Quantitative Trait Loci (QTLs) mapping for growth traits in the mouse: A review

The attainment of a specific mature body size is one of the most fundamental differences among species of mammals. Moreover, body size seems to be the central factor underlying differences in traits such as growth rate, energy metabolism and body composition. An important proportion of this variability is of genetic origin. The goal of the genetic analysis of animal growth is to understand its "genetic architecture", that is the number and position of loci affecting the trait, the magnitude of their effects, allele frequencies and types of gene action. In this review, the different strategies developed to identify and characterize genes involved in the regulation of growth in the mouse are described, with emphasis on the methods developed to map loci contributing to the regulation of quantitative traits (QTLs).     

Replicated analysis of the genetic architecture of quantitative traits in two wild great tit populations

Currently, there is much debate on the genetic architecture of quantitative traits in wild populations. Is trait variation influenced by many genes of small effect or by a few genes of major effect? Where is additive genetic variation located in the genome? Do the same loci cause similar phenotypic variation in different populations? Great tits (Parus major) have been studied extensively in long‐term studies across Europe and consequently are considered an ecological ‘model organism’. Recently, genomic resources have been developed for the great tit, including a custom SNP chip and genetic linkage map. In this study, we used a suite of approaches to investigate the genetic architecture of eight quantitative traits in two long‐term study populations of great tits—one in the Netherlands and the other in the United Kingdom. Overall, we found little evidence for the presence of genes of large effects in either population. Instead, traits appeared to be influenced by many genes of small effect, with conservative estimates of the number of contributing loci ranging from 31 to 310. Despite concordance between population‐specific heritabilities, we found no evidence for the presence of loci having similar effects in both populations. While population‐specific genetic architectures are possible, an undetected shared architecture cannot be rejected because of limited power to map loci of small and moderate effects. This study is one of few examples of genetic architecture analysis in replicated wild populations and highlights some of the challenges and limitations researchers will face when attempting similar molecular quantitative genetic studies in free‐living populations.     

Systems biology strategy to study lipotoxicity and the metabolic syndrome

Systems biology views and studies the biological systems in the context of complex interactions between their building blocks and processes. Given its multi-level complexity, metabolic syndrome (MetS) makes a strong case for adopting the systems biology approach. Despite many MetS traits being highly heritable, it is becoming evident that the genetic contribution to these traits is mediated via gene–gene and gene–environment interactions across several spatial and temporal scales, and that some of these traits such as lipotoxicity may even be a product of long-term dynamic changes of the underlying genetic and molecular networks. This presents several conceptual as well as methodological challenges and may demand a paradigm shift in how we study the undeniably strong genetic component of complex diseases such as MetS. The argument is made here that for adopting systems biology approaches to MetS an integrative framework is needed which glues the biological processes of MetS with specific physiological mechanisms and principles and that lipotoxicity is one such framework. The metabolic phenotypes, molecular and genetic networks can be modeled within the context of such integrative framework and the underlying physiology.     

Modular Skeletal Evolution in Sticklebacks Is Controlled by Additive and Clustered Quantitative Trait Loci

Understanding the genetic architecture of evolutionary change remains a long-standing goal in biology. In vertebrates, skeletal evolution has contributed greatly to adaptation in body form and function in response to changing ecological variables like diet and predation. Here we use genome-wide linkage mapping in threespine stickleback fish to investigate the genetic architecture of evolved changes in many armor and trophic traits. We identify >100 quantitative trait loci (QTL) controlling the pattern of serially repeating skeletal elements, including gill rakers, teeth, branchial bones, jaws, median fin spines, and vertebrae. We use this large collection of QTL to address long-standing questions about the anatomical specificity, genetic dominance, and genomic clustering of loci controlling skeletal differences in evolving populations. We find that most QTL (76%) that influence serially repeating skeletal elements have anatomically regional effects. In addition, most QTL (71%) have at least partially additive effects, regardless of whether the QTL controls evolved loss or gain of skeletal elements. Finally, many QTL with high LOD scores cluster on chromosomes 4, 20, and 21. These results identify a modular system that can control highly specific aspects of skeletal form. Because of the general additivity and genomic clustering of major QTL, concerted changes in both protective armor and trophic traits may occur when sticklebacks inherit either marine or freshwater alleles at linked or possible “supergene” regions of the stickleback genome. Further study of these regions will help identify the molecular basis of both modular and coordinated changes in the vertebrate skeleton.     

Genetic variation of ecophysiological traits in two gynodioecious species of Schiedea (Caryophyllaceae)

Evolution of dimorphic breeding systems may involve changes in ecophysiological traits as well as floral morphology because of greater resource demands on females. Differences between related species suggest that ecophysiological traits should be heritable, and species with higher female frequencies should show greater sexual differentiation. We used modified partial diallel crossing designs to estimate narrow-sense heritabilities and genetic correlations of sex-specific ecophysiological and morphological traits in closely related gynodioecious Schiedea salicaria (13% females) and Schiedea adamantis (39% females). In S. salicaria, hermaphrodites and females differed in photosynthetic rate and specific leaf area (SLA). Narrow-sense heritabilities were significant for stomatal conductance, SLA and inflorescence number in hermaphrodites, and for SLA and inflorescence number in females. Schiedea adamantis had no sexual dimorphism in measured traits; stomatal conductance, stem number and inflorescence number were heritable in females, and stem number was heritable in hermaphrodites. In both species, significant genetic correlations of traits between sexes were rare, indicating that traits can evolve independently in response to sex-differential selection. Significant genetic correlations were detected between certain traits within sexes of both species. Low heritability of some ecophysiological traits may reflect low additive genetic variability or high phenotypic plasticity in these traits.     

Genomic dissection of variation in clutch size and egg mass in a wild great tit (Parus major) population

Clutch size and egg mass are life history traits that have been extensively studied in wild bird populations, as life history theory predicts a negative trade‐off between them, either at the phenotypic or at the genetic level. Here, we analyse the genomic architecture of these heritable traits in a wild great tit (Parus major) population, using three marker‐based approaches – chromosome partitioning, quantitative trait locus (QTL) mapping and a genome‐wide association study (GWAS). The variance explained by each great tit chromosome scales with predicted chromosome size, no location in the genome contains genome‐wide significant QTL, and no individual SNPs are associated with a large proportion of phenotypic variation, all of which may suggest that variation in both traits is due to many loci of small effect, located across the genome. There is no evidence that any regions of the genome contribute significantly to both traits, which combined with a small, nonsignificant negative genetic covariance between the traits, suggests the absence of genetic constraints on the independent evolution of these traits. Our findings support the hypothesis that variation in life history traits in natural populations is likely to be determined by many loci of small effect spread throughout the genome, which are subject to continued input of variation by mutation and migration, although we cannot exclude the possibility of an additional input of major effect genes influencing either trait.     

Lack of concordance between genetic diversity estimates at the molecular and quantitative-trait levels

In many applications of population genetics, particularly in the field of conservation biology, estimates of molecular diversity are used as surrogate indicators of less easily acquired measures of genetic variation for quantitative traits. The general validity of this approach to inferring levels of quantitative genetic variation within populations is called into question by the demonstration that estimates of molecular and quantitative-genetic variation are essentially uncorrelated in natural populations of Daphnia, one of the few organisms for which multiple estimates of both quantities are available. On the other hand, molecular measures of population subdivision seem to give conservatively low estimates of the degree of genetic subdivision at the level of quantitative traits. This suggests that although molecular markers provide little information on the level of genetic variation for quantitative traits within populations, they may be valid indicators of population subdivision for such characters.     

Genetic basis of yield as viewed from a crop physiologist's perspective

The final yield of a crop is the product of growth during the growing season and a number of developmental processes occurring throughout the life cycle of a crop, with most genes influencing the final outcome to a degree. However, recent advances in molecular biology have developed the potential to identify and map many genes or QTLs related to various important traits, including yield, plant adaptation and tolerance to stresses. Significant G×E interactions for yield have been identified, as have interactions associated with QTLs for yield. However, there is little evidence available to confirm that a QTL for yield from a parental line in one mapping population may improve yield when transferred into an adapted, high‐yielding line of another population. In order to narrow the apparent gap between the genotype and the phenotype with regard to yield, it is important to identify key traits related to yield and then attempt to identify and locate the genes controlling them. The partitioning of the developmental time to anthesis into different phases: from sowing to the onset of stem elongation and from then to anthesis, as a relatively simple physiological attribute putatively related to yield, is discussed. If the relationship holds in a wider range of conditions and the genetic factors responsible are located then the genetic basis of yield should be identified. There has also been significant progress in crop simulation modelling. Using knowledge of crop physiology and empirical relationships these models can simulate the performance of crops, including the G×E interactions. Such models require information regarding the genetic basis of yield, which are included in the form of genetic coefficients. Essentially models are constructed as decision‐making tools for management but may be of use in detecting prospective traits for selection within a breeding programme. Problems associated with this approach are discussed. This review discusses the need to use crop physiology approaches to analyse components of yield in order to reliably identify the genetic basis of yield.     

Maintenance of a genetic polymorphism by fluctuating selection on sex‐limited traits

Fluctuating selection is often thought to be ineffective in maintaining a genetic polymorphism except when generations overlap, for example when a seed bank causes a storage effect. Here, I demonstrate that fluctuating selection on sex‐limited traits automatically includes such a ‘storage effect’ because sex‐limited alleles are shielded from selection in the sex where they are not expressed. With analytical calculations and numerical simulations I show that fluctuating selection can maintain a genetic polymorphism in sex‐limited traits. Such a protected polymorphism can reduce the cost of sex when female‐limited traits are involved. But, this effect will probably be small compared to the two‐fold advantage of asexual reproduction unless many polymorphic loci interact or exceptionally strong environmental fluctuations are present. It is argued that genetic polymorphisms maintained by fluctuating selection on sex‐limited traits may partly explain the large genetic variance of traits under strong sexual selection.     

Genetic architecture and balancing selection: the life and death of differentiated variants

Balancing selection describes any form of natural selection, which results in the persistence of multiple variants of a trait at intermediate frequencies within populations. By offering up a snapshot of multiple co‐occurring functional variants and their interactions, systems under balancing selection can reveal the evolutionary mechanisms favouring the emergence and persistence of adaptive variation in natural populations. We here focus on the mechanisms by which several functional variants for a given trait can arise, a process typically requiring multiple epistatic mutations. We highlight how balancing selection can favour specific features in the genetic architecture and review the evolutionary and molecular mechanisms shaping this architecture. First, balancing selection affects the number of loci underlying differentiated traits and their respective effects. Control by one or few loci favours the persistence of differentiated functional variants by limiting intergenic recombination, or its impact, and may sometimes lead to the evolution of supergenes. Chromosomal rearrangements, particularly inversions, preventing adaptive combinations from being dissociated are increasingly being noted as features of such systems. Similarly, due to the frequency of heterozygotes maintained by balancing selection, dominance may be a key property of adaptive variants. High heterozygosity and limited recombination also influence associated genetic load, as linked recessive deleterious mutations may be sheltered. The capture of deleterious elements in a locus under balancing selection may reinforce polymorphism by further promoting heterozygotes. Finally, according to recent genomewide scans, balanced polymorphism might be more pervasive than generally thought. We stress the need for both functional and ecological studies to characterize the evolutionary mechanisms operating in these systems.     

Entering the second century of maize quantitative genetics

Maize is the most widely grown cereal in the world. In addition to its role in global agriculture, it has also long served as a model organism for genetic research. Maize stands at a genetic crossroads, as it has access to all the tools available for plant genetics but exhibits a genetic architecture more similar to other outcrossing organisms than to self-pollinating crops and model plants. In this review, we summarize recent advances in maize genetics, including the development of powerful populations for genetic mapping and genome-wide association studies (GWAS), and the insights these studies yield on the mechanisms underlying complex maize traits. Most maize traits are controlled by a large number of genes, and linkage analysis of several traits implicates a ‘common gene, rare allele'' model of genetic variation where some genes have many individually rare alleles contributing. Most natural alleles exhibit small effect sizes with little-to-no detectable pleiotropy or epistasis. Additionally, many of these genes are locked away in low-recombination regions that encourage the formation of multi-gene blocks that may underlie maize''s strong heterotic effect. Domestication left strong marks on the maize genome, and some of the differences in trait architectures may be due to different selective pressures over time. Overall, maize''s advantages as a model system make it highly desirable for studying the genetics of outcrossing species, and results from it can provide insight into other such species, including humans.     

GENOME DIVERGENCE AND THE GENETIC ARCHITECTURE OF BARRIERS TO GENE FLOW BETWEEN LYCAEIDES IDAS AND L. MELISSA

Genome divergence during speciation is a dynamic process that is affected by various factors, including the genetic architecture of barriers to gene flow. Herein we quantitatively describe aspects of the genetic architecture of two sets of traits, male genitalic morphology and oviposition preference, that putatively function as barriers to gene flow between the butterfly species Lycaeides idas and L. melissa. Our analyses are based on unmapped DNA sequence data and a recently developed Bayesian regression approach that includes variable selection and explicit parameters for the genetic architecture of traits. A modest number of nucleotide polymorphisms explained a small to large proportion of the variation in each trait, and average genetic variant effects were nonnegligible. Several genetic regions were associated with variation in multiple traits or with trait variation within‐ and among‐populations. In some instances, genetic regions associated with trait variation also exhibited exceptional genetic differentiation between species or exceptional introgression in hybrids. These results are consistent with the hypothesis that divergent selection on male genitalia has contributed to heterogeneous genetic differentiation, and that both sets of traits affect fitness in hybrids. Although these results are encouraging, we highlight several difficulties related to understanding the genetics of speciation.     

Evolutionary genomics of animal personality

Research on animal personality can be approached from both a phenotypic and a genetic perspective. While using a phenotypic approach one can measure present selection on personality traits and their combinations. However, this approach cannot reconstruct the historical trajectory that was taken by evolution. Therefore, it is essential for our understanding of the causes and consequences of personality diversity to link phenotypic variation in personality traits with polymorphisms in genomic regions that code for this trait variation. Identifying genes or genome regions that underlie personality traits will open exciting possibilities to study natural selection at the molecular level, gene-gene and gene-environment interactions, pleiotropic effects and how gene expression shapes personality phenotypes. In this paper, we will discuss how genome information revealed by already established approaches and some more recent techniques such as high-throughput sequencing of genomic regions in a large number of individuals can be used to infer micro-evolutionary processes, historical selection and finally the maintenance of personality trait variation. We will do this by reviewing recent advances in molecular genetics of animal personality, but will also use advanced human personality studies as case studies of how molecular information may be used in animal personality research in the near future.     

Marker assisted selection in crop plants

Genetic mapping of major genes and quantitative traits loci (QTLs) for many important agricultural traits is increasing the integration of biotechnology with the conventional breeding process. Exploitation of the information derived from the map position of traits with agronomical importance and of the linked molecular markers, can be achieved through marker assisted selection (MAS) of the traits during the breeding process. However, empirical applications of this procedure have shown that the success of MAS depends upon several factors, including the genetic base of the trait, the degree of the association between the molecular marker and the target gene, the number of individuals that can be analyzed and the genetic background in which the target gene has to be transferred. MAS for simply inherited traits is gaining increasing importance in breeding programs, allowing an acceleration of the breeding process. Traits related to disease resistance to pathogens and to the quality of some crop products are offering some important examples of a possible routinary application of MAS. For more complex traits, like yield and abiotic stress tolerance, a number of constraints have determined severe limitations on an efficient utilization of MAS in plant breeding, even if there are a few successful applications in improving quantitative traits. Recent advances in genotyping technologies together with comparative and functional genomic approaches are providing useful tools for the selection of genotypes with superior agronomical performancies.     

Conservation genetics of freshwater fish

Genetic markers have helped to resolve many difficult taxonomic problems and map patterns of diversity within and among remnant populations of threatened and endangered species. Knowledge of historical patterns of gene flow can help to manage dispersal among anthropogenically fragmented populations. Genetic considerations are used in the design of captive breeding programmes that avoid inbreeding depression and artificial selection that may impact on Darwinian fitness. Case studies from endangered populations of topminnows from North American deserts are used to illustrate a variety of methods used in conservation genetic studies. Several merits of studying putatively neutral, molecular markers v. adaptive phenotypic traits are discussed.     

Candidate gene analysis of metamorphic timing in ambystomatid salamanders

Although much is known about the ecological significance of metamorphosis and metamorphic timing, few studies have examined the underlying genetic architecture of these traits, and no study has attempted to associate phenotypic variation to molecular variation in specific genes. Here we report on a candidate gene approach (CGA) to test specific loci for a statistical contribution to variation in metamorphic timing. Three segregating populations (SP1, SP2 and SP3) were constructed utilizing three species of paedomorphic Mexican ambystomatid salamander, including the axolotl, Ambystoma mexicanum. We used these replicated species to test the hypothesis that inheritance of alternate genotypes at two thyroid hormone receptor loci (TRalpha, TRbeta) affects metamorphic timing in ambystomatid salamanders. A significant TRalpha*SP effect indicated that variation in metamorphic timing may be influenced by TRalpha genotype, however, the effect was not a simple one, as both the magnitude and direction of the phenotypic effect depended upon the genetic background. These are the first data to implicate a specific gene in contributing to variation in metamorphic timing. In general, candidate gene approaches can be extended to any number of loci and to any organism where simple genetic crosses can be performed to create segregating populations. The approach is thus of particular value in ecological studies where target genes have been identified but the study organism is not one of the few well-characterized model systems that dominate genetic research.     

Quantitative genetics of human skin color

Skin color has long been of interest to human geneticists and often used as an example of a human quantitative trait under relatively wellunderstood genetic control. Although the basic biology of melanin production and the method of measurement are areas in which skin color studies are fairly well advanced, compared to other quantitative traits, the evolutionary significance and mode of inheritance are still being debated. In view of the many steps involved in the production and dispersion of melanin and the large number of loci involved in coat color of laboratory animals, it is suggested that genetic control of human skin color must be fairly complex. Studies that have found evidence for relatively few loci effecting the differences between racial groups may either be using inappropriate methods, or they may be concentrating attention on only that portion of genetic variability that distinguishes between major world groups, particularly blacks and whites. Genetic analysis of intermediate groups and pedigree analysis of rare pigmentation conditions may yield more information on skin color genetics.     

Understanding and using quantitative genetic variation

Quantitative genetics, or the genetics of complex traits, is the study of those characters which are not affected by the action of just a few major genes. Its basis is in statistical models and methodology, albeit based on many strong assumptions. While these are formally unrealistic, methods work. Analyses using dense molecular markers are greatly increasing information about the architecture of these traits, but while some genes of large effect are found, even many dozens of genes do not explain all the variation. Hence, new methods of prediction of merit in breeding programmes are again based on essentially numerical methods, but incorporating genomic information. Long-term selection responses are revealed in laboratory selection experiments, and prospects for continued genetic improvement are high. There is extensive genetic variation in natural populations, but better estimates of covariances among multiple traits and their relation to fitness are needed. Methods based on summary statistics and predictions rather than at the individual gene level seem likely to prevail for some time yet.     

Partitioning of genetic variation across the genome using multimarker methods in a wild bird population

The underlying basis of genetic variation in quantitative traits, in terms of the number of causal variants and the size of their effects, is largely unknown in natural populations. The expectation is that complex quantitative trait variation is attributable to many, possibly interacting, causal variants, whose effects may depend upon the sex, age and the environment in which they are expressed. A recently developed methodology in animal breeding derives a value of relatedness among individuals from high‐density genomic marker data, to estimate additive genetic variance within livestock populations. Here, we adapt and test the effectiveness of these methods to partition genetic variation for complex traits across genomic regions within ecological study populations where individuals have varying degrees of relatedness. We then apply this approach for the first time to a natural population and demonstrate that genetic variation in wing length in the great tit (Parus major) reflects contributions from multiple genomic regions. We show that a polygenic additive mode of gene action best describes the patterns observed, and we find no evidence of dosage compensation for the sex chromosome. Our results suggest that most of the genomic regions that influence wing length have the same effects in both sexes. We found a limited amount of genetic variance in males that is attributed to regions that have no effects in females, which could facilitate the sexual dimorphism observed for this trait. Although this exploratory work focuses on one complex trait, the methodology is generally applicable to any trait for any laboratory or wild population, paving the way for investigating sex‐, age‐ and environment‐specific genetic effects and thus the underlying genetic architecture of phenotype in biological study systems.