Opposite effects on facial morphology due to gene dosage sensitivity.
ABSTRACT: Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.
Project description:A contribution of structural genomic variation to the heritability of complex metabolic phenotypes was illuminated by the recent characterization of chromosome-engineered mouse models for genomic disorders associated with metabolic dysfunction. Herein we discuss our study, "A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men," which describes the opposing metabolic phenotypes of mouse models for two prototypical genomic disorders,(1) (,) (2) Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS). SMS and PTLS are caused by reciprocal deletion or duplication copy number variations (CNVs), respectively, on chromosome 17p11.2. The implications of the results of this study and the potential relevance of these findings for future studies in the field of metabolism are discussed.
Project description:PURPOSE:To detect and quantify choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD) using optical coherence tomography (OCT) angiography. DESIGN:Observational, cross-sectional study. PARTICIPANTS:A total of 5 normal subjects and 5 subjects with neovascular AMD were included. METHODS:A total of 5 eyes with neovascular AMD and 5 normal age-matched controls were scanned by a high-speed (100 000 A-scans/seconds) 1050-nm wavelength swept-source OCT. The macular angiography scan covered a 3 × 3-mm area and comprised 200 × 200 × 8 A-scans acquired in 3.5 seconds. Flow was detected using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. Motion artifacts were removed by 3-dimensional (3D) orthogonal registration and merging of 4 scans. The 3D angiography was segmented into 3 layers: inner retina (to show retinal vasculature), outer retina (to identify CNV), and choroid. En face maximum projection was used to obtain 2-dimensional angiograms from the 3 layers. The CNV area and flow index were computed from the en face OCT angiogram of the outer retinal layer. Flow (decorrelation) and structural data were combined in composite color angiograms for both en face and cross-sectional views. MAIN OUTCOME MEASURES:The CNV angiogram, CNV area, and CNV flow index. RESULTS:En face OCT angiograms of CNV showed sizes and locations that were confirmed by fluorescein angiography (FA). Optical coherence tomography angiography provided more distinct vascular network patterns that were less obscured by subretinal hemorrhage. The en face angiograms also showed areas of reduced choroidal flow adjacent to the CNV in all cases and significantly reduced retinal flow in 1 case. Cross-sectional angiograms were used to visualize CNV location relative to the retinal pigment epithelium and Bruch's layer and classify type I and type II CNV. A feeder vessel could be identified in 1 case. Higher flow indexes were associated with larger CNV and type II CNV. CONCLUSIONS:Optical coherence tomography angiography provides depth-resolved information and detailed images of CNV in neovascular AMD. Quantitative information regarding CNV flow and area can be obtained. Further studies are needed to assess the role of quantitative OCT angiography in the evaluation and treatment of neovascular AMD.
Project description:Echo planar imaging (EPI) is the method of choice for the majority of functional magnetic resonance imaging (fMRI), yet EPI is prone to geometric distortions and thus misaligns with conventional anatomical reference data. The poor geometric correspondence between functional and anatomical data can lead to severe misplacements and corruption of detected activation patterns. However, recent advances in imaging technology have provided EPI data with increasing quality and resolution. Here we present a framework for deriving cortical surface reconstructions directly from high-resolution EPI-based reference images that provide anatomical models exactly geometric distortion-matched to the functional data. Anatomical EPI data with 1mm isotropic voxel size were acquired using a fast multiple inversion recovery time EPI sequence (MI-EPI) at 7T, from which quantitative T1 maps were calculated. Using these T1 maps, volumetric data mimicking the tissue contrast of standard anatomical data were synthesized using the Bloch equations, and these T1-weighted data were automatically processed using FreeSurfer. The spatial alignment between T2(?)-weighted EPI data and the synthetic T1-weighted anatomical MI-EPI-based images was improved compared to the conventional anatomical reference. In particular, the alignment near the regions vulnerable to distortion due to magnetic susceptibility differences was improved, and sampling of the adjacent tissue classes outside of the cortex was reduced when using cortical surface reconstructions derived directly from the MI-EPI reference. The MI-EPI method therefore produces high-quality anatomical data that can be automatically segmented with standard software, providing cortical surface reconstructions that are geometrically matched to the BOLD fMRI data.
Project description:Employing message endorser is a popular strategy in encouraging consumers to protect the environment. This research explores how the social status of endorsers and the forms of normative messages can influence the effectiveness of endorsement for pro-environmental behaviors. Drawing on the focus theory of normative conduct and the match-up hypothesis, the authors propose that the effects of endorser social status on consumers' responses to green advertising are contingent on whether the normative messages is framed as injunctive norms or descriptive norms. In three experiments, the results indicate that participants show more positive attitudes toward the advertisement and higher intentions to act environmentally friendly when endorsers with high social status are presented in combination with injunctive norm appeals. In contrast, ordinary consumer endorsers produce stronger impact on attitudes and behavioral intentions when descriptive norm appeals are used. These findings show that marketers using endorsers to promote pro-environmental behaviors should develop normative message accordingly.
Project description:A quantitative long-term fluid consumption and fluid-licking assay was performed in two mouse models with either an ?2?Mb genomic deletion, Df(11)17, or the reciprocal duplication copy number variation (CNV), Dp(11)17, analogous to the human genomic rearrangements causing either Smith-Magenis syndrome [SMS; OMIM #182290] or Potocki-Lupski syndrome [PTLS; OMIM #610883], respectively. Both mouse strains display distinct quantitative alterations in fluid consumption compared to their wild-type littermates; several of these changes are diametrically opposing between the two chromosome engineered mouse models. Mice with duplication versus deletion showed longer versus shorter intervals between visits to the waterspout, generated more versus less licks per visit and had higher versus lower variability in the number of licks per lick-burst as compared to their respective wild-type littermates. These findings suggest that copy number variation can affect long-term fluid consumption behavior in mice. Other behavioral differences were unique for either the duplication or deletion mutants; the deletion CNV resulted in increased variability of the licking rhythm, and the duplication CNV resulted in a significant slowing of the licking rhythm. Our findings document a readily quantitated complex behavioral response that can be directly and reciprocally influenced by a gene dosage effect.
Project description:Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects (CHDs) are scarce, as cardiac tissue is difficult to obtain, especially in non-affected individuals. We explored the occurrence of copy number differences in monozygotic (MZ) twins discordant for the presence of a CHD, as an illustrative model for chromosomal mosaicism in CHDs. Array comparative genomic hybridization was performed on peripheral blood-derived DNA obtained from 6 discordant MZ twin pairs and on sex-matched reference samples. To identify CNV differences between both twin members as well as potential CNVs in both twins contributing to the phenotype, DNA from each twin was hybridized against its co-twin, and against a normal control. Three copy number differences in 1 out of 6 MZ twin pairs were detected, confirming the occurrence of somatic CNV events in MZ twins. Further investigation by copy number and (epi)genome sequencing analyses in MZ twins, discordant for the presence of CHDs, is required to improve our knowledge on how postzygotic genetic, environmental and stochastic factors can affect human heart development.
Project description:The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, Dp(11)17/+ mice display much less weight gain and metabolic change than WT mice, demonstrating that the Dp(11)17 CNV protects against metabolic syndrome. Reciprocally, Df(11)17/+ mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of Dp(11)17 and Df(11)17 CNVs are not only due to dosage alterations of Rai1, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP-associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits.
Project description:One fundamental function of social norms is to promote social coordination. Moreover, greater social coordination may be called for when tight norms govern social relations with others. Hence, the sensitivity to social norm violations may be jointly modulated by relational goals and a belief that the social context is tight (vs loose). We tested this analysis using an electrocortical marker of norm-violation detection (N400). Ninety-one young American adults were subliminally primed with either relational or neutral goals. Then they saw behaviors that were either norm-violating or normal. In the relational priming condition, the norm-violation N400 increased as a function of the perceived tightness of societal norms. In the control priming condition, however, the norm-violation N400 was weak regardless of perceived tightness. Thus, normative tightness was associated with increased neural processing of norm violations only when relational goals were activated. Implications for norm psychology are discussed.
Project description:According to the norm-based version of the multidimensional face space model (nMDFS, Valentine, 1991), any given face and its corresponding anti-face (which deviates from the norm in exactly opposite direction as the original face) should be equidistant to a hypothetical prototype face (norm), such that by definition face and anti-face should bear the same level of perceived typicality. However, it has been argued that familiarity affects perceived typicality and that representations of familiar faces are qualitatively different (e.g., more robust and image-independent) from those for unfamiliar faces. Here we investigated the role of face familiarity for rated typicality, using two frequently used operationalisations of typicality (deviation-based: DEV), and distinctiveness (face in the crowd: FITC) for faces of celebrities and their corresponding anti-faces. We further assessed attractiveness, likeability and trustworthiness ratings of the stimuli, which are potentially related to typicality. For unfamiliar faces and their corresponding anti-faces, in line with the predictions of the nMDFS, our results demonstrate comparable levels of perceived typicality (DEV). In contrast, familiar faces were perceived much less typical than their anti-faces. Furthermore, familiar faces were rated higher than their anti-faces in distinctiveness, attractiveness, likability and trustworthiness. These findings suggest that familiarity strongly affects the distribution of facial representations in norm-based face space. Overall, our study suggests (1) that familiarity needs to be considered in studies of mental representations of faces, and (2) that familiarity, general distance-to-norm and more specific vector directions in face space make different and interactive contributions to different types of facial evaluations.
Project description:The sensitivity to fairness undergoes relevant changes across development. Whether such changes depend on primary inequity aversion or on sensitivity to a social norm of fairness is still debated. Using a modified version of the Ultimatum Game that creates informational asymmetries between Proposer and Responder, a previous study showed that both perceptions of fairness and fair behavior depend upon normative expectations, i.e., beliefs about what others expect one should do in a specific situation. Individuals tend to comply with the norm when risking sanctions, but disregard the norm when violations are undetectable. Using the same methodology with children aged 8-10 years, the present study shows that children's beliefs and behaviors differ from what is observed in adults. Playing as Proposers, children show a self-serving bias only when there is a clear informational asymmetry. Playing as Responders, they show a remarkable discrepancy between their normative judgment about fair procedures (a coin toss to determine the offer) and their behavior (rejection of an unfair offer derived from the coin toss), supporting the existence of an outcome bias effect. Finally, our results reveal no influence of theory of mind on children's decision-making behavior.