Biomedical subjects

James M Cheverud

Publications and source records attributed to James M Cheverud.

At least 19 recordsLinked to original sources

PubMed2005

Epistatic pleiotropy and the genetic architecture of covariation within early and late-developing skull trait complexes in mice.

The role of epistasis as a source of trait variation is well established, but its role as a source of covariation among traits (i.e., as a source of "epistatic pleiotropy") is rarely considered. In this study we examine the relative importance of epistatic pleiotropy in producing covariation within early and late-developing skull trait complexes in a population of mice derived from an intercross of the Large and Small inbred strains. Significant epistasis was found for several pairwise combinations of the 21 quantitative trait loci (QTL) affecting early developing traits and among the 20 QTL affecting late-developing traits. The majority of the epistatic effects were restricted to single traits but epistatic pleiotropy still contributed significantly to covariances. Because of their proportionally larger effects on variances than on covariances, epistatic effects tended to reduce within-group correlations of traits and reduce their overall degree of integration. The expected contributions of single-locus and two-locus epistatic pleiotropic QTL effects to the genetic covariance between traits were analyzed using a two-locus population genetic model. The model demonstrates that, for single-locus or epistatic pleiotropy to contribute to trait covariances in the study population, both traits must show the same pattern of single-locus or epistatic effects. As a result, a large number of the cases where loci show pleiotropic effects do not contribute to the covariance between traits in this population because the loci show a different pattern of effect on the different traits. In general, covariance patterns produced by single-locus and epistatic pleiotropy predicted by the model agreed well with actual values calculated from the QTL analysis. Nearly all single-locus and epistatic pleiotropic effects contributed positive components to covariances between traits, suggesting that genetic integration in the skull is achieved by a complex combination of pleiotropic effects.

Age Factors↗

PubMed2005

Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains.

Maternal effects on offspring phenotypes occur because mothers in many species provide an environment for their developing young. Although these factors are correctly "environmental" with respect to the offspring genome, their variance may have both a genetic and an environmental basis in the maternal generation. Here, reciprocal crosses between C57BL/6J and 10 LGXSM recombinant inbred (RI) strains were performed, and litters were divided at weaning into high-fat and low-fat dietary treatments. Differences between reciprocal litters were used to measure genetic maternal effects on offspring phenotypes. Nearly all traits, including weekly body weights and adult blood serum traits, show effects indicative of genetic variation in maternal effects across RI strains, allowing the quantitative trait loci involved to be mapped. Although much of the literature on maternal effects relates to early life traits, we detect strong and significant maternal effects on traits measured at adulthood (as much as 10% of the trait variance at 17 or more weeks after weaning). We also found an interaction affecting adult phenotype between the effects of maternal care between RI strain mothers and C57BL/6J mothers and a later environmental factor (dietary fat intake) for some age-specific weights.

Animals↗

PubMed2005

A non-stationary model for functional mapping of complex traits.

SUMMARY: Understanding the genetic control of growth is fundamental to agricultural, evolutionary and biomedical genetic research. In this article, we present a statistical model for mapping quantitative trait loci (QTL) that are responsible for genetic differences in growth trajectories during ontogenetic development. This model is derived within the maximum likelihood context, implemented with the expectation-maximization algorithm. We incorporate mathematical aspects of growth processes to model the mean vector and structured antedependence models to approximate time-dependent covariance matrices for longitudinal traits. Our model has been employed to map QTL that affect body mass growth trajectories in both male and female mice of an F2 population derived from the Large and Small mouse strains. The results from this model are compared with those from the autoregressive-based functional mapping approach. Based on results from computer simulation studies, we suggest that these two models are alternative to one another and should be used simultaneously for the same dataset.

Aging↗

PubMed2005

Os parietale divisum.

Divisions of the parietal bone are extraordinarily rare, and have been described previously only in skull specimens in the anatomical literature. We report a case of os parietale divisum (divided parietal bone) in an infant with plagiocephaly. A 36-weeks gestation male with multiple congenital anomalies presented to the deformational plagiocephaly clinic at 11 weeks of age. CT imaging demonstrated a suture dividing the left parietal bone into two segments. He had a plagiocephalic appearance, with the greater occipital and parietal protuberances ipsilateral to the abnormal left parietal suture, and a correspondingly flatter right occiput. Head circumference was in the normal range, and the anterior fontanelle was patent and of normal size. He had mild right-sided right frontal and malar protuberance. Mandibular asymmetry was noted with a chin-point to the right of midline. He had a left-sided head tilt. He was treated with cranial molding helmet therapy for his head shape and physical therapy for his head tilt. After 16 months of helmet therapy, he had little improvement of his head shape. This case is an in vivo presentation of a rare variant, os parietale divisum.

Abnormalities, Multiple↗

PubMed2005

Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines.

Levels of human obesity have increased over the past 20 years worldwide, primarily due to changes in diet and activity levels. Although environmental changes are clearly responsible for the increasing prevalence of obesity, individuals may show genetic variation in their response to an obesogenic environment. Here, we measure genetic variation in response to a high-fat diet in a mouse model, an F16 Advanced Intercross Line derived from the cross of SM/J and LG/J inbred mouse strains. The experimental population was separated by sex and fed either a high-fat (42% of energy from fat) or low-fat (15% of energy from fat) diet. A number of phenotypic traits related to obesity and diabetes such as growth rate, glucose tolerance traits, organ weights and fat pad weights were collected and analysed in addition to serum levels of insulin, free fatty acids, cholesterol and triglycerides. Most traits are different between the sexes and between dietary treatments and for a few traits, including adult growth, fat pad weights, insulin and glucose tolerance, the dietary effect is stronger in one sex than the other. We find that fat pad weights, liver weight, serum insulin levels and adult growth rates are all phenotypically and genetically correlated with one another in both dietary treatments. Critically, these traits have relatively low genetic correlations across environments (average r =0.38). Dietary responses are also genetically correlated across these traits. We found substantial genetic variation in dietary response and low cross environment genetic correlations for traits aligned with adiposity. Therefore, genetic effects for these traits are different depending on the environment an animal is exposed to.

Animals↗

PubMed2005

Fine-mapping gene-by-diet interactions on chromosome 13 in a LG/J x SM/J murine model of obesity.

Obesity is one of the most serious threats to human health today. Although there is general agreement that environmental factors such as diet have largely caused the current obesity pandemic, the environmental changes have not affected all individuals equally. To model gene-by-environment interactions in a mouse model system, our group has generated an F(16) advanced intercross line (AIL) from the SM/J and LG/J inbred strains. Half of our sample was fed a low-fat (15% energy from fat) diet while the other half was fed a high-fat (43% energy from fat) diet. The sample was assayed for a variety of obesity- and diabetes-related phenotypes such as growth rate, response to glucose challenge, organ and fat pad weights, and serum lipids and insulin. An examination in the F(16) sample of eight adiposity quantitative trait loci previously identified in an F(2) intercross of SM/J and LG/J mouse strains reveals locus-by-diet interactions for all previously mapped loci. Adip7, located on proximal chromosome 13, demonstrated the most interactions and therefore was selected for fine mapping with microsatellite markers. Three phenotypic traits, liver weight in male animals, serum insulin in male animals, and reproductive fat pad weight, show locus-by-diet interactions in the 127-kb region between markers D13Mit1 and D13Mit302. The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains.

Animals↗

PubMed2005

Convergence and the multidimensional niche.

Convergent evolution has played an important role in the development of the ecological niche concept. We investigated patterns of convergent and divergent evolution of Caribbean Anolis lizards. These lizards diversified independently on each of the islands of the Greater Antilles, producing the same set of habitat specialists on each island. Using a phylogenetic comparative framework, we examined patterns of morphological convergence in five functionally distinct sets of morphological characters: body size, body shape, head shape, lamella number, and sexual size dimorphism. We find evidence for convergence among members of the habitat specialist types for each of these five datasets. Furthermore, the patterns of convergence differ among at least four of the five datasets; habitat specialists that are similar for one set of characters are often greatly different for another. This suggests that the habitat specialist niches into which these anoles have evolved are multidimensional, involving several distinct and independent aspects of morphology.

Adaptation, Biological↗

PubMed2005

Size as a line of least evolutionary resistance: diet and adaptive morphological radiation in New World monkeys.

New World monkeys (NWM) display substantial variation (two orders of magnitude) in body size. Despite this, variation in skull size and associated shape show a conserved allometric relationship, both within and between genera. Maximum likelihood estimates of quantitative ancestral states were used to compare the direction of morphological differentiation with the phenotypic (p(max)) and genetic (g(max)) lines of least evolutionary resistance (LLER). Diversification in NWM skulls occurred principally along the LLER defined by size variation. We also obtained measures of morphological amount and pace of change using our skull data together with published genetic distances to test whether the LLER influenced the amount and pace of diversification. Moreover, data on an ecological factor (diet) was obtained from the literature and used to test the association of this niche-related measure with the morphological diversification. Two strategies were used to test the association of LLER with the morphological and dietary amount and pace of change, one focusing on both contemporary genera and maximum likelihood reconstructed ancestors and the other using only the 16 contemporary genera in a phylogenetic comparative analysis. Our results suggest that the LLER influenced the path, amount, and pace of morphological change. Evolution also occurred away from the LLER in some taxa but this occurred at a slower pace and resulted in a relatively low amount of morphological change. We found that longer branch lengths (time) are associated with larger differences in p(max) orientation. However, on a macroevolutionary scale there is no such trend. Diet is consistently associated with both absolute size differences and morphological integration patterns, and we suggest that this ecological factor might be driving adaptive radiation in NWM. Invasion of diet-based adaptive zones involves changes in absolute size, due to metabolic and foraging constraints, resulting in simple allometric skull diversification along the LLER. While it is clear that evolutionary change occurred along the LLER, it is not clear whether this macroevolutionary pattern results from a conservation of within-population genetic covariance patterns or long-term adaptation along a size dimension or whether both constraints and selection were inextricably involved.

Adaptation, Physiological↗

PubMed2005

Mechanistic mapping of ontogenetic growth based on biological principles.

Ontogenetic growth can be described by mathematical equations constructed on the goodness of fit. Recently, the biological mechanism underlying mathematical growth equations has been explored using basic cellular properties. Here, we derive a general statistical model for understanding the genetic regulation of ontogenetic growth by integrating those biologically-proven meaningful growth equations into a quantitative trait locus (QTL) mapping framework. We can characterize the dynamic patterns of effects of QTL governing growth curves and estimate the global effect of the underlying QTL throughout the entire course of growth. The model provides the basis for deciphering genetic relationships for growth rates and the timing of life history events for any kind of organisms.

Animals↗

PubMed2004

Detecting genetic drift versus selection in human evolution.

Recent paleoanthropological discoveries reveal a diverse, potentially speciose human fossil record. Such extensive morphological diversity results from the action of divergent evolutionary forces on an evolving lineage. Here, we apply quantitative evolutionary theory to test whether random evolutionary processes alone can explain the morphological diversity seen among fossil australopith and early Homo crania from the Plio-Pleistocene. We show that although selection may have played an important role in diversifying hominin facial morphology in the late Pliocene, this is not the case during the early evolution of the genus Homo, where genetic drift was probably the primary force responsible for facial diversification.

Animals↗

PubMed2004

Pleiotropic effects on mandibular morphology II: differential epistasis and genetic variation in morphological integration.

The evolution of morphological modularity through the sequestration of pleiotropy to sets of functionally and developmentally related traits requires genetic variation in the relationships between traits. Genetic variation in relationships between traits can result from differential epistasis, where epistatic relationships for pairs of loci are different for different traits. This study maps relationship quantitative trait loci (QTLs), specifically QTLs that affect the relationship between individual mandibular traits and mandible length, across the genome in an F2 intercross of the LG/J and SM/J inbred mouse strains (N = 1045). We discovered 23 relationship QTLs scattered throughout the genome. All mandibular traits were involved in one or more relationship QTL. When multiple traits were affected at a relationship QTL, the traits tended to come from a developmentally restricted region of the mandible, either the muscular processes or the alveolus. About one-third of the relationship QTLs correspond to previously located trait QTLs affecting the same traits. These results comprise examples of genetic variation necessary for an evolutionary response to selection on the range of pleiotropic effects.

Animals↗

PubMed2004

A mechanistic model for genetic machinery of ontogenetic growth.

Two different genetic mechanisms can be proposed to explain variation in growth trajectories. The allelic sensitivity hypothesis states that growth trajectory is controlled by the time-dependent expression of alleles at the deterministic quantitative trait loci (dQTL) formed during embryogenesis. The gene regulation hypothesis states that the differentiation in growth process is due to the opportunistic quantitative trait loci (oQTL) through their mediation with new developmental signals. These two hypotheses of genetic control have been elucidated in the literature. Here, we propose a new statistical model for discerning these two mechanisms in the context of growth trajectories by integrating growth laws within a QTL-mapping framework. This model is developed within the maximum-likelihood context, implemented with a grid approach for estimating the genomic positions of the deterministic and opportunistic QTL and the simplex algorithm for estimating the growth curve parameters of the genotypes at these QTL and the parameters modeling the residual (co)variance matrix. Our model allows for extensive hypothesis tests for the genetic control of growth processes and developmental events by these two types of QTL. The application of this new model to an F(2) progeny in mice leads to the detection of deterministic and opportunistic QTL on chromosome 1 for mouse body mass growth. The estimates of QTL positions and effects from our model are broadly in agreement with those by traditional interval-mapping approaches. The implications of this model for biological and biomedical research are discussed.

Algorithms↗

PubMed2004

A unifying statistical model for QTL mapping of genotype x sex interaction for developmental trajectories.

Most organisms display remarkable differences in morphological, anatomical, and developmental features between the two sexes. It has been recognized that these sex-dependent differences are controlled by an array of specific genetic factors, mediated through various environmental stimuli. In this paper, we present a unifying statistical model for mapping quantitative trait loci (QTL) that are responsible for sexual differences in growth trajectories during ontogenetic development. This model is derived within the maximum likelihood context, incorporated by sex-stimulated differentiation in growth form that is described by mathematical functions. A typical structural model is implemented to approximate time-dependent covariance matrices for longitudinal traits. This model allows for a number of biologically meaningful hypothesis tests regarding the effects of QTL on overall growth trajectories or particular stages of development. It is particularly powerful to test whether and how the genetic effects of QTL are expressed differently in different sexual backgrounds. Our model has been employed to map QTL affecting body mass growth trajectories in both male and female mice of an F2 population derived from the large (LG/J) and small (SM/J) mouse strains. We detected four growth QTL on chromosomes 6, 7, 11, and 15, two of which trigger different effects on growth curves between the two sexes. All the four QTL display significant genotype-sex interaction effects on the timing of maximal growth rate in the ontogenetic growth of mice. The implications of our model for studying the genetic architecture of growth trajectories and its extensions to some more general situations are discussed.

Animals↗

PubMed2004

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

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

Adaptation, Physiological↗

PubMed2004

Systematics and evolution of the Jacchus group of marmosets (Platyrrhini).

Interspecific differentiation and geographic variation patterns in 39 skull traits of eastern Brazilian marmosets are analyzed. Eastern Callithrix taxa are distinct morphologically, and no evidence of intergradation among taxa is observed. Instead, there are sharp, stepped morphological boundaries among taxa, consistent with species-level distinction. The morphological similarity cluster diagram obtained from Mahalanobis distances is different from available molecular trees, and the general picture emerging is that the eastern Callithrix taxa should be considered as good species arising recently in South American history. In particular, C. kuhlii is morphologically distinct from other marmoset taxa, including C. geoffroyi and C. penicillata, which were previously hypothesized to be the parental populations that formed C. kuhlii by hybridization. Furthermore, C. kuhlii populations from southeastern Bahia do not overlap morphologically with any C. penicillata population, including the upper São Francisco River populations that display skin colors and pelage patterns to some extent similar to true Kuhli's marmosets. There is a negative, though insignificant, correlation between the morphological distance matrix and a Mahalanobis distance matrix estimated from nine climatic variables, a pattern opposite to that expected under a parapatric speciation model. This result, together with the lack of clinal variation in skull traits, suggests that an allopatric model of speciation might best explain eastern marmoset diversification.

Analysis of Variance↗

PubMed2004

Cranial evolution in sakis (Pithecia, Platyrrhini) I: interspecific differentiation and allometric patterns.

Patterns of interspecific differentiation in saki monkey (Pithecia) skulls are quantitatively described. The taxonomic arrangement previously proposed by Hershkovitz ([1987] Am. J. Primatol. 12:387-468) is consistent with quantitative differences in saki morphology. Discriminant analyses on 39 skull traits show that Pithecia species and subspecies are well-differentiated. Morphological distances (D2) among sakis clearly show the morphological unity of the pithecia-chrysocephala (Pithecia) and irrorata-vanzolinii-monacha (Monacha) species groups. The Pithecia species group is distributed north of the Amazon and has a smaller cranium than the Monacha group, distributed south of that river. Despite the size difference, multivariate static allometric patterns among sakis are quite similar. After removing size and allometric changes in shape from the data, species and subspecies are still differentiated, although to a lesser extent. D2 distances obtained from these scale-corrected data are similar in magnitude and pattern to the original D2, but show a closer similarity of P. monacha with the Pithecia group. P. monacha is a scaled-up version of the smaller sakis.

Animals↗

PubMed2004

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Animals↗

PubMed2004

Evidence for nucleolus organizer regions as the units of regulation in nucleolar dominance in Arabidopsis thaliana interecotype hybrids.

Nucleolar dominance describes the silencing of one parent's ribosomal RNA (rRNA) genes in a genetic hybrid. In Arabidopsis thaliana, rRNA genes are clustered in two nucleolus organizer regions, NOR2 and NOR4. In F(8) recombinant inbreds (RI) of the A. thaliana ecotypes Ler and Cvi, lines that display strong nucleolar dominance inherited a specific combination of NORs, Cvi NOR4 and Ler NOR2. These lines express almost all rRNA from Cvi NOR4. The reciprocal NOR genotype, Ler NOR4/Cvi NOR2, allowed for expression of rRNA genes from both NORs. Collectively, these data reveal that neither Cvi rRNA genes nor NOR4 are always dominant. Furthermore, strong nucleolar dominance does not occur in every RI line inheriting Cvi NOR4 and Ler NOR2, indicating stochastic effects or the involvement of other genes segregating in the RI mapping population. A partial explanation is provided by an unlinked locus, identified by QTL analysis, that displays an epistatic interaction with the NORs and affects the relative expression of NOR4 vs. NOR2. Collectively, the data indicate that nucleolar dominance is a complex trait in which NORs, rather than individual rRNA genes, are the likely units of regulation.

Arabidopsis↗