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PubMed2006

Genome-wide association: a promising start to a long race.

A recent study by Cheung et al. demonstrates how to identify expression quantitative trait loci (eQTLs) underlying gene expression phenotypes through a combination of genome-wide linkage analysis and subsequent fine mapping or by genome-wide association (GWA) analysis. This study emphasizes the complexity of human traits, highlighting the challenges faced by investigators--in particular, insufficient linkage disequilibrium between the trait and marker variant, genetic heterogeneity and correcting for multiple testing will all adversely impact the power to detect loci by association. These issues must be considered carefully if the GWA approach is to succeed in mapping complex phenotypes.

Chromosome Mapping↗
PubMed1986

What does Eysenck's psychoticism scale really measure?

The following sources of evidence are discussed in order to examine the component parts-in terms of primary traits-of Eysenck's psychoticism scale, which he refers to as a 'superfactor' but which is here viewed as a composite or complex of primary traits. Factor analytic studies by the author and by Barratt & Kline not only showed agreement as to factor composition but also each found a psychoticism factor and supply evidence as to the question posed. Additionally a correlational study by the author and a study by Eysenck supply evidence. Thus from factor analytic and correlational evidence a high P scorer possesses these traits: impulsiveness, lack of cooperation, oral pessimism, rigidity, low superego controls, low social sensitivity, low persistence, lack of anxiety and lack of feelings of inferiority. Of the three main 'superfactors' advocated by Eysenck-neuroticism (N), extraversion (E) and psychoticism (P)-the evidence indicated that psychoticism was the least univocal.

Extraversion, Psychological↗
PubMed2000

On the evolution of misunderstandings about evolutionary psychology.

Some of the controversy surrounding evolutionary explanations of human behavior may be due to cognitive information-processing patterns that are themselves the result of evolutionary processes. Two such patterns are (1) the tendency to oversimplify information so as to reduce demand on cognitive resources and (2) our strong desire to generate predictability and stability from perceptions of the external world. For example, research on social stereotyping has found that people tend to focus automatically on simplified social-categorical information, to use such information when deciding how to behave, and to rely on such information even in the face of contradictory evidence. Similarly, an undying debate over nature vs. nurture is shaped by various data-reduction strategies that frequently oversimplify, and thus distort, the intent of the supporting arguments. This debate is also often marked by an assumption that either the nature or the nurture domain may be justifiably excluded at an explanatory level because one domain appears to operate in a sufficiently stable and predictable way for a particular argument. As a result, critiques in-veighed against evolutionary explanations of behavior often incorporate simplified--and erroneous--assumptions about either the mechanics of how evolution operates or the inevitable implications of evolution for understanding human behavior. The influences of these tendencies are applied to a discussion of the heritability of behavioral characteristics. It is suggested that the common view that Mendelian genetics can explain the heritability of complex behaviors, with a one-gene-one-trait process, is misguided. Complex behaviors are undoubtedly a product of a more complex interaction between genes and environment, ensuring that both nature and nurture must be accommodated in a yet-to-be-developed post-Mendelian model of genetic influence. As a result, current public perceptions of evolutionary explanations of behavior are handicapped by the lack of clear articulation of the relationship between inherited genes and manifest behavior.

Biological Evolution↗
PubMed2005

Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes.

Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I - NADH dehydrogenase) of synoviocyte mitochondria from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases.

Arthritis, Rheumatoid↗
PubMed1996

The geneticist's approach to complex disease.

Many studies are in progress worldwide to elucidate the genetics of complex diseases. Nevertheless, few articles are available that provide the scientific rationale and give guidelines for such ambitious endeavours. We describe the methodology and background necessary to study the genetics of complex disease and discuss how to analyze the data. We also provide a table of some ongoing studies. In particular, we wish to emphasize the analysis of intermediate, heritable, quantitative traits as a means of dissecting the genetic basis of a complex trait.

Animals↗
PubMed2003

Molecular phylogenetics of allodapine bees, with implications for the evolution of sociality and progressive rearing.

Allodapine bees have long been regarded as providing useful material for examining the origins of social behavior. Previous researchers have assumed that sociality arose within the Allodapini and have linked the evolution of sociality to a transition from mass provisioning to progressive provisioning of brood. Early phylogenetic studies of allodapines were based on morphological and life-history data, but critical aspects of these studies relied on small character sets, where the polarity and coding of characters is problematic. We used nucleotide sequence data from one nuclear and two mitochondrial gene fragments to examine phylogenetic structure among nine allodapine genera. Our data set comprised 1506 nucleotide positions, of which 402 were parsimony informative. Maximum parsimony, log determinant, and maximum likelihood analyses produced highly similar phylogenetic topologies, and all analyses indicated that the tropical African genus Macrogalea was the sister group to all other allodapines. This finding conflicts with that of previous studies, in which Compsomelissa + Halterapis formed the most basal group. Changing the basal node of the Allodapini has major consequences for understanding evolution in this tribe. Our results cast doubt on the previous hypotheses that progressive provisioning and castelike social behavior evolved among lineages leading to the extant allodapine taxa. Instead, our results suggest that mass provisioning in Halterapis is a derived feature and that social behavior is an ancestral trait for all allodapine lineages. The forms of social behavior present in extant allodapines are likely to have resulted from a long evolutionary history, which may help explain the complexity of social traits found in many allodapine bees.

Africa↗
PubMed2000

Heredity and the autonomic nervous system in human hypertension.

Because the complex phenotype of human hypertension is at least in part genetically determined, how individual genes ultimately contribute to the disease is not well understood. By contrast, intermediate phenotypes are traits associated with complex disease, but which may display simpler genetic properties such as greater heritability, more consistent and earlier penetrance and bimodality, and may suggest particular candidate susceptibility genes. Because autonomic nervous system activity is altered in hypertension, we examined biochemical, physiologic, and pharmacologic autonomic traits that fulfill at least some of these properties. Such biochemical, physiologic, or pharmacologic autonomic traits may be especially valuable as phenotypic anchor points in linkage or association studies probing the genetic basis of human hypertension.

Autonomic Nervous System↗
PubMed2003

Genome-wide linkage analysis of longitudinal phenotypes using sigma2A random effects (SSARs) fitted by Gibbs sampling.

The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses. Additive genetic effects (sigma2A.time) were estimated to account for approximately 9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (sigma2A) were estimated to account for approximately 43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14. Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data.

Adult↗
PubMed2005

The genetic architecture of house fly mating behavior.

This chapter summarizes several experimental approaches used to identify the effects of dominance, epistasis, and genotype-by-environment interactions in the genetic architecture of the mating behavior of the common house fly (Musca domestica L.). Quantitative genetic investigations of mating behavior hold special intrigue for unraveling the complexities of fitness traits, with applications to theory on sexual selection and speciation. Besides being well suited to large-scale quantitative genetic protocols, the house fly has a remarkably complex courtship repertoire, affording special opportunities for studies on communication, social interactions, and learning. Increased additive genetic variances for the courtship repertoire of experimentally bottlenecked populations provided evidence for the presence of dominance and/or epistasis. Negative genetic variances in these populations suggested genotype-by-environment interactions, where the environment is the mating partner. Line cross assays of populations that had been subjected to selection for divergent courtship repertoire confirmed that both dominance and epistasis have significant effects. These crosses also showed more directly that the expression of the male's genotype is dependent upon the preferences of his mating partner. Repeatability studies also detailed how males alter their courtship performances with successive encounters within and across females, such that the males learn to improve their techniques in securing copulations. A review of 41 animal behavior studies found that a wide range of traits and taxa have dominance, epistasis, and genotype-y-environment interactions, although house fly courtship may remain a unique model where learning is an intersexually selected trait. Future development of more sophisticated molecular techniques for the M. domestica genome will help unravel the underlying biochemical and developmental pathways of these quantitative genetic interactions for a more complete understanding of the processes of inbreeding depression, outbreeding depression, and pleiotropy.

Animals↗
PubMed2004

Fine mapping of a malting-quality QTL complex near the chromosome 4H S telomere in barley.

Malting quality has long been an active objective in barley (Hordeum vulgare L.) breeding programs.However, it is difficult for breeders to manipulate malting-quality traits because of inheritance complexity and difficulty in evaluation of these quantitative traits. Quantitative trait locus (QTL) mapping provides breeders a promising basis with which to manipulate quantitative trait genes. A malting-quality QTL complex, QTL2, was mapped previously to a 30-cM interval in the short-arm telomere region of barley chromosome 4H in a "Step-toe"/"Morex" doubled haploid population by the North American Barley Genome Project, using an interval mapping method with a relatively low-resolution genetic map. The QTL2 complex has moderate effects on several malting-quality traits, including malt extract percentage(ME), a-amylase activity (AA), diastatic power (DP), malt 13-glucan content (BG), and seed dormancy, which makes it a promising candidate gene source in malting barley-cultivar development. Fine mapping QTL2 is desirable for precisely studying barley malting-quality trait inheritance and for efficiently manipulating QTL2 in breeding. A reciprocal-substitution mapping method was employed to fine map QTL2. Molecular marker-assisted backcrossing was used to facilitate the generation of isolines. Fourteen different types of "Steptoe" isolines, including regenerated "Steptoe" and 13 different types of "Morex" isolines,including regenerated "Morex", were made within a 41.5-cM interval between MWG634 and BCD265B on chromosome 4H. Duplicates were identified for 12 "Steptoe" and 12 "Morex" isoline types. The isolines together with "Steptoe" and "Morex" were grown variously at three locations in 2 years for a total of five field environments.Four malting-quality traits were measured: ME, DP, AA,and BG. Few significant differences were found between duplicate isolines for these traits. A total of 15 putative QTLs were mapped; three for ME, four for DP, six for AA,and two for BG. Background genotype seemed to make a difference in expression/detection of QTLs. Of the 15 QTLs identified, ten were from the "Morex" and only five from the "Steptoe" background. By combining the results from different years, field environments, and genetic backgrounds and taking into account overlapping QTLsegments, six QTLs can be conservatively estimated: two each for ME and AA and one each for DP and BG with chromosome segments ranging from 0.7 cM to 27.9 cM. A segment of 15.8 cM from the telomere (MWG634-CDO669) includes all or a portion of all QTLs identified. Further study and marker-assisted breeding should focus on this 15.8-cM chromosome region.

Breeding↗
PubMed2001

A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.

Osteoporosis is a complex disease that affects >10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease. In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high-bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted beta-propeller module of the low-density lipoprotein receptor-related protein 5 (LRP5), that results in the HBM phenotype. During analysis of >1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.

Alleles↗
PubMed2000

The gene encoding interleukin-13: a susceptibility locus for asthma and related traits.

Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31.

Asthma↗
PubMed2006

Genetic determinants of carotid ultrasound traits.

Atherosclerosis is a complex disease with various intermediate phenotypes that are themselves complex and influenced by many factors. Through the use of carotid ultrasound techniques, the intermediate stages of vascular disease can be imaged and studied for association with potential genetic determinants. In this article we review the most recent available data (reports published since 2004) on the genetic determinants of atherosclerosis, as measured by one-, two-, and three-dimensional ultrasonography of the carotid arteries. In general, associations are disparate and modest. For intima-media thickness, promising associations have been found for both TNFRSF1A R92Q and PPARG P12A, but associations also differed in the same individuals depending on the specific ultrasound trait studied (eg, linear intima-media thickness versus total plaque volume in carotid arteries). Some of the challenging issues for future studies include accounting for gene-environment interactions, sex-specific associations, and the distinctiveness of different carotid ultrasound measures.

Carotid Artery Diseases↗
PubMed1992

Genetic dissection of the transcription cycle. A mutant RNA polymerase that cannot hold onto a promoter.

Deletion of 10 amino acids from a conserved motif in the beta subunit of Escherichia coli RNA polymerase (RNAP) leads to an interrupted transcription cycle and lethal phenotype. RNAP carrying the mutant subunit retains catalytic function and specificity of promoter recognition but is unable to efficiently hold onto DNA in the binary complex, resulting in a diminished initiation frequency. However, inefficient initiation by the mutant enzyme leads to processive and stable ternary elongating complex. Thus, the mutation dissects the traits of promoter selectivity, binary complex stability, and ternary complex processivity reflecting compartmentalization of function within the RNAP molecule.

Amino Acid Sequence↗
PubMed1987

Transmission of human craniofacial dimensions.

The transmissibilities of 11 human craniofacial dimensions are estimated by path analysis based upon familial correlations obtained in four different populations. Estimates from both the individual populations and from pooled correlations indicate that the observed variation in craniofacial dimensions is determined by genetic and nongenetic factors in roughly equal measure (.45 less than t 2 less than .60). These results implicate the possibility of complex gene-environment and gene-gene interactions in the development of the size and shape of the head and face and call for more detailed familial studies of these traits. This additional complexity further suggests the need for caution in interpreting such metrical variation, especially from a diagnostic or classificatory viewpoint.

Canada↗
PubMed2004

Quantitative genetic variation: a post-modern view.

It has become commonplace to map individual quantitative trait loci (QTL) in experimental organisms; the means (line-crosses and dense maps of markers) and motivation (the close relationship between continuous physiological traits and common, complex diseases) are self-evident. Progress in mapping human QTL has been more gradual, an inevitable consequence of genetic mapping in a natural population setting. The common objective of these studies has been to understand the molecular mechanisms underlying individual QTL. Recent theoretical and practical advances shift this focus to a more comprehensive or genomic perspective on quantitative variation. Fisher's infinitesimal model of adaptive evolution, which satisfied quantitative geneticists for over 50 years, has been modified in the light of data from QTL mapping experiments in plants and animals. The resulting exponential model provides a pleasing empirical fit to the distribution of QTL effect sizes, predicts that a large amount of quantitative variation will be explained by a limited number of genes and suggests a new mathematical framework for linkage mapping. Molecular analysis of QTL suggests that coding variants (e.g. allozymes) underlie a fraction of quantitative variation and that variants that affect gene expression (expression QTL, eQTL) have a substantial role. This is supported by genomic experiments that combine expression profiling with classical genetic mapping approaches to reveal a remarkable wealth of quantitative heritable variation in the transcriptome and that cis-and trans-acting regulatory factors are organized in networks reflecting pleiotropy. It is hoped that these advances will enhance our understanding of the genetic basis of complex inherited diseases.

Animals↗
PubMed2001

Direct and indirect sexual selection and quantitative genetics of male traits in guppies (Poecilia reticulata).

The ornamentation and displays on which sexual attractiveness and thus mating success are based may be complex and comprise several traits. Predicting the outcome of sexual selection on such complex phenotypes requires an understanding of both the direct operation of selection on each trait and the indirect consequences of selection operating directly on genetically correlated traits. Here we report the results of a quantitative genetic analysis of the ornamentation, sexual attractiveness, and mating success of male guppies (Poecilia reticulata). We analyze male ornamentation both from the point of view of single ornamental traits (e.g., the area of each color) and of composite measures of the way the entire pattern is likely to be perceived by females (e.g., the mean and contrast in chroma). We demonstrate that there is substantial additive genetic variation in almost all measures of male ornamentation and that much of this variation may be Y linked. Attractiveness and mating success are positively correlated at the phenotypic and genetic level. Orange area and chroma, the area of a male's tail, and the color contrast of his pattern overall are positively correlated with attractiveness and/or mating success at the phenotypic and genetic levels. Using attractiveness and mating success as measures of fitness, we estimate gradients of linear directional sexual selection operating on each male trait and use equations of multivariate evolutionary change to predict the response of male ornamentation to this sexual selection. From these analyses, we predict that indirect selection may have important effects on the evolution of male guppy color patterns.

Animals↗
PubMed2026

Population Genomics Approaches Identify a Cryptic, Emerging Generalist Pest Complex.

Information about biological traits essential for pest management, such as species identity, diet and movement often require laborious and time-intensive studies on pest natural history, in both laboratory and field settings. However, new agricultural pest threats are continually emerging, often requiring prompt responses with limited information. Using a combination of molecular gut content analysis and RAD-seq, we examined the species identities, plant diet composition, and population genetic structure of an emerging and important agricultural pest in the US, the peanut burrower bug, Pangaeus bilineatus Say (Hemiptera, Cydnidae). We found that two, morphologically similar, burrowing bug species (including P. bilineatus) were commonly caught in light traps near peanut fields, one of which (Dallasiellus lugubris) was not previously considered a pest of peanut. Molecular gut content analysis revealed a wide, but somewhat distinct, variety of plants among the diets of both bug species. Surprisingly, peanut was a rare part of the diet of either species. RAD-seq analysis revealed evidence consistent with weak isolation-by-distance and modest spatial genetic differentiation for both species. Together, these results suggest a potential pest complex where previously only one species was in focus. Moreover, their broad diets and spatially restricted population dispersal patterns may also explain the sporadic nature of damage that has been recorded for this potential pest complex. Responses to emerging pest challenges can benefit from insights generated by population genomics techniques, opening up new avenues for research and supporting efforts to quickly tailor management strategies for novel pests.

burrower bug↗

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