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1.  Relationship of age and body mass index to the expression of obesity and osteoarthritis related genes in human meniscus 
Objective
Aging and obesity contribute to the initiation and progression of osteoarthritis with little information on their relation to gene expression in joint tissues, particularly the meniscus. Here, we test the hypothesis that patient age and body mass index (BMI) correlate with the expression of osteoarthritis- and obesity-related gene signatures in the meniscus.
Design
Meniscus was obtained from patients (N=68) undergoing arthroscopic partial meniscectomy. The mRNA expression of twenty-four osteoarthritis-related and four obesity-related genes in meniscus was assessed by qRT-PCR. The relationship between gene expression and patient age and BMI was analyzed using Spearman’s rank-order correlation. Hierarchical cluster dendrogram and heat maps were generated to study inter-gene associations.
Results
Age was negatively correlated (P<0.05) with the expression of MMP-1 (r=−0.447), NFκB2 (r=−0.361), NFκBIA (r=−0.312), IκBA (r=−0.308), IL-8 (r=−0.305), ADAMTS-4 (r=−0.294), APLN (r=−0.250) and IL-6 (r=−0.244). Likewise, BMI was negatively correlated with the expression of APLN (r=−0.328), ACAN (r=−0.268) and MMP-1 (r=−0.261). After adjusting for the correlation between age and BMI (r=0.310; P=0.008), the only independent effect of BMI on gene expression was for APLN (r=−0.272). However, age had an independent effect on expression on ADAMTS-4 (r=−0.253), MMP-1 (r=−0.399), IL-8 (r=−0.327), COL1A1 (r=−0.287), NFκBIA (r=−0.278), NFκB2 (r=−0.312) and IκBA (r=−0.299). The gene-correlation analysis identified four clusters of potentially relevant genes: transcription factors, matrix degrading enzymes, cytokines and chemokines, and obesity genes.
Conclusion
Age and BMI were negatively correlated with several osteoarthritis- and obesity-related genes. While the bulk of these changes appeared to be driven by age, expression of APLN was related to BMI. Inter-gene correlations implicated a common regulatory role of strongly correlated genes. Although age-related variations in gene expression are potentially more pertinent than obesity-related differences for the role of the meniscus in osteoarthritis development, further investigation into the role of APLN in meniscus and joint health is warranted.
doi:10.1038/ijo.2012.221
PMCID: PMC3751987  PMID: 23318714
Meniscus tear; gene expression; osteoarthritis; age; body mass index; obesity
2.  Genomic imprinting and parent-of-origin effects on complex traits 
Nature reviews. Genetics  2013;14(9):609-617.
Parent-of-origin effects occur when the phenotypic effect of an allele depends on whether it is inherited from an individual’s mother or father. Several phenomena can cause parent-of-origin effects, with the best characterized being parent-of-origin dependent gene expression associated with genomic imprinting. Imprinting plays a critical role in a diversity of biological processes and in certain contexts it structures epigenetic relationships between DNA sequence and phenotypic variation. The development of new mapping approaches applied to the growing abundance of genomic data has demonstrated that imprinted genes can be important contributors to complex trait variation. Therefore, to understand the genetic architecture and evolution of complex traits, including complex diseases and traits of agricultural importance, it is crucial to account for these parent-of-origin effects. Here we discuss patterns of phenotypic variation associated with imprinting, evidence supporting its role in complex trait variation, and approaches for identifying its molecular signatures.
doi:10.1038/nrg3543
PMCID: PMC3926806  PMID: 23917626
3.  Weak Genetic Relationship Between Trabecular Bone Morphology and Obesity in Mice 
Bone  2012;51(1):46-53.
Obesity, in addition to being associated with metabolic diseases, such as diabetes, has also been found to lower the risk of osteoporotic fractures. The relationship between obesity and bone trabecular structure is complex, involving responses to mechanical loading and the effects of adipocyte-derived hormones, both directly interacting with bone tissue and indirectly through central nervous system signaling. Here we examine the effects of sex, a high fat diet, and genetics on the trabecular density and structure of the lumbar and caudal vertebra and the proximal tibia along with body weight, fat pad weight, and serum leptin levels in a murine obesity model, the LGXSM Recombinant Inbred (RI) mouse strains. The sample included 481 mice from 16 RI strains. We found that vertebral trabecular density was higher in males while the females had higher tibial trabecular density. The high fat diet led to only slightly higher trabecular density in both sexes despite its extreme effects on obesity and serum leptin levels. Trait heritabilities are moderate to strong and genetic correlations among trabecular features are high. Most genetic variation contrasts strains with large numbers of thick, closely-spaced, highly interconnected, plate-like trabeculae with a high bone volume to total volume ratio against strains displaying small numbers of thin, widely-spaced, sparsely connected, rod-like trabeculae with a low bone volume to total volume ratio. Genetic correlations between trabecular and obesity-related traits were low and not statistically significant. We mapped trabecular properties to 20 genomic locations. Only one-quarter of these locations also had effects on obesity. In this population obesity has a relatively minor effect on trabecular bone morphology. Key Words: bone; trabecular morphology; obesity; quantitative trait loci; mice
doi:10.1016/j.bone.2012.03.031
PMCID: PMC3371175  PMID: 22503703
4.  Fine-mapping of Obesity-related Quantitative Trait Loci in an F9/10 Advanced Intercross Line 
Obesity (Silver Spring, Md.)  2009;18(7):10.1038/oby.2009.411.
Obesity develops in response to a combination of environmental effects and multiple genes of small effect. Although there has been significant progress in characterizing genes in many pathways contributing to metabolic disease, knowledge about the relationships of these genes to each other and their joint effects upon obesity lags behind. The LG, SM advanced intercross line (AIL) model of obesity has been used to characterize over 70 loci involved in fatpad weight, body weight, and organ weights. Each of these quantitative trait loci (QTLs) encompasses large regions of the genome and require fine-mapping to isolate causative sequence changes and possible mechanisms of action as indicated by the genetic architecture. In this study we fine-map QTLs first identified in the F2 and F2/3 populations in the combined F9/10 advanced intercross generations. We observed significantly narrowed QTL confidence regions, identified many single QTL that resolve into multiple QTL peaks, and identified new QTLs that may have been previously masked due to opposite gene effects at closely linked loci. We also present further characterization of the pleiotropic and epistatic interactions underlying these obesity-related traits.
doi:10.1038/oby.2009.411
PMCID: PMC3848327  PMID: 19910941
5.  Relative contribution of additive, dominance and imprinting effects to phenotypic variation in body size and growth between divergent selection lines of mice 
Evolution; international journal of organic evolution  2008;63(5):10.1111/j.1558-5646.2009.00638.x.
Epigenetic effects attributed to genomic imprinting are increasingly recognized as an important source of variation in quantitative traits. However, little is known about their relative contribution to phenotypic variation compared to those of additive and dominance effects, and almost nothing about their role in phenotypic evolution. Here we address these questions by investigating the relative contribution of additive, dominance and imprinting effects of quantitative trait loci (QTL) to variation in ‘early’ and ‘late’ body weight in an intercross of mice selected for divergent adult body weight. We identified 18 loci on 13 chromosomes; additive effects accounted for most of the phenotypic variation throughout development, and imprinting effects were always small. Genetic effects on early weight showed more dominance, less additive and, surprisingly, less imprinting variation than that of late weight. The predominance of additivity of QTL effects on body weight follows the expectation that additive effects account for the evolutionary divergence between selection lines. We hypothesize that the appearance of more imprinting effects on late body weight may be a consequence of divergent selection on adult body weight, which may have indirectly selected for alleles showing partial imprinting effects due to their associated additive effects, highlighting a potential role of genomic imprinting in the response to selection.
doi:10.1111/j.1558-5646.2009.00638.x
PMCID: PMC3846273  PMID: 19187253
6.  Molecular Insight into the Association Between Cartilage Regeneration and Ear Wound Healing in Genetic Mouse Models: Targeting New Genes in Regeneration 
G3: Genes|Genomes|Genetics  2013;3(11):1881-1891.
Tissue regeneration is a complex trait with few genetic models available. Mouse strains LG/J and MRL are exceptional healers. Using recombinant inbred strains from a large (LG/J, healer) and small (SM/J, nonhealer) intercross, we have previously shown a positive genetic correlation between ear wound healing, knee cartilage regeneration, and protection from osteoarthritis. We hypothesize that a common set of genes operates in tissue healing and articular cartilage regeneration. Taking advantage of archived histological sections from recombinant inbred strains, we analyzed expression of candidate genes through branched-chain DNA technology directly from tissue lysates. We determined broad-sense heritability of candidates, Pearson correlation of candidates with healing phenotypes, and Ward minimum variance cluster analysis for strains. A bioinformatic assessment of allelic polymorphisms within and near candidate genes was also performed. The expression of several candidates was significantly heritable among strains. Although several genes correlated with both ear wound healing and cartilage healing at a marginal level, the expression of four genes representing DNA repair (Xrcc2, Pcna) and Wnt signaling (Axin2, Wnt16) pathways was significantly positively correlated with both phenotypes. Cluster analysis accurately classified healers and nonhealers for seven out of eight strains based on gene expression. Specific sequence differences between LG/J and SM/J were identified as potential causal polymorphisms. Our study suggests a common genetic basis between tissue healing and osteoarthritis susceptibility. Mapping genetic variations causing differences in diverse healing responses in multiple tissues may reveal generic healing processes in pursuit of new therapeutic targets designed to induce or enhance regeneration and, potentially, protection from osteoarthritis.
doi:10.1534/g3.113.007302
PMCID: PMC3815053  PMID: 24002865
tissue regeneration; articular cartilage; QuantiGene Plex assay; recombinant inbred lines; osteoarthritis
7.  Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice 
Genome Biology and Evolution  2013;5(10):1926-1936.
Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis-regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.
doi:10.1093/gbe/evt144
PMCID: PMC3814202  PMID: 24065733
autonomy; pleiotropy; constraint; genetic interaction; character
8.  Heritability of Articular Cartilage Regeneration and its Association with Ear-Wound Healing 
Arthritis and Rheumatism  2012;64(7):2300-2310.
Objective
Emerging evidence suggests that genetic components contribute significantly to cartilage degeneration in osteoarthritis pathophysiology but little evidence is available on genetics of cartilage regeneration. Therefore, we investigated cartilage regeneration in genetic murine models using common inbred strains and a set of recombinant inbred lines generated from LG/J (healer of ear-wounds) and SM/J (non-healer) inbred strains.
Methods
An acute full-thickness cartilage injury was introduced through microsurgery in the trochlear groove of 8-weeks old mice (N=265). Knee joints were sagittally sectioned and stained with toluidine blue to evaluate regeneration. For ear-wound phenotype, a bilateral 2-mm through-and-through puncture was made (N=229) at 6-weeks and healing outcomes measured after 30-days. Broad-sense heritability and genetic correlations were calculated for both phenotypes.
Results
Time-course studies from recombinant inbred lines show no significant regeneration until 16-weeks post-surgery; at that time, the strains can be segregated into three categories: good, intermediate and poor healers. Heritability (H2) showed that both cartilage regeneration (H2=26%; p=0.006) and ear-wound closure (H2=53%; p<0.00001) are significantly heritable. The genetic correlations between the two healing phenotypes for common inbred strains (r=0.92) and recombinant inbred lines (r=0.86) were found to be extremely high.
Conclusion
We report that i) articular cartilage regeneration is heritable, ii) the differences between the lines being due to genetic differences and iii) a strong genetic correlation between the two phenotypes exists indicating that they plausibly share a common genetic basis. We, therefore, surmise that LG/J by SM/J intercross can be used to dissect the genetic basis of variation in cartilage regeneration.
doi:10.1002/art.34396
PMCID: PMC3360138  PMID: 22275233
articular cartilage; ear-wound; regeneration; genetics; heritability
9.  Diet-Dependent Genetic and Genomic Imprinting Effects on Obesity in Mice 
Obesity (Silver Spring, Md.)  2010;19(1):160-170.
Although the current obesity epidemic is of environmental origin, there is substantial genetic variation in individual response to an obesogenic environment. In this study, we perform a genome-wide scan for quantitative trait loci (QTLs) affecting obesity per se, or an obese response to a high-fat diet in mice from the LG/J by SM/J Advanced Intercross (AI) Line (Wustl:LG,SM-G16). A total of 1,002 animals from 78 F16 full sibships were weaned at 3 weeks of age and half of each litter placed on high- and low-fat diets. Animals remained on the diet until 20 weeks of age when they were necropsied and the weights of the reproductive, kidney, mesenteric, and inguinal fat depots were recorded. Effects on these phenotypes, along with total fat depot weight and carcass weight at necropsy, were mapped across the genome using 1,402 autosomal single-nucleotide polymorphism (SNP) markers. Haplotypes were reconstructed and additive, dominance, and imprinting genotype scores were derived every 1 cM along the F16 map. Analysis was performed using a mixed model with additive, dominance, and imprinting genotype scores, their interactions with sex, diet, and with sex-by-diet as fixed effects and with family and its interaction with sex, diet, and sex-by-diet as random effects. We discovered 95 trait-specific QTLs mapping to 40 locations. Most QTLs had additive effects with dominance and imprinting effects occurring at two-thirds of the loci. Nearly every locus interacted with sex and/ or diet in important ways demonstrating that gene effects are primarily context dependent, changing depending on sex and/or diet.
doi:10.1038/oby.2010.141
PMCID: PMC3677968  PMID: 20539295
10.  Cartilage and Bone Changes during Development of Post-Traumatic Osteoarthritis in Selected LGXSM Recombinant Inbred Mice 
Osteoarthritis and Cartilage  2012;20(6):562-571.
Introduction
Little evidence is available on the natural course of osteoarthritis development and the genes that protect and predispose individuals to it. This study was designed to compare strain-dependent development of osteoarthritis and its association with tissue regeneration in mice. Two recombinant inbred lines LGXSM-6 and LGXSM-33 generated from LG/J and SM/J intercross were used. Previous studies have indicated that LGXSM-6 can regenerate both articular cartilage and ear hole punch while LGXSM-33 cannot.
Methods
Transection of the medial meniscotibial ligament was performed on 10-week-old male mice to induce osteoarthritis. Cartilage damage was analyzed by histology and bone morphology was evaluated using micro-CT. Ear punches were performed and evaluated by measurement of residual hole diameter.
Results
Cartilage analysis showed that LGXSM-33 developed a significantly higher grade of osteoarthritis than LGXSM-6. Bone analysis showed that LGXSM-33 had substantial subchondral bone and trabecular bone thickening 8 weeks post-surgery, while LGXSM-6 showed bone loss over time. We also confirmed that LGXSM-6 can heal ear tissues significantly better than LGXSM-33.
Conclusions
Osteoarthritis was found to be negatively correlated with the degree of tissue regeneration. LGXSM-33, a poor healer of ear tissues (and articular cartilage), developed more osteoarthritis compared to LGXSM-6, which had better regenerative ability for ear tissues and articular cartilage. While these lines have different distribution of the alleles, we assume that the phenotypic differences observed here are due to genetic differences further suggesting that similar sets of physiological processes and gene variants may mediate variation in human osteoarthritis development and tissue regeneration.
doi:10.1016/j.joca.2012.01.022
PMCID: PMC3353722  PMID: 22361237
11.  The importance of context to the genetic architecture of diabetes-related traits is revealed in a genome-wide scan of a LG/J x SM/J murine model 
Variations in diabetic phenotypes are caused by complex interactions of genetic effects, environmental factors, and the interplay between the two. We tease apart these complex interactions by examining genome-wide genetic and epigenetic effects on diabetes-related traits among different sex, diet, and sex-by-diet cohorts in a Mus musculus model. We conducted a genome-wide scan for quantitative trait loci affecting serum glucose and insulin levels and response to glucose stress in an F16 Advanced Intercross Line of the LG/J and SM/J intercross (Wustl:LG, SM-G16). Half of each sibship was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (parent-of-origin imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. We find that different cohorts often have unique genetic effects at the same loci, and that genetic signals can be masked or erroneously assigned to specific cohorts if they are not considered individually. Our data demonstrate that the effects of genes on complex trait variation are highly context dependent, and that the same genomic sequence can affect traits differently depending on an individual’s sex and/or dietary environment. Our results have important implications for studies of complex traits in humans.
doi:10.1007/s00335-010-9313-3
PMCID: PMC3650899  PMID: 21210123
quantitative trait loci; imprinting; context-dependency; mouse models; diabetes
12.  Heritability of Alveolar Bone Loss from Periodontal Disease in a Baboon Population. A Pilot Study 
Journal of periodontology  2010;82(4):575-580.
Background
Reports from studies of twins, disease aggregation in families, animal models for periodontal disease, and various genetic-analysis studies have determined that genetics plays a role in the susceptibility to periodontal disease. The purpose of this pilot study was to evaluate the effect of genetics on periodontal disease by evaluating the heritability of alveolar bone loss in a captive baboon population.
Methods
A collection of baboon skulls from a pedigreed colony (for which scientists and veterinarians maintain complete genealogical and veterinary records) were obtained from the Southwest National Primate Research Center and used in this pilot study. Measurements of alveolar bone loss were performed on 390 dry baboon skulls. A periodontal probe was used to measure alveolar bone loss. Maximum likelihood methods (designed to handle complex genealogies) were used to determine the heritability of alveolar bone loss. This software utilized known pedigrees in the captive baboon sample and tested the relationship between pairwise kinship and alveolar bone loss data to determine the heritability of alveolar bone loss from periodontal disease.
Results
Genetic data were available for 347 of the 390 specimens. Using age and sex as covariates, genetic analysis indicated a heritability of 35% (standard error=20%, p=0.01). While sex was not a significant factor in periodontal disease (p=0.96), age was highly significantly associated with periodontal disease (p<0.0001).
Conclusion
In this pilot study, analysis of alveolar bone loss measurements from captive baboons indicates that bone loss increases with age and that a portion of periodontal disease risk may be due to genetic variance. These findings provide evidence that periodontal disease is heritable in captive baboons and indicate that a larger, more-detailed study is warranted.
doi:10.1902/jop.2010.100189
PMCID: PMC3575216  PMID: 21043800
periodontitis; alveolar bone; genetics; baboons
13.  Quantitative Trait Loci Affecting Liver Fat Content in Mice 
G3: Genes|Genomes|Genetics  2012;2(9):1019-1025.
Nonalcoholic fatty liver disease, a condition in which excess fat accumulates in the liver, is strongly associated with the metabolic syndrome, including obesity and other related conditions. This disease has the potential to progress from steatosis to steatohepatitis, fibrosis, and cirrhosis. The recent increase in the prevalence of the metabolic syndrome is largely driven by changes in diet and activity levels. Individual variation in the response to this obesogenic environment, however, is attributable in part to genetic variation between individuals, but very few mammalian genetic loci have been identified with effects on fat accumulation in the liver. To study the genetic basis for variation in liver fat content in response to dietary fat, liver fat proportion was determined using quantitative magnetic resonance imaging in 478 mice from 16 LG/J X SM/J recombinant inbred strains fed either a high-fat (42% kcal from fat) or low-fat (15% kcal from fat) diet. An analysis of variance confirmed that there is a genetic basis for variation in liver fat content within the population with significant effects of sex and diet. Three quantitative trail loci that contribute to liver fat content also were mapped.
doi:10.1534/g3.112.003343
PMCID: PMC3429915  PMID: 22973538
nonalcoholic fatty liver disease; NAFLD; QTL; mouse; LG/J; SM/J
14.  Neuroanatomic and behavioral traits for autistic disorders in age-specific restricted index selection mice 
Neuroscience  2011;189:215-222.
The pathogenesis of neurodevelopmental disorders such as autism is believed to be influenced by interactions between genetic and environmental factors, and appropriate animal models are needed to assess the influence of such factors on relevant neurodevelopmental phenotypes. A set of inbred mouse strains (Atchley strains) including A12 (E+L0) and A22 (E-L0) were generated by age-specific restricted index selection from a baseline random-bred ICR mouse population obtained from Harlan Sprague-Dawley (Atchley et al., 1997; Indianapolis, IN). As compared with the A22 strain, A12 mice had significantly increased early (P0-P10) body weight gain with minimal changes in late (P28 to P56) body weight gain. We found that these strains also differed in brain weight, brain volume, cell proliferation, and FGF-2 levels in certain brain regions. Specifically, brain weight and volume were significantly greater in A12 mice than that in A22 mice at P10 and P28. Quantitative analysis of Bromodeoxyuridine (BrdU) labeling of proliferating cells showed that the number of BrdU-positive cells in the A12 strain was significantly greater in the frontal cortex and lesser in the dentate gyrus than that in the A22 strain at P28. Western blot revealed that fibroblast growth factors-2 (FGF-2), but not brain-derived neurotrophic factor (BDNF), expression was significantly increased in the frontal cortex of A12 strain at P28. Also, A12 mice exhibited decreased intra-strain social interaction and increased repetitive stereotyped behaviors at P28. Our study suggests that A12 mice may partially mimic the anatomic and behavioral traits of patients with neurodevelopmental disorders such as autism spectrum disorders, and therefore may yield insights into the developmental mechanisms involved in their pathogenesis.
doi:10.1016/j.neuroscience.2011.05.017
PMCID: PMC3150457  PMID: 21624435
neurodevelopment; brain weight; brain volume; neurogenesis; social interaction; Autism
15.  Evolution of pleiotropy: Epistatic interaction pattern supports a mechanistic model underlying variation in genotype-phenotype map 
The genotype-phenotype map consists of developmental and physiological mechanisms mapping genetic onto phenotypic variation. It determines the distribution of heritable phenotypic variance on which selection can act. Comparative studies of morphology as well as of gene regulatory networks show that the genotype-phenotype map itself evolves, yet little is known about the actual evolutionary mechanisms involved. The study of such mechanisms requires exploring the variation in genotype-phenotype maps at the population level, which presently is easier to quantify by statistical genetic methods rather than by regulatory network structures. We focus on the evolution of pleiotropy, a major structural aspect of the genotype-phenotype map. Pleiotropic genes affect multiple traits and underlie genetic covariance between traits, often causing evolutionary constraints. Previous quantitative genetic studies have demonstrated population-level variation in pleiotropy in the form of loci, at which genotypes differ in the genetic covariation between traits. This variation can potentially fuel evolution of the genotype-phenotype map under selection and/or drift. Here, we propose a developmental mechanism underlying population genetic variation in covariance, and test its predictions. Specifically, the mechanism predicts that the loci identified as responsible for genetic variation in pleiotropy are involved in trait-specific epistatic interactions. We test this prediction for loci affecting allometric relationships between traits in an advanced intercross between inbred mouse strains. The results consistently support the prediction. We further find a high degree of sign epistasis in these interactions, which we interpret as an indication of adaptive gene complexes within the diverged parental lines.
doi:10.1002/jez.b.21410
PMCID: PMC3112255  PMID: 21462316
16.  Hypothalamic expression of Peg3 gene is associated with maternal care differences between SM/J and LG/J mouse strains 
Brain and Behavior  2012;2(4):365-376.
Maternal care is essential in mammals, and variations in the environment provided by mothers may directly influence the viability of newborns and emotional behavior later in life. A previous study investigated genetic variations associated with maternal care in an intercross of LG/J and SM/J inbred mouse strains and identified two single-locus QTLs (quantitative trait loci). Here, we selected three candidate genes located within these QTLs intervals; Oxt on chromosome 2, and FosB and Peg3 on chromosome 7 and tested their association with maternal care. LG/J females showed impaired postpartum nest building and pup retrieval, a one-day delay in milk ejection, reduced exploratory activity, and higher anxiety-like behavior when compared to SM/J females. The nucleotide sequences of Oxt and FosB were similar between strains, as were their hypothalamic expression levels. Conversely, Peg3 nucleotide sequences showed four nonsynonymous replacement substitutions on LG/J dams, T11062G, G13744A, A13808G, and G13813A, and a 30 base pair (10 aa) in tandem repeat in the coding region with three copies in SM/J and five copies in LG/J. Maternal care impaired LG/J mothers express 37% lower Peg3 mRNA levels in the hypothalamus on the second postpartum day. We also found an association of the Peg3 repeat-variant and poor maternal care in F2 heterozygote females derived from a LG/J × SM/J intercross. These results may suggest that the maternally imprinted Peg3 gene is responsible for the single-locus QTL on chromosome 7 that has been shown to influence maternal care in these strains. Furthermore, these data provide additional support for an epigenetic regulation of maternal behavior.
doi:10.1002/brb3.58
PMCID: PMC3432959  PMID: 22950040
Chromosome; epigenetic; FosB; gene expression; gene variation; hypothalamus; imprinting; maternal behavior; Oxt; QTL
17.  Developmental and Genetic Origins of Murine Long Bone Length Variation 
If we wish to understand whether development influences the rate or direction of morphological evolution, we must first understand the developmental bases of morphological variation within species. However, quantitative variation in adult morphology is the product of molecular and cellular processes unfolding from embryonic development through juvenile growth to maturity. The Atchley-Hall model provides a useful framework for dissecting complex morphologies into their component parts as a way of determining which developmental processes contribute to variation in adult form. We have examined differences in postnatal allometry and the patterns of genetic correlation between age-specific traits for 10 recombinant inbred strains of mice generated from an intercross of LG/J and SM/J. Long bone length is closely tied to body size, but variation in adult morphology is more closely tied to differences in growth rate between 3 and 5 weeks of age. These analyses show that variation generated during early development is overridden by variation generated later in life. To more precisely determine the cellular processes generating this variation we then examined the cellular dynamics of long bone growth plates at the time of maximum elongation rate differences in the parent strains. Our analyses revealed that variation in long bone length is the result of faster elongation rates of the LG/J stain. The developmental bases for these differences in growth rate involve the rate of cell division and chondrocyte hypertrophy in the growth plate.
doi:10.1002/jez.b.21388
PMCID: PMC3160521  PMID: 21328530
Growth plate; Long Bone; Mouse; Evo-Devo; Quantitative Genetics
18.  Genetic and Environmental Contributions to Variation in Baboon Cranial Morphology 
The development, function, and integration of morphological characteristics are all hypothesized to influence the utility of traits for phylogenetic reconstruction by affecting the way in which morphological characteristics evolve. We use a baboon model to test the hypotheses about phenotypic and quantitative genetic variation of traits in the cranium that bear on a phenotype’s propensity to evolve. We test the hypotheses that: 1) individual traits in different functionally and developmentally defined regions of the cranium are differentially environmentally, genetically, and phenotypically variable; 2) genetic covariance with other traits constrains traits in one region of the cranium more than those in others; 3) and regions of the cranium subject to different levels of mechanical strain differ in the magnitude of variation in individual traits. We find that the levels of environmental and genetic variation in individual traits are randomly distributed across regions of the cranium rather than being structured by developmental origin or degree of exposure to strain. Individual traits in the cranial vault tend to be more constrained by covariance with other traits than those in other regions. Traits in regions subject to high degrees of strain during mastication are not any more variable at any level than other traits. If these results are generalizable to other populations, they indicate that there is no reason to suppose that individual traits from any one part of the cranium are intrinsically less useful for reconstructing patterns of evolution than those from any other part.
doi:10.1002/ajpa.21341
PMCID: PMC3258659  PMID: 20623673
evolvability; heritability; constraint; homoiology; phylogenetic analysis
19.  Comparison of Mandibular Phenotypic and Genetic Integration between Baboon and Mouse 
Evolutionary biology  2009;36(1):19-36.
In this study we compare patterns of mandibular integration between mice and baboons using both phenotypic and quantitative genetic data. Specifically, we test how well each species fits with the mosaic model of mandibular integration suggested by Atchley and Hall (Biol Rev Camb Philos Soc 66:101–157, 1991) based on developmental modules. We hypothesize that patterns of integration will be similar for mice and baboons and that both species will show strong integration within developmental modules and weaker integration between modules. Corresponding landmark data were collected from the hemi-mandibles of an advanced intercross mouse sample (N = 1239) and mandibles from a baboon sample of known pedigree from the Southwest Foundation for Biomedical Research (N = 430). We used four methods of analysis to quantify and compare the degree of mandibular integration between species including two methods based on a priori assumptions, and two a posteriori analyses. We found that patterns of integration are broadly similar for baboon and mouse mandibles, with both species displaying a modular pattern of integration. While there is a general trend of similarity in integration patterns between species, there were some marked differences. Mice are strongly correlated among distances within the coronoid process and the incisive alveolar region, whereas baboons are strongly integrated within the condylar process. We discuss the potential evolutionary implications of the similar patterns of integration between these species with an emphasis on the role of modularity.
doi:10.1007/s11692-009-9056-9
PMCID: PMC3249057  PMID: 22212926
Integration; Mandible; Mammalian; Modularity
20.  Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations 
PLoS Genetics  2011;7(9):e1002256.
Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F16 advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.
Author Summary
We look at gene-by-diet and gene-by-sex interactions underlying natural variation in multiple metabolic traits mapping to the same regions of the genome in a mouse model. We find that the underlying genetic architecture of these traits is different in different sex and diet contexts. We further use expression data and whole-genome polymorphism data to identify compelling candidates for experimental follow-up. We use these results to examine theoretical evolutionary predictions about how variation in populations can be maintained. There has been much discussion of late on how to use evolutionary theory to inform medical genomics. Mouse models may be especially appropriate for bridging the divide between evolutionary and biomedical research, because they allow the study of the effects of natural alleles on normal variation and because human-mouse homology is well defined. Our study is unique in examining quantitative trait loci from both evolutionary and biomedical perspectives, and we highlight the complex connections of the traits comprising the metabolic syndrome and the evolutionary implications of their underlying genetic architecture. This is important for understanding disease etiology and is relevant to personalized medicine.
doi:10.1371/journal.pgen.1002256
PMCID: PMC3169520  PMID: 21931559
21.  Metabolic syndrome components in murine models 
1. Abstract
Animal models have enriched understanding of the physiological basis of metabolic disorders and advanced identification of genetic risk factors underlying the metabolic syndrome (MetS). Murine models are especially appropriate for this type of research, and are an excellent resource not only for identifying candidate genomic regions, but also for illuminating the possible molecular mechanisms or pathways affected in individual components of MetS. In this review, we briefly discuss findings from mouse models of metabolic disorders, particularly in light of issues raised by the recent flood of human genome-wide association studies (GWAS) results. We describe how mouse models are revealing that genotype interacts with environment in important ways, indicating that the underlying genetics of MetS is highly context dependant. Further we show that epistasis, imprinting and maternal effects each contribute to the genetic architecture underlying variation in metabolic traits, and mouse models provide an opportunity to dissect these aspects of the genetic architecture that are difficult if not impossible to ascertain in humans. Finally we discuss how knowledge gained from mouse models can be used in conjunction with comparative genomic methods and bioinformatic resources to inform human MetS research.
PMCID: PMC2854879  PMID: 20088816
Metabolic Syndrome; hypertension; obesity; type-2 diabetes; cardiovascular disease; murine models; bioinformatics; comparative genomics; genome-wide association studies
22.  Evolution of adaptive phenotypic variation patterns by direct selection for evolvability 
A basic assumption of the Darwinian theory of evolution is that heritable variation arises randomly. In this context, randomness means that mutations arise irrespective of the current adaptive needs imposed by the environment. It is broadly accepted, however, that phenotypic variation is not uniformly distributed among phenotypic traits, some traits tend to covary, while others vary independently, and again others barely vary at all. Furthermore, it is well established that patterns of trait variation differ among species. Specifically, traits that serve different functions tend to be less correlated, as for instance forelimbs and hind limbs in bats and humans, compared with the limbs of quadrupedal mammals. Recently, a novel class of genetic elements has been identified in mouse gene-mapping studies that modify correlations among quantitative traits. These loci are called relationship loci, or relationship Quantitative Trait Loci (rQTL), and affect trait correlations by changing the expression of the existing genetic variation through gene interaction. Here, we present a population genetic model of how natural selection acts on rQTL. Contrary to the usual neo-Darwinian theory, in this model, new heritable phenotypic variation is produced along the selected dimension in response to directional selection. The results predict that selection on rQTL leads to higher correlations among traits that are simultaneously under directional selection. On the other hand, traits that are not simultaneously under directional selection are predicted to evolve lower correlations. These results and the previously demonstrated existence of rQTL variation, show a mechanism by which natural selection can directly enhance the evolvability of complex organisms along lines of adaptive change.
doi:10.1098/rspb.2010.2113
PMCID: PMC3097830  PMID: 21106581
modularity; allometry; canalization; differential epistasis
23.  A framework for detecting and characterizing genetic background-dependent imprinting effects 
Genomic imprinting, where the effects of alleles depend on their parent-of-origin, can be an important component of the genetic architecture of complex traits. Although there has been a rapidly increasing number of studies of genetic architecture that have examined imprinting effects, none have examined whether imprinting effects depend on genetic background. Such effects are critical for the evolution of genomic imprinting because they allow the imprinting state of a locus to evolve as a function of genetic background. Here we develop a two-locus model of epistasis that includes epistatic interactions involving imprinting effects and apply this model to scan the mouse genome for loci that modulate the imprinting effects of quantitative trait loci (QTL). The inclusion of imprinting leads to nine orthogonal forms of epistasis, five of which do not appear in the usual two-locus decomposition of epistasis. Each form represents a change in the imprinting status of one locus across different classes of genotypes at the other locus. Our genome scan identified two different locus pairs that show complex patterns of epistasis, where the imprinting effect at one locus changes across genetic backgrounds at the other locus. Thus, our model provides a framework for the detection of genetic background-dependent imprinting effects that should provide insights into the background dependence and evolution of genomic imprinting. Our application of the model to a genome scan supports this assertion by identifying pairs of loci that show reciprocal changes in their imprinting status as the background provided by the other locus changes.
doi:10.1007/s00335-009-9209-2
PMCID: PMC2975584  PMID: 19657694
24.  Change in maternal environment induced by cross-fostering alters genetic and epigenetic effects on complex traits in mice 
The interaction between maternally provided environment and offspring genotype is a major determinant of offspring development and fitness in many organisms. Recent research has demonstrated that not only genetic effects, but also epigenetic effects may be subject to modifications by the maternal environment. Genomic imprinting resulting in parent-of-origin-dependent gene expression is among the best studied of epigenetic effects. However, very little is known about the degree to which genomic imprinting effects can be modulated by the maternally provided environment, which has important implications for phenotypic plasticity. In this study, we investigated this unresolved question using a cross-fostering design in which mouse pups were nursed by either their own or an unrelated mother. We scanned the entire genome to search for quantitative trait loci whose effects depend on cross-fostering and detected 10 of such loci. Of the 10 loci, 4 showed imprinting by cross-foster interactions. In most cases, the interaction effect was due to the presence of an effect in either cross-fostered or non-cross-fostered animals. Our results demonstrate that genomic imprinting effects may often be modified by the maternal environment and that such interactions can impact key fitness-related traits suggesting a greater plasticity of genomic imprinting than previously assumed.
doi:10.1098/rspb.2009.0515
PMCID: PMC2817211  PMID: 19474037
cross-fostering; genomic imprinting; maternal environment; QTL; phenotypic plasticity; mice
25.  GENETIC VARIATION IN BABOON CRANIOFACIAL SEXUAL DIMORPHISM 
Sexual dimorphism is a widespread phenomenon and contributes greatly to intraspecies variation. Despite a long history of active research, the genetic basis of dimorphism for complex traits remains unknown. Understanding the sex-specific differences in genetic architecture for cranial traits in a highly dimorphic species could identify possible mechanisms through which selection acts to produce dimorphism. Using distances calculated from three-dimensional landmark data from CT scans of 402 baboon skulls from a known genealogy, we estimated genetic variance parameters in both sexes to determine the presence of gene-by-sex (G × S) interactions and X-linked heritability. We hypothesize that traits exhibiting the greatest degree of sexual dimorphism (facial traits in baboons) will demonstrate either stronger G × S interactions or X-linked effects. We found G × S interactions and X-linked effects for a few measures that span the areas connecting the face to the neurocranium but for no traits restricted to the face. This finding suggests that facial traits will have a limited response to selection for further evolution of dimorphism in this population. We discuss the implications of our results with respect to the origins of cranial sexual dimorphism in this baboon sample, and how the genetic architecture of these traits affects their potential for future evolution.
doi:10.1111/j.1558-5646.2008.00593.x
PMCID: PMC2836714  PMID: 19210535
Evolution; genetic correlation; genetic variance; heritability; morphometrics; X-linkage

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