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Previous studies showed that there is variation in ontogenetic trajectories of human limb dimensions and proportions. However, little is known about the evolutionary significance of this variation. This study used a global sample of modern human immature long bone measurements and a multivariate linear mixed-effects model to study 1) whether the variation in ontogenetic trajectories of limb dimensions is consistent with ecogeographic predictions and 2) the effects of different evolutionary forces on the variation in ontogenetic trajectories. We found that genetic relatedness arising from neutral (nonselective) evolution, allometric variation associated with the change in size, and directional effects from climate all contributed to the variation in ontogenetic trajectories of all major long bone dimensions in modern humans. After accounting for the effects of neutral evolution and holding other effects considered in the current study constant, extreme temperatures have weak, positive associations with diaphyseal length and breadth measurements, while mean temperature shows negative associations with diaphyseal dimensions. The association with extreme temperatures fits the expectations of ecogeographic rules, while the association with mean temperature may explain the observed among-group variation in intralimb indices. The association with climate is present throughout ontogeny, suggesting an explanation of adaptation by natural selection as the most likely cause. On the other hand, genetic relatedness among groups, as structured by neutral evolutionary factors, is an important consideration when interpreting skeletal morphology, even for nonadult individuals.
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Flujo Genético , Extremidad Superior , Humanos , Adaptación Fisiológica , Huesos , Evolución BiológicaRESUMEN
In 1972, R.C. Lewontin concluded that it follows from the fact that the large majority of human genetic variation (≈ 85%) is among individuals within local populations that racial taxonomy is unjustified. Three decades later, Edwards demonstrated that while the accuracy with which individuals may be assigned to groups is poor for a single locus, consideration of multi-locus data allows for highly accurate assignments. Edwards concluded that Lewontin's dismissal of racial taxonomy was unwarranted. Edwards misidentified the aim of Lewontin's critique, which was directed at the utility of racial classification and not at assigning individuals to groups using genetic data. Moreover, Edwards conflated distinct kinds of correlation when sketching out his argument. If we follow Edwards' argument to its natural terminus, it becomes clear that it is consideration of all of the correlation structure among local groups in human genetic data that renders racial taxonomy scientifically useless. Lewontin considers the correlation structure relevant to his analysis of racial taxonomy and does not make his eponymous misstep. Rather, critics of Lewontin who use racial taxonomies in their work are the primary offenders when it comes to committing Lewontin's fallacy.
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Brain and skull tissues interact through molecular signalling and mechanical forces during head development, leading to a strong correlation between the neurocranium and the external brain surface. Therefore, when brain tissue is unavailable, neurocranial endocasts are often used to approximate brain size and shape. Evolutionary changes in brain morphology may have resulted in secondary changes to neurocranial morphology, but the developmental and genetic processes underlying this relationship are not well understood. Using automated phenotyping methods, we quantified the genetic basis of endocast variation across large genetically varied populations of laboratory mice in two ways: (1) to determine the contributions of various genetic factors to neurocranial form and (2) to help clarify whether a neurocranial variation is based on genetic variation that primarily impacts bone development or on genetic variation that primarily impacts brain development, leading to secondary changes in bone morphology. Our results indicate that endocast size is highly heritable and is primarily determined by additive genetic factors. In addition, a non-additive inbreeding effect led to founder strains with lower neurocranial size, but relatively large brains compared to skull size; suggesting stronger canalization of brain size and/or a general allometric effect. Within an outbred sample of mice, we identified a locus on mouse chromosome 1 that is significantly associated with variation in several positively correlated endocast size measures. Because the protein-coding genes at this locus have been previously associated with brain development and not with bone development, we propose that genetic variation at this locus leads primarily to variation in brain volume that secondarily leads to changes in neurocranial globularity. We identify a strain-specific missense mutation within Akt3 that is a strong causal candidate for this genetic effect. Whilst it is not appropriate to generalize our hypothesis for this single locus to all other loci that also contribute to the complex trait of neurocranial skull morphology, our results further reveal the genetic basis of neurocranial variation and highlight the importance of the mechanical influence of brain growth in determining skull morphology.
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Encéfalo , Cráneo , Animales , Evolución Biológica , Encéfalo/anatomía & histología , Cabeza , Ratones , Cráneo/anatomía & histologíaRESUMEN
Canalization, or robustness to genetic or environmental perturbations, is fundamental to complex organisms. While there is strong evidence for canalization as an evolved property that varies among genotypes, the developmental and genetic mechanisms that produce this phenomenon are very poorly understood. For evolutionary biology, understanding how canalization arises is important because, by modulating the phenotypic variation that arises in response to genetic differences, canalization is a determinant of evolvability. For genetics of disease in humans and for economically important traits in agriculture, this subject is important because canalization is a potentially significant cause of missing heritability that confounds genomic prediction of phenotypes. We review the major lines of thought on the developmental-genetic basis for canalization. These fall into two groups. One proposes specific evolved molecular mechanisms while the other deals with robustness or canalization as a more general feature of development. These explanations for canalization are not mutually exclusive and they overlap in several ways. General explanations for canalization are more likely to involve emergent features of development than specific molecular mechanisms. Disentangling these explanations is also complicated by differences in perspectives between genetics and developmental biology. Understanding canalization at a mechanistic level will require conceptual and methodological approaches that integrate quantitative genetics and developmental biology.
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Evolución Biológica , Epigénesis Genética , Epistasis Genética , Estudios de Asociación Genética , Genotipo , Fenotipo , Adaptación Fisiológica/genética , Animales , Biología Evolutiva/métodos , Redes Reguladoras de Genes , Interacción Gen-Ambiente , Técnicas Genéticas , Variación Genética , Genética , Humanos , Plantas/genética , Carácter Cuantitativo Heredable , Selección GenéticaRESUMEN
Variation in pelvic morphology has a complex genetic basis and its patterning and specification is governed by conserved developmental pathways. Whether the mechanisms underlying the differentiation and specification of the pelvis also produce the morphological covariation on which natural selection may act, is still an open question in evolutionary developmental biology. We use high-resolution quantitative trait locus (QTL) mapping in the F34 generation of an advanced intercross experiment (LG,SM-G34 ) to characterize the genetic architecture of the mouse pelvis. We test the prediction that genomic features linked to developmental patterning and differentiation of the hind limb and pelvis and the regulation of chondrogenesis are overrepresented in QTL. We find 31 single QTL trait associations at the genome- or chromosome-wise significance level coalescing to 27 pleiotropic loci. We recover further QTL at a more relaxed significance threshold replicating locations found in a previous experiment in an earlier generation of the same population. QTL were more likely than chance to harbor Pitx1 and Sox9 Class II chromatin immunoprecipitation-seq features active during development of skeletal features. There was weak or no support for the enrichment of seven more categories of developmental features drawn from the literature. Our results suggest that genotypic variation is channeled through a subset of developmental processes involved in the generation of phenotypic variation in the pelvis. This finding indicates that the evolvability of complex traits may be subject to biases not evident from patterns of covariance among morphological features or developmental patterning when either is considered in isolation.
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Factores de Transcripción Paired Box/metabolismo , Pelvis/crecimiento & desarrollo , Factor de Transcripción SOX9/metabolismo , Animales , Evolución Biológica , Regulación del Desarrollo de la Expresión Génica , Genómica , Genotipo , Ratones , Factores de Transcripción Paired Box/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Factor de Transcripción SOX9/genéticaRESUMEN
BACKGROUND: Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression. RESULTS: Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape. CONCLUSIONS: Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.
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Labio Leporino/genética , Fisura del Paladar/genética , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica/fisiología , Animales , Variación Biológica Individual , Labio Leporino/complicaciones , Labio Leporino/patología , Fisura del Paladar/complicaciones , Fisura del Paladar/patología , Metilación de ADN , Embrión de Mamíferos , Cara/embriología , Cara/patología , Estudios de Asociación Genética , Heterogeneidad Genética , Humanos , Ratones , Ratones Transgénicos , Hueso Paladar/embriología , Hueso Paladar/patología , Fenotipo , Retroelementos/genética , Proteínas Wnt/genéticaRESUMEN
During the late Pleistocene, isolated lineages of hominins exchanged genes thus influencing genomic variation in humans in both the past and present. However, the dynamics of this genetic exchange and associated phenotypic consequences through time remain poorly understood. Gene exchange across divergent lineages can result in myriad outcomes arising from these dynamics and the environmental conditions under which it occurs. Here we draw from our collective research across various organisms, illustrating some of the ways in which gene exchange can structure genomic/phenotypic diversity within/among species. We present a range of examples relevant to questions about the evolution of hominins. These examples are not meant to be exhaustive, but rather illustrative of the diverse evolutionary causes/consequences of hybridization, highlighting potential drivers of human evolution in the context of hybridization including: influences on adaptive evolution, climate change, developmental systems, sex-differences in behavior, Haldane's rule and the large X-effect, and transgressive phenotypic variation.
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Evolución Biológica , Hominidae , Hibridación Genética/genética , Animales , Antropología Física , Femenino , Genoma Humano/genética , Hominidae/anatomía & histología , Hominidae/genética , Humanos , Masculino , Ratones , Hombre de Neandertal/anatomía & histología , Hombre de Neandertal/genética , Fenotipo , Cráneo/anatomía & histologíaRESUMEN
Variation in body form among human groups is structured by a blend of natural selection driven by local climatic conditions and random genetic drift. However, attempts to test ecogeographic hypotheses have not distinguished between adaptive traits (i.e., those that evolved as a result of selection) and those that evolved as a correlated response to selection on other traits (i.e., nonadaptive traits), complicating our understanding of the relationship between climate and morphological distinctions among populations. Here, we use evolutionary quantitative methods to test if traits previously identified as supporting ecogeographic hypotheses were actually adaptive by estimating the force of selection on individual traits needed to drive among-group differentiation. Our results show that not all associations between trait means and latitude were caused by selection acting directly on each individual trait. Although radial and tibial length and biiliac and femoral head breadth show signs of responses to directional selection matching ecogeographic hypotheses, the femur was subject to little or no directional selection despite having shorter values by latitude. Additionally, in contradiction to ecogeographic hypotheses, the humerus was under directional selection for longer values by latitude. Responses to directional selection in the tibia and radius induced a nonadaptive correlated response in the humerus that overwhelmed its own trait-specific response to selection. This result emphasizes that mean differences between groups are not good indicators of which traits are adaptations in the absence of information about covariation among characteristics.
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Evolución Biológica , Constitución Corporal/genética , Cuerpo Humano , Carácter Cuantitativo Heredable , Selección Genética , Constitución Corporal/etnología , Clima , Flujo Génico , Flujo Genético , Humanos , Masculino , Filogeografía , Grupos RacialesRESUMEN
Variation in the shape of the human face and in stature is determined by complex interactions between genetic and environmental influences. One such environmental influence is malnourishment, which can result in growth faltering, usually diagnosed by means of comparing an individual's stature with a set of age-appropriate standards. These standards for stature, however, are typically ascertained in groups where people are at low risk for growth faltering. Moreover, genetic differences among populations with respect to stature are well established, further complicating the generalizability of stature-based diagnostic tools. In a large sample of children aged 5-19 years, we obtained high-resolution genomic data, anthropometric measures and 3D facial images from individuals within and around the city of Mwanza, Tanzania. With genome-wide complex trait analysis, we partitioned genetic and environmental variance for growth outcomes and facial shape. We found that children with growth faltering have faces that look like those of older and taller children, in a direction opposite to the expected allometric trajectory, and in ways predicted by the environmental portion of covariance at the community and individual levels. The environmental variance for facial shape varied subtly but significantly among communities, whereas genetic differences were minimal. These results reveal that facial shape preserves information about exposure to undernourishment, with important implications for refining assessments of nutritional status in children and the developmental-genetics of craniofacial variation alike.
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Desarrollo Infantil , Huesos Faciales/diagnóstico por imagen , Desnutrición/diagnóstico , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Crecimiento , Humanos , Imagenología Tridimensional , Masculino , Tanzanía , Adulto JovenRESUMEN
Hereditarians have claimed that recent advances in psychological and psychiatric genetics support their contention that socially important aspects of behavior and cognition in individuals and groups are largely insensitive to environmental context. This has been countered by anti-hereditarians who (correctly) claim that the conclusion of genetic ineluctability is false. Anti-hereditarians, however, sometimes use problematic arguments based on complexity and the ignorance that comes with complexity and a demand for mechanistic, as opposed to variational, explanations for the ways in which genes affect phenotype. I argue here, as a committed anti-hereditarian, that the complexity gambit and the demand for mechanisms open anti-hereditarian arguments to counterattack from hereditarians. Refocusing the argument onto issues about when heritability, genotypic scores, and genome-wide association studies may be appropriately applied and reemphasizing the point that context matters are stronger measures to counter hereditarian claims.
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Herencia , Genética Humana , Enfermedades Genéticas Congénitas/genética , Variación Genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
OBJECTIVES: Morphological integration, or the tendency for covariation, is commonly seen in complex traits such as the human face. The effects of growth on shape, or allometry, represent a ubiquitous but poorly understood axis of integration. We address the question of to what extent age and measures of size converge on a single pattern of allometry for human facial shape. METHODS: Our study is based on two large cross-sectional cohorts of children, one from Tanzania and the other from the United States (N = 7,173). We employ 3D facial imaging and geometric morphometrics to relate facial shape to age and anthropometric measures. RESULTS: The two populations differ significantly in facial shape, but the magnitude of this difference is small relative to the variation within each group. Allometric variation for facial shape is similar in both populations, representing a small but significant proportion of total variation in facial shape. Different measures of size are associated with overlapping but statistically distinct aspects of shape variation. Only half of the size-related variation in facial shape can be explained by the first principal component of four size measures and age while the remainder associates distinctly with individual measures. CONCLUSIONS: Allometric variation in the human face is complex and should not be regarded as a singular effect. This finding has important implications for how size is treated in studies of human facial shape and for the developmental basis for allometric variation more generally.
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Tamaño Corporal/fisiología , Cara/anatomía & histología , Adolescente , Adulto , Antropología Física , Evolución Biológica , Biometría , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Imagenología Tridimensional , Masculino , Tanzanía , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVES: This study assesses the extent to which relationships among groups complicate comparative studies of adaptation in recent human cranial variation and the extent to which departures from neutral additive models of evolution hinder the reconstruction of population relationships among groups using cranial morphology. MATERIALS AND METHODS: Using a maximum likelihood evolutionary model fitting approach and a mixed population genomic and cranial data set, I evaluate the relative fits of several widely used models of human cranial evolution. Moreover, I compare the goodness of fit of models of cranial evolution constrained by genomic variation to test hypotheses about population specific departures from neutrality. RESULTS: Models from population genomics are much better fits to cranial variation than are traditional models from comparative human biology. There is not enough evolutionary information in the cranium to reconstruct much of recent human evolution but the influence of population history on cranial variation is strong enough to cause comparative studies of adaptation serious difficulties. Deviations from a model of random genetic drift along a tree-like population history show the importance of environmental effects, gene flow, and/or natural selection on human cranial variation. Moreover, there is a strong signal of the effect of natural selection or an environmental factor on a group of humans from Siberia. DISCUSSION: The evolution of the human cranium is complex and no one evolutionary process has prevailed at the expense of all others. A holistic unification of phenome, genome, and environmental context, gives us a strong point of purchase on these problems, which is unavailable to any one traditional approach alone. Am J Phys Anthropol 160:582-592, 2016. © 2016 Wiley Periodicals, Inc.
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Evolución Biológica , Flujo Genético , Selección Genética/genética , Cráneo/anatomía & histología , Cráneo/fisiología , Antropología Física , Cefalometría , Genética de Población , Humanos , MasculinoRESUMEN
Causal explanations for the dramatic changes that occurred during the evolution of the human hip focus largely on selection for bipedal function and locomotor efficiency. These hypotheses rest on two critical assumptions. The first-that these anatomical changes served functional roles in bipedalism-has been supported in numerous analyses showing how postcranial changes likely affected locomotion. The second-that morphological changes that did play functional roles in bipedalism were the result of selection for that behavior-has not been previously explored and represents a major gap in our understanding of hominin hip evolution. Here we use evolutionary quantitative genetic models to test the hypothesis that strong directional selection on many individual aspects of morphology was responsible for the large differences observed across a sample of fossil hominin hips spanning the Plio-Pleistocene. Our approach uses covariance among traits and the differences between relatively complete fossils to estimate the net selection pressures that drove the major transitions in hominin hip evolution. Our findings show a complex and changing pattern of natural selection drove hominin hip evolution, and that many, but not all, traits hypothesized to play functional roles in bipedalism evolved as a direct result of natural selection. While the rate of evolutionary change for all transitions explored here does not exceed the amount expected if evolution was occurring solely through neutral processes, it was far above rates of evolution for morphological traits in other mammalian groups. Given that stasis is the norm in the mammalian fossil record, our results suggest that large shifts in the adaptive landscape drove hominin evolution.
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Evolución Biológica , Fósiles , Articulación de la Cadera , Cadera , Hominidae , Selección Genética , Animales , Antropología Física , Femenino , Cadera/anatomía & histología , Cadera/fisiología , Articulación de la Cadera/anatomía & histología , Articulación de la Cadera/fisiología , Hominidae/anatomía & histología , Hominidae/fisiología , Humanos , MasculinoRESUMEN
Genetic resemblances among groups are non-randomly distributed in humans. This population structure may influence the correlations between traits and environmental drivers of natural selection thus complicating the interpretation of the fossil record when modern human variation is used as a referential model. In this paper, we examine the effects of population structure and natural selection on postcranial traits that reflect body size and shape with application to the more general issue of how climate - using latitude as a proxy - has influenced hominin morphological variation. We compare models that include terms reflecting population structure, ascertained from globally distributed microsatellite data, and latitude on postcranial phenotypes derived from skeletal dimensions taken from a large global sample of modern humans. We find that models with a population structure term fit better than a model of natural selection along a latitudinal cline in all cases. A model including both latitude and population structure terms is a good fit to distal limb element lengths and bi-iliac breadth, indicating that multiple evolutionary forces shaped these morphologies. In contrast, a model that included only a population structure term best explained femoral head diameter and the crural index. The results demonstrate that population structure is an important part of human postcranial variation, and that clinally distributed natural selection is not sufficient to explain among-group differentiation. The distribution of human body form is strongly influenced by the contingencies of modern human origins, which calls for new ways to approach problems in the evolution of human variation, past and present.
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Evolución Biológica , Tamaño Corporal , Simulación por Computador , Modelos Biológicos , Selección Genética , Antropología Física , Tamaño Corporal/genética , Tamaño Corporal/fisiología , Femenino , Fósiles , Humanos , MasculinoRESUMEN
Sensory organs must develop alongside the skull within which they are largely encased, and this relationship can manifest as the skull constraining the organs, organs constraining the skull, or organs constraining one another in relative size. How this interplay between sensory organs and the developing skull plays out during the evolution of sensory diversity; however, remains unknown. Here, we examine the developmental sequence of the cochlea, the organ responsible for hearing and echolocation, in species with distinct diet and echolocation types within the ecologically diverse bat super-family Noctilionoidea. We found the size and shape of the cochlea largely correlates with skull size, with exceptions of Pteronotus parnellii, whose high duty cycle echolocation (nearly constant emission of sound pulses during their echolocation process allowing for detailed information gathering, also called constant frequency echolocation) corresponds to a larger cochlear and basal turn, and Monophyllus redmani, a small-bodied nectarivorous bat, for which interactions with other sensory organs restrict cochlea size. Our findings support the existence of developmental constraints, suggesting that both developmental and anatomical factors may act synergistically during the development of sensory systems in noctilionoid bats.
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Studies of cranial differences between modern humans and Neandertals have identified several characteristics for which the two groups differ in their mean values, the proportional relationships with other traits, or both. However, the limited number of fairly complete Neandertals has hindered investigations into patterns of integration - covariance and correlation among traits - in this fossil group. Here, we use multiple approaches specifically designed to deal with fragmentary fossils to test if metric cranial traits in Neandertals fit modern human patterns of integration. Based on 37 traits collected from a sample of 2524 modern humans from Howells' data set and 20 Neandertals, we show that overall patterns of cranial integration are significantly different between Neandertals and modern humans. However, at the same time, Neandertals are consistent with a modern human pattern of integration for more than three-quarters of the traits. Additionally, the differences between the predicted and actual values for the deviating traits are rather small, indicating that the differences in integration are subtle. Traits for which Neandertals deviate from modern human integration patterns tend to be found in regions where Neandertals and modern humans are known to also differ in their mean values. We conclude that the evolution of patterns of cranial integration is a cause for caution but also presents an opportunity for understanding cranial differences between modern humans and Neandertals.
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Fósiles , Hominidae/anatomía & histología , Cráneo/anatomía & histología , Análisis de Varianza , Animales , Evolución Biológica , Cefalometría , HumanosRESUMEN
Recent research has shown that genetic drift may have produced many cranial differences between Neandertals and modern humans. If this is the case, then it should be possible to estimate population genetic parameters from Neandertal and modern human cranial measurements in a manner analogous to how estimates are made from DNA sequences. Building on previous work in evolutionary quantitative genetics and on microsatellites, we present a divergence time estimator for neutrally evolving morphological measurements. We then apply this estimator to 37 standard cranial measurements collected on 2,524 modern humans from 30 globally distributed populations and 20 Neandertal specimens. We calculate that the lineages leading to Neandertals and modern humans split approximately 311,000 (95% C.I.: 182,000 to 466,000) or 435,000 (95% C.I.: 308,000 to 592,000) years ago, depending on assumptions about changes in within-population variation. These dates are quite similar to those recently derived from ancient Neandertal and extant human DNA sequences. Close correspondence between cranial and DNA-sequence results implies that both datasets largely, although not necessarily exclusively, reflect neutral divergence, causing them to track population history or phylogeny rather than the action of diversifying natural selection. The cranial dataset covers only aspects of cranial anatomy that can be readily quantified with standard osteometric tools, so future research will be needed to determine whether these results are representative. Nonetheless, for the measurements we consider here, we find no conflict between molecules and morphology.
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Evolución Biológica , Variación Genética , Hominidae/genética , Animales , Calibración , Cefalometría , Fósiles , Historia Antigua , Humanos , Cráneo/anatomía & histología , Factores de TiempoRESUMEN
Parent-of-origin-dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life.
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Tamaño Corporal/genética , Genoma , Impresión Genómica , Ratones/genética , Animales , Peso Corporal , Cromosomas de los Mamíferos/genética , Femenino , Genotipo , Masculino , Ratones/fisiología , Ratones Endogámicos , Modelos Genéticos , Fenotipo , Sitios de Carácter Cuantitativo , OvinosRESUMEN
Genomic imprinting results in the differential expression of genes, depending on which allele is inherited from the mother and which from the father. The effects of such differential gene expression are reflected in phenotypic differences between the reciprocal heterozygotes (Aa vs. aA). Although many imprinted genes have been identified and play a key role in development, little is known about the contribution of imprinting to quantitative variation in trait expression. Here, we examine this problem by mapping imprinting effects on adult body composition traits in the F(3) generation of an intercross between the Large (LG/J) and Small (SM/J) inbred mouse strains. We identified eight pleiotropic imprinted quantitative trait loci (iQTL) located throughout the genome. Most iQTL are in novel locations that have not previously been associated with imprinting effects, but those on chromosomes 7, 12, and centromeric 18 lie in regions previously identified as containing imprinted genes. Our results show that the effects of genomic imprinting are relatively small, with reciprocal heterozygotes differing by approximately 0.25 standard deviation units and the effects at each locus accounting for 1% to 4% of the phenotypic variance. We detected a variety of imprinting patterns, with paternal expression being the most common. These results indicate that genomic imprinting has small, but detectable, effects on the normal variation of complex traits in adults and is likely to be more common than usually thought.
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Envejecimiento/fisiología , Composición Corporal/genética , Impresión Genómica/genética , Animales , Peso Corporal , Femenino , Masculino , Ratones , Sitios de Carácter CuantitativoRESUMEN
Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high-dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait - craniofacial shape - in a sample of n = 1145 mice from the Diversity Outbred (DO) experimental line. We use biological process Gene Ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application that provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex trait genetics.