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PubMed1994

Targeted gene duplication and disruption for analyzing quantitative genetic traits in mice.

Experimental analysis of complex quantitative genetic traits, such as essential hypertension, should be greatly facilitated by being able to manipulate the expression of a gene in living animals without altering the nucleotide sequence, chromosomal location, or regulatory elements of the gene. To explore this possibility, we have used targeted gene disruption and duplication to generate mice that are genetically identical [(129 x C57BL6)F1] except for having one, two, or three functional copies of the gene coding for angiotensinogen. The two-copy animals have two normal copies of the angiotensinogen gene; the one-copy and three-copy animals have one normal copy with the other either disrupted or duplicated by gene targeting. The duplicated pair of genes was generated by a special form of gap-repair gene targeting that tandemly duplicates the whole of a gene together with 5' and 3' flanking regions. We find progressively and significantly higher levels of the gene product in the animals having increasing numbers of gene copies: the one-copy animals have steady-state plasma angiotensinogen levels approximately 35% of normal (P < 0.0001), and the three-copy animals have levels approximately 124% of normal (P < 0.004). Detailed information about regulatory sequences is not required for this type of experiment; nor is it necessary to have DNA clones or targeting constructs that cover the whole of the target gene. Varying gene copy numbers by targeting consequently offers a promising approach to quantitative genetics.

Angiotensinogen↗
PubMedDate not supplied

Linkage analysis of quantitative trait loci: sib pairs or sibships?

Sib pair linkage studies are now widely used to investigate the genetic factors implicated in complex quantitative traits. To increase the power of these approaches, it has been proposed to select extremely discordant (ED) sib pairs which are expected to contain the highest linkage information. However, it is known that sibships of larger size contain more linkage information than independent sib pairs. In this paper we compare, in terms of power and cost considerations, the ED strategy, which uses information on sib pairs only, to the recently developed 'Maximum Likelihood Binomial' sibship-oriented method performed on the whole sibships from which the ED sib pairs have been extracted. We show that the use of these whole sibships is an efficient alternative to approaches focusing on ED sib pairs only.

Algorithms↗
PubMed2002

Molecular phylogenies support multiple morphological reductions in the liverwort subclass Marchantiidae (Bryophyta).

The phylogeny of one of the putative basal-most group of land plants, the Marchantiidae, is estimated with morphological characters and with sequences of the nuclear (LSU) rDNA gene (first four domains of the 5' end of the 26S rRNA and four subsequent regions) from 34 species and 27 genera. Molecular and morphological data display high degrees of incongruence. The molecular tree topology predominates in the combined analysis. A trend from complex towards simpler morphological traits is apparent from the molecular and combined trees, whereas a trend from simple towards complex traits prevails in the morphological tree. Previously published molecular data corroborate the molecular results. It is suggested that the incongruence stems from the presence of coherent sets of reduction-related morphological traits varying in concert in the morphological data. Marchantiidae is traditionally subdivided into Marchantiales, Sphaerocarpales and Monocleales, with the majority of taxa referred to the first group. The molecular and the combined data both indicate unequivocally that Sphaerocarpales and Monocleales are nested within Marchantiales, and this result is not explicitly refuted by the morphological data.

DNA, Ribosomal↗
PubMed2006

Complex social behaviour derived from maternal reproductive traits.

A fundamental goal of sociobiology is to explain how complex social behaviour evolves, especially in social insects, the exemplars of social living. Although still the subject of much controversy, recent theoretical explanations have focused on the evolutionary origins of worker behaviour (assistance from daughters that remain in the nest and help their mother to reproduce) through expression of maternal care behaviour towards siblings. A key prediction of this evolutionary model is that traits involved in maternal care have been co-opted through heterochronous expression of maternal genes to result in sib-care, the hallmark of highly evolved social life in insects. A coupling of maternal behaviour to reproductive status evolved in solitary insects, and was a ready substrate for the evolution of worker-containing societies. Here we show that division of foraging labour among worker honey bees (Apis mellifera) is linked to the reproductive status of facultatively sterile females. We thereby identify the evolutionary origin of a widely expressed social-insect behavioural syndrome, and provide a direct demonstration of how variation in maternal reproductive traits gives rise to complex social behaviour in non-reproductive helpers.

Aging↗
PubMed2005

Epistasis and genotype-environment interaction for quantitative trait loci affecting flowering time in Arabidopsis thaliana.

A major goal of evolutionary biology is to understand the genetic architecture of the complex quantitative traits that may lead to adaptations in natural populations. Of particular relevance is the evaluation of the frequency and magnitude of epistasis (gene-gene and gene-environment interaction) as it plays a controversial role in models of adaptation within and among populations. Here, we explore the genetic basis of flowering time in Arabidopsis thaliana using a series of quantitative trait loci (QTL) mapping experiments with two recombinant inbred line (RIL) mapping populations [Columbia (Col) x Landsberg erecta (Ler), Ler x Cape Verde Islands (Cvi)]. We focus on the response of RILs to a series of environmental conditions including drought stress, leaf damage, and apical damage. These data were explicitly evaluated for the presence of epistasis using Bayesian based multiple-QTL genome scans. Overall, we mapped fourteen QTL affecting flowering time. We detected two significant QTL-QTL interactions and several QTL-environment interactions for flowering time in the Ler x Cvi population. QTL-environment interactions were due to environmentally induced changes in the magnitude of QTL effects and their interactions across environments--we did not detect antagonistic pleiotropy. We found no evidence for QTL interactions in the Ler x Col population. We evaluate these results in the context of several other studies of flowering time in Arabidopsis thaliana and adaptive evolution in natural populations.

Arabidopsis↗
PubMed2006

Genetic architecture of the dog: sexual size dimorphism and functional morphology.

Purebred dogs are a valuable resource for genetic analysis of quantitative traits. Quantitative traits are complex, controlled by many genes that are contained within regions of the genome known as quantitative trait loci (QTL). The genetic architecture of quantitative traits is defined by the characteristics of these genes: their number, the magnitude of their effects, their positions in the genome and their interactions with each other. QTL analysis is a valuable tool for exploring genetic architecture, and highlighting regions of the genome that contribute to the variation of a trait within a population.

Animals↗
PubMed2000

A score test for the linkage analysis of qualitative and quantitative traits based on identity by descent data from sib-pairs.

We propose a general likelihood-based approach to the linkage analysis of qualitative and quantitative traits using identity by descent (IBD) data from sib-pairs. We consider the likelihood of IBD data conditional on phenotypes and test the null hypothesis of no linkage between a marker locus and a gene influencing the trait using a score test in the recombination fraction theta between the two loci. This method unifies the linkage analysis of qualitative and quantitative traits into a single inferential framework, yielding a simple and intuitive test statistic. Conditioning on phenotypes avoids unrealistic random sampling assumptions and allows sib-pairs from differing ascertainment mechanisms to be incorporated into a single likelihood analysis. In particular, it allows the selection of sib-pairs based on their trait values and the analysis of only those pairs having the most informative phenotypes. The score test is based on the full likelihood, i.e. the likelihood based on all phenotype data rather than just differences of sib-pair phenotypes. Considering only phenotype differences, as in Haseman and Elston (1972) and Kruglyak and Lander (1995), may result in important losses in power. The linkage score test is derived under general genetic models for the trait, which may include multiple unlinked genes. Population genetic assumptions, such as random mating or linkage equilibrium at the trait loci, are not required. This score test is thus particularly promising for the analysis of complex human traits. The score statistic readily extends to accommodate incomplete IBD data at the test locus, by using the hidden Markov model implemented in the programs MAPMAKER/SIBS and GENEHUNTER (Kruglyak and Lander, 1995; Kruglyak et al., 1996). Preliminary simulation studies indicate that the linkage score test generally matches or outperforms the Haseman-Elston test, the largest gains in power being for selected samples of sib-pairs with extreme phenotypes.

Journal Article↗
PubMed1996

A review of the use of ribosomal DNA (rDNA) to differentiate among cryptic Anopheles species.

Cryptic species complexes are groups of closely related species that are difficult or impossible to distinguish by morphological traits. These complexes are known from a wide variety of arthropods and are common among the well-studied, medically-important insects. For example, many of the anopheline vectors of malaria parasites are members of cryptic species complexes. Complexes typically include both vector and non-vector species, and two or more member species are often found sympatrically. Until the late 1950, only two such Anopheles complexes were known, the A. gambiae complex from Africa and the A. maculipennis complex from Europe. Today, dozens of Anopheles cryptic species complexes are recognized, and accumulating evidence suggests that most important malaria vectors are likely to be members of such complexes. A variety of methods have been developed for identifying the species of individual specimens from these complexes, although until recently only those based on species-specific allozymes and polytene chromosome inversions were widely used. The limitations inherent in these methods have been circumvented with DNA-based procedures, which are especially useful because both sexes and all developmental stages can be identified, and DNA can be recovered from samples stored by a wide variety of simple methods. Several DNA-based identification techniques have been developed, including hybridization assays based on species-specific repeat sequences, and diagnostic PCR fragments produced either by the use of random PCR primers or by amplifying DNA with primers based on known species-specific sequences. In this review we discuss the relative marks of different methods of cryptic species identification, with emphasis on the use of ribosomal DNA as a target for species-diagnostic PCR assays.

Animals↗
PubMed2002

Variance components models for gene-environment interaction in quantitative trait locus linkage analysis.

Gene-environment interaction (G x E) is likely to be a common and important source of variation for complex behavioral traits. Gene-environment interaction, or genetic control of sensitivity to the environment, can be incorporated into variance components twin and sib-pair analyses by partitioning genetic effects into a mean part, which is independent of the environment, and a part that is a linear function of the environment. An approach described in a companion paper (Purcell, 2002) is applied to sib-pair variance components linkage analysis in two ways: allowing for quantitative trait locus by environment interaction and utilizing information on any residual interactions detected prior to analysis. As well as elucidating environmental pathways, consideration of G x E in quantitative and molecular studies will potentially direct and enhance gene-mapping efforts.

Computer Simulation↗
PubMedDate not supplied

Extreme selection strategies in gene mapping studies of oligogenic quantitative traits do not always increase power.

It is well known that obtaining adequate statistical power to detect linkage to or association with genes for complex quantitative traits can be very difficult. In response, investigators have developed a number of power-enhancing strategies that consider restraints such as genotyping (and/or phenotyping) costs. In the context of both association and sib pair linkage studies of quantitative traits, one of the most widely discussed techniques is the selective sampling of phenotypically extreme individuals. Several papers have demonstrated that such extreme sampling can markedly increase power (under certain circumstances). However, the parenthetical phrase in the previous sentence has generally not been made explicit and it appears to be implied that the more phenotypically extreme the individuals, the more power one has. In this paper, we show by simulation that this is not true under all circumstances. In particular, we show that under oligogenic models, where some biallelic quantitative trait loci (QTLs) have markedly asymmetric allele frequencies and large mean displacement among genotypes, and others have less asymmetric allele frequencies and smaller mean displacement among genotypes, power to detect linkage to or association with the latter QTL can actually decrease by sampling more extreme sib pairs. This suggests that more extreme sampling is not always better. The 'optimal' sampling scheme may depend on both what one suspects the underlying genetic architecture to be and which of the oligogenic QTL one has greatest interest in detecting.

Chromosome Mapping↗
PubMed2003

A 1-Mb resolution radiation hybrid map of the canine genome.

The purebred dog population consists of >300 partially inbred genetic isolates or breeds. Restriction of gene flow between breeds, together with strong selection for traits, has led to the establishment of a unique resource for dissecting the genetic basis of simple and complex mammalian traits. Toward this end, we present a comprehensive radiation hybrid map of the canine genome composed of 3,270 markers including 1,596 microsatellite-based markers, 900 cloned gene sequences and ESTs, 668 canine-specific bacterial artificial chromosome (BAC) ends, and 106 sequence-tagged sites. The map was constructed by using the RHDF5000-2 whole-genome radiation hybrid panel and computed by using MULTIMAP and TSP/CONCORDE. The 3,270 markers map to 3,021 unique positions and define an average intermarker distance corresponding to 1 Mb. We also define a minimal screening set of 325 highly informative well spaced markers, to be used in the initiation of genome-wide scans. The well defined synteny between the dog and human genomes, established in part as a function of this work by the identification of 85 conserved fragments, will allow follow-up of initial findings of linkage by selection of candidate genes from the human genome sequence. This work continues to define the canine system as the method of choice in the pursuit of the genes causing mammalian variation and disease.

Animals↗
PubMed1996

Molecular phylogeny analysis of fiddler crabs: test of the hypothesis of increasing behavioral complexity in evolution.

The current phylogenetic hypothesis for the evolution and biogeography of fiddler crabs relies on the assumption that complex behavioral traits are assumed to also be evolutionary derived. Indo-west Pacific fiddler crabs have simpler reproductive social behavior and are more marine and were thought to be ancestral to the more behaviorally complex and more terrestrial American species. It was also hypothesized that the evolution of more complex social and reproductive behavior was associated with the colonization of the higher intertidal zones. Our phylogenetic analysis, based upon a set of independent molecular characters, however, demonstrates how widely entrenched ideas about evolution and biogeography led to a reasonable, but apparently incorrect, conclusion about the evolutionary trends within this pantropical group of crustaceans. Species bearing the set of "derived traits" are phylogenetically ancestral, suggesting an alternative evolutionary scenario: the evolution of reproductive behavioral complexity in fiddler crabs may have arisen multiple times during their evolution. The evolution of behavioral complexity may have arisen by coopting of a series of other adaptations for high intertidal living and antipredator escape. A calibration of rates of molecular evolution from populations on either side of the Isthmus of Panama suggest a sequence divergence rate for 16S rRNA of 0.9% per million years. The divergence between the ancestral clade and derived forms is estimated to be approximately 22 million years ago, whereas the divergence between the American and Indo-west Pacific is estimated to be approximately 17 million years ago.

Journal Article↗
PubMed1999

Disease taxonomy--monogenic muscular dystrophy.

The field of the autosomal recessive progressive muscular dystrophies has clarified significantly following the recent elucidation of the genetic and molecular etiology of a number of these entities. These studies illustrate how genetics provides a rationale and objective basis for a new, refined nosology. Furthermore, whereas most of these studies point towards the pivotal role played by a number of structural proteins--all directly or indirectly associated with dystrophin--a calpain protease was shown to be involved in the Réunion-type limb girdle muscular dystrophy. This discovery raises the issue of whether these mechanisms are all part of one and the same pathway or of distinct pathophysiological pathways (structuropathy versus enzymopathy) leading to similar phenotypes. Finally, all of these diseases are considered as classical monogenic traits. Some findings suggest, however, that epistatic interactions have been overlooked and that the inheritance models could be slightly more complex. These results are discussed in light of the coming challenges of the identification of genes underlying complex multifactorial traits.

Humans↗
PubMed2006

Interval mapping for loci affecting unordered categorical traits.

Many traits including shapes and colors of flowers, fruits and seeds in plants, as well as coat colors and some behavioral properties in animals, are recorded in discrete categories. If categories are ordered, genetic analyses of the categorical traits are often performed using the threshold model, which considers a latent continuous variable, called the liability, underlying a trait and assumes the monotonic relationship between the phenotype and the liability. In some categorical traits, however, descriptions of phenotypes are purely nominal and the phenotypic scores cannot be ordered. The threshold model is unreasonable for the analyses of such unordered categorical traits. In this study, we developed a method for interval mapping of loci affecting unordered categorical traits with more than two categories. The probability of the phenotype of an individual falling in each of the categories was expressed by a polychotomous logistic model, in which the log-odds for each category relative to the reference category were assumed to follow a linear model including genotype at a locus affecting a trait as covariate. Based on the model, the interval mapping using a maximum likelihood method was devised for the analysis of complex categorical traits described with unordered categories. We confined ourselves to the case of F2 populations derived from a cross between two inbred lines, although this approach can easily be extended to the analyses for other populations of general structures. As results of analyses of simulated data show, the method showed high efficiency in detecting the loci affecting unordered categorical traits.

Animals↗
PubMed2005

The theoretical underpinnings of affective temperaments: implications for evolutionary foundations of bipolar disorder and human nature.

We sketch out putative evolutionary roles for affective temperaments within the theoretical framework of mood disorders conceptualized as extremes in an oligogenic model of inheritance, whereby the constituent traits in their dilute phenotypes confer adaptive advantages to individuals and/or their social group. Depressive traits, among other functions, would subserve sensitivity to the suffering of other members of the species, overlapping with those of the generalized anxious temperament, thereby enhancing the survival of not only kin but also other conspecifics. The pursuit of romantic opportunities in cyclothymia suggests that it may have evolved as a mechanism in reproductive success; cyclothymics' creative bent in poetry, music, painting, cooking or fashion design (among men, in particular) also appears useful for sexual seduction. Hyperthymic traits would lend distinct advantages in leadership, exploration, territoriality and mating. These are just some of the possibilities of the rich and complex temperamental traits subserving bipolarity within an evolutionary framework. We test selected aspects of these hypotheses with the use of correlations between the constituent traits of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS) and correlations between the TEMPS and the Temperament and Character Inventory (TCI). Such data support the counterbalancing protective influence of harm avoidance on the risk-taking behavior of cyclothymic individuals, in both men and women. Finally, we outline a hypothesis on the evolutionary function of anxious-depressive traits for women.

Affective Symptoms↗
PubMed2006

Complex genetic interactions in a quantitative trait locus.

Whether in natural populations or between two unrelated members of a species, most phenotypic variation is quantitative. To analyze such quantitative traits, one must first map the underlying quantitative trait loci. Next, and far more difficult, one must identify the quantitative trait genes (QTGs), characterize QTG interactions, and identify the phenotypically relevant polymorphisms to determine how QTGs contribute to phenotype. In this work, we analyzed three Saccharomyces cerevisiae high-temperature growth (Htg) QTGs (MKT1, END3, and RHO2). We observed a high level of genetic interactions among QTGs and strain background. Interestingly, while the MKT1 and END3 coding polymorphisms contribute to phenotype, it is the RHO2 3'UTR polymorphisms that are phenotypically relevant. Reciprocal hemizygosity analysis of the Htg QTGs in hybrids between S288c and ten unrelated S. cerevisiae strains reveals that the contributions of the Htg QTGs are not conserved in nine other hybrids, which has implications for QTG identification by marker-trait association. Our findings demonstrate the variety and complexity of QTG contributions to phenotype, the impact of genetic background, and the value of quantitative genetic studies in S. cerevisiae.

3' Untranslated Regions↗
PubMed1998

Polygenic inheritance and micro/minisatellites.

While it has often been stated that the identification of the genes involved in complex polygenic traits may be extremely difficult, the principles learned in the past century about single gene-single disease inheritance may not be relevant to polygenic inheritance. A new paradigm specific to complex disorders may be needed. It is proposed that micro- and minisatellite polymorphisms play a role in the expression of many genes. As a result, these genes exist in the population with many functional alleleomorphic variants. While each variant has only a modest effect on a given phenotype, because the variants are common, and most quantitative traits are controlled by a number of genes, there is a reasonable probability that an individual will inherit a threshold number of functional variants beyond which there is an appreciable effect on the phenotype. Twelve different aspects of such a new model for complex inheritance, some corollary implications, and three examples of its immediate application, are presented with the hope that the model may allow an acceleration of the identification of the genes involved in complex polygenic disorders.

DNA↗
PubMed2006

Multilocus analysis of atopy in Korean children using multifactor-dimensionality reduction.

BACKGROUND: Atopy is considered to be a complex genetic trait and does not follow a simple mendelian pattern of inheritance. It is now well recognised that gene-gene interactions are important in complex genetic disease. AIM: To analyse the influence of gene-gene interactions in the development of atopy. METHODS: A total of 2055 ethnically identical participants aged 10-18 years living in rural areas on Jeju Island, Korea, were randomly recruited. Atopy was defined as a positive skin prick test response to one or more common inhalant allergens. Gene-gene interactions among 12 polymorphic loci were analysed in the seven candidate genes of atopy using the multidimensionality-reduction method. RESULTS: A significant interaction was found between V297I in the gene coding vascular endothelial growth factor receptor 2 (KDR) and -308G-->A in the gene coding tumour necrosis factor (TNF)alpha on the risk of atopy, with a cross-validation consistency of 10 out of 10 and a prediction error of 35.9% (p = 0.001). Conventional logistic regression also revealed significant interactions between KDR and TNF for atopy. Individuals with the variant allele of -308G-->A in TNF (GA or AA) and V297I in KDR (VI or II) had a significantly higher risk of atopy (OR 2.23; 95% CI 1.48 to 3.57). CONCLUSION: KDR and TNF may synergistically influence the development of atopy through gene-gene interaction in Korean children and adolescents.

Adolescent↗