North American sojourners to the highlands with at least 2 months of acclimatization time to 3,600 m (n = 27); and 3) subjects of European ancestry born and raised at 3,600 m (n = 22). Aymara subjects maintained approximately 1 percentage point higher SaO(2) during submaximal work up to 70% of their maximal work capacity, and showed a smaller rate of decline in SaO(2) with increasing work compared to both European study groups. The higher-exercise SaO(2) of Aymara compared to Europeans born and raised at 3,600 m suggests genetic adaptation. The two European study groups, who differed by exposure to high altitude during their growth and development period, did not show any significant difference in either resting or exercise SaO(2). This suggests that the developmental mode of adaptation is less important than the genetic mode of adaptation in determining exercise SaO(2). A weak correlation was detected (across study groups only) between the residual forced vital capacity (FVC) and the residual SaO(2) measured at the highest level of submaximal work output (P = 0.024, R = 0.26). While firm conclusions based on this correlation are problematic, it is suggested that a part of the higher SaO(2) observed in Aymara natives is due to a larger lung volume and pulmonary diffusion capacity for oxygen. Results from this study are compared to similar studies conducted with Tibetan natives, and are interpreted in light of recent quantitative genetic analyses conducted in both the Andes and Himalayas.

Adaptation, Physiological↗
PubMedDate not supplied

Francis Galton: his approach to polygenic disease.

Gregor Mendel is considered to be the founding father of modern genetics, and his laws of inheritance have led to the successful analysis of rare monogenic diseases such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolaemia, and many others. Francis Galton chose multifactorial inheritance as his starting point, and his methods of analysis have withstood the test of time. He used detailed family records to study the inherited tendency of complex traits between parents and offspring, and between identical and non-identical twins to refine the analysis, and devised new statistics to attempt to measure the extent of inheritance. For all these reasons, he can be considered the founding father of quantitative genetics.

England↗
PubMed2003

Three-state frailty model for age at onset of dementia and death in Swedish twins.

We present a frailty model to estimate the relative importance of genetic and environmental factors on age at onset of dementia in a twin design. We use modern survival methodology to define a model that accounts simultaneously for longitudinal aspects, e.g., left truncation and right censoring in data, and the multivariate nature of twin data. Additionally, we present a novel three-state frailty model, with nondemented, demented, and dead states, describing variation in the onset of disease and mortality simultaneously in one model, while accounting for possible dependence for the two competing events. The frailty structure, i.e., the latent random effects structure, mimics the traditional twin model for continuous variables used in quantitative genetics, and as such describes within-pair dependence. This in turn leads to estimates for intrapair correlations, as well as for additive genetic, and shared and nonshared environmental components of variance. A hierarchical Bayesian model formulation and Gibbs sampling are used to estimate posterior distributions of the parameters. The models are applied to Swedish Twin Registry data on the onset of dementia in elderly twins. Based on the three-state frailty model, we estimate the intrapair correlations for dementia to be 0.87 [90% credible interval: 0.61,0.98] and 0.68[0.18,0.91] for MZ and DZ twins, respectively. Based on our model, we estimate that genetic effects account for about one third, and shared environmental effects for almost a half, of the variation in dementia hazards between individuals. More data, however, are needed to gain precision in these estimates.

Age of Onset↗
PubMed1997

The age dependency of gene expression for plasma lipids, lipoproteins, and apolipoproteins.

The aim of this study was to investigate and disentangle the genetic and nongenetic causes of stability and change in lipids and (apo)lipoproteins that occur during the lifespan. Total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) were measured in a group of 160 middle-aged parents and their twin offspring (first project) and in a group of 203 middle-aged twin pairs (second project). Combining the data of both projects enabled the estimation of the extent to which measured lipid parameters are influenced by different genes in adolescence and adulthood. To that end, an extended quantitative genetic model was specified, which allowed the estimation of heritabilities for each sex and generation separately. Heritabilities were similar for both sexes and both generations. Larger variances in the parental generation could be ascribed to proportional increases in both unique environmental and additive genetic variance from childhood to adulthood, which led to similar heritability estimates in adolescent and middle-aged twins. Although the magnitudes of heritabilities were similar across generations, results showed that, for total cholesterol, triglycerides, HDL, and LDL, partly different genes are expressed in adolescence compared to adulthood. For triglycerides, only 46% of the genetic variance was common to both age groups; for total cholesterol this was 80%. Intermediate values were found for HDL (66%) and LDL (76%). For ApoA1, ApoB, and Lp(a), the same genes seem to act in both generations.

Adolescent↗
PubMed2005

The mouse genome.

The house mouse has been used as a privileged model organism since the early days of genetics, and the numerous experiments made with this small mammal have regularly contributed to enrich our knowledge of mammalian biology and pathology, ranging from embryonic development to metabolic disease, histocompatibility, immunology, behavior, and cancer. Over the past two decades, a number of large-scale integrated and concerted projects have been undertaken that will probably open a new era in the genetics of the species. The sequencing of the genome, which will allow researchers to make comparisons with other mammals and identify regions conserved by evolution, is probably the most important project, but many other initiatives, such as the massive production of point or chromosomal mutations associated with comprehensive and standardized phenotyping of the mutant phenotypes, will help annotation of the approximately 25,000 genes packed in the mouse genome. In the same way, and as another consequence of the sequencing, the discovery of many single nucleotide polymorphisms and the development of new tools and resources, like the Collaborative Cross, will contribute to the development of modern quantitative genetics. It is clear that mouse genetics has changed dramatically over the last 10-15 years and its future looks promising.

Animals↗