scholarly journals Knocking-out the human face genes TBX15 and PAX1 in mice alters facial and other physical morphology

2021 ◽  
Author(s):  
Yu Qian ◽  
ziyi Xiong ◽  
Yi Li ◽  
haibo Zhou ◽  
Manfred Kayser ◽  
...  
Keyword(s):  
Association Studies ◽  
Three Dimensional ◽  
Mutant Mice ◽  
Genome Wide Association Studies ◽  
Facial Morphology ◽  
Morphological Alterations ◽  
Functional Roles ◽  
Adult Mice ◽  
Phenotype Analysis ◽  
The Face

DNA variants in or closed to the human TBX15 and PAX1 genes have been repeatedly associated with facial morphology in independent genome-wide association studies, while their functional roles in determining facial morphology remains to be understood. We generated Tbx15 knockout ( Tbx15 -/- ) and Pax1 knockout ( Pax1 -/- ) mice by applying the one-step CRISPR/Cas9 method. A total of 75 adult mice were used for subsequent phenotype analysis, including 38 Tbx15 mice (10 homozygous Tbx15 -/- , 18 heterozygous Tbx15 +/- , 10 wild-type WT) and 37 Pax1 mice (12 homozygous Pax1 -/- , 15 heterozygous Pax1 +/- , 10 WT mice). Facial and other physical morphological phenotypes were obtained from three-dimensional (3D) images acquired with the HandySCAN BLACK scanner. Compared to WT mice, the Tbx15 -/- mutant mice had significantly shorter faces ( P =1.08E-8, R2=0.61) and their ears were in a significantly lower position ( P =3.54E-8, R2=0.62) manifesting an “ear dropping” characteristic. Besides these face alternations, Tbx15 -/- mutant mice displayed significantly lower weight as well as shorter body and limb length. Pax1 -/- mutant mice showed significantly longer noses ( P =1.14E-5, R2=0.46) relative to WT mice, but otherwise displayed less obvious morphological alterations than Tbx15 -/- mutant mice did. Because the Tbx15 and Pax1 effects on facial morphology we revealed here in mice are largely consistent with previously reported TBX15 and PAX1 face associations in humans, we suggest that the functional role these two genes play on determining the face of mice is similar to the functional impact their human homologues have on the face of humans.

Adolescent Idiopathic Scoliosis – Future Molecular-Based Diagnostic and Prognostic Testing

2019 ◽  
Vol 21 (4) ◽  
pp. 253-260
Author(s):  
Radoslav Zamborský ◽  
Boris Liščák ◽  
Martin Trepáč ◽  
Andrey Švec ◽  
Ľuboš Danisovič
Keyword(s):  
Adolescent Idiopathic Scoliosis ◽  
Idiopathic Scoliosis ◽  
Association Studies ◽  
Three Dimensional ◽  
Reliability And Validity ◽  
Genome Project ◽  
Genome Wide Association Studies ◽  
Appropriate Treatment ◽  
Surgical Treatments ◽  
The Human Genome Project

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine mainly affecting the younger population. Earlier detection of the disorder leads to appropriate treatment and better outcomes, thus avoiding highly invasive surgical treatments. The currently available tests for the disease identification have lost their reliability and validity with time. In the past few decades, efforts have been directed towards developing a highly reliable prognostic test for AIS. Towards this end, several strategies have been employed including biochemical, biomechanical and gene-based tests. Among the three, the gene-based technology has received much attention in recent past. Notably, this is due to the fact that the human genome project, followed by genome-wide association studies (GWAS), facilitated the identification of candidate genes for disorders like AIS. Several promising biomarker genes have been identified. However, their global validations were disappointing as these genes were shown to be limited to a particular group of people/ethnicities. Such observations limit the development of a reliable global molecular/biochemical test for AIS. The currently used AIS ScoliScoreTM also has several limitations. With continued disappointments in the identification of biomarkers for AIS and lack of appropriate tests, researchers have diverted their efforts towards several alternative avenues. A ray of hope is emerging from recent observations on the association of non-coding microRNAs and epigenetic factors that might arise as future reliable markers for AIS, thus paving the way for appropriate clinical management of this disorder.

scholarly journals Identification of five novel genetic loci related to facial morphology by genome-wide association studies

BMC Genomics ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Seongwon Cha ◽  
Ji Eun Lim ◽  
Ah Yeon Park ◽  
Jun-Hyeong Do ◽  
Si Woo Lee ◽  
...  
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Facial Morphology ◽  
Genetic Loci ◽  
Genome Wide

scholarly journals BigTop: A Three-Dimensional Virtual Reality tool for GWAS Visualization

2019 ◽  
Author(s):  
Samuel T. Westreich ◽  
Maria Nattestad ◽  
Christopher Meyer
Keyword(s):  
Virtual Reality ◽  
Association Studies ◽  
Three Dimensional ◽  
Three Dimensions ◽  
Gene Location ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Two Dimensional ◽  
Three Dimensional Representation ◽  
Manhattan Plot

AbstractBackgroundGenome-wide association studies (GWAS) are typically visualized using a two-dimensional Manhattan plot, displaying chromosomal location of SNPs along the x-axis and the negative log-10 of their p-value on the y-axis. This traditional plot provides a broad overview of the results, but offers little opportunity for interaction or expansion of specific regions, and is unable to show additional dimensions of the dataset.ResultsWe created BigTop, a visualization framework in virtual reality (VR), designed to render a Manhattan plot in three dimensions, wrapping the graph around the user in a simulated cylindrical room. BigTop uses the z-axis to display minor allele frequency of each SNP, allowing for the identification of allelic variants of genes. BigTop also offers additional interactivity, allowing users to select any individual SNP and receive expanded information, including SNP name, exact values, and gene location, if applicable. BigTop is built in JavaScript using the React and A-Frame frameworks, and can be rendered using commercially available VR headsets or in a two-dimensional web browser such as Google Chrome. Data is read into BigTop in JSON format, and can be provided as either JSON or a tab-separated text file.ConclusionsUsing additional dimensions and interactivity options offered through VR, we provide a new, interactive, three-dimensional representation of the traditional Manhattan plot for displaying and exploring GWAS data.

scholarly journals Using three-dimensional regulatory chromatin interactions from adult and fetal cortex to interpret genetic results for psychiatric disorders and cognitive traits

2018 ◽  
Author(s):  
Paola MD Giusti-Rodriguez ◽  
Patrick F Sullivan
Keyword(s):  
Psychiatric Disorders ◽  
Association Studies ◽  
Three Dimensional ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
3D Genome ◽  
Cognitive Traits

Genome-wide association studies have identified hundreds of genetic associations for complex psychiatric disorders and cognitive traits. However, interpretation of most of these findings is complicated by the presence of many significant and highly correlated genetic variants located in non-coding regions. Here, we address this issue by creating a high-resolution map of the three-dimensional (3D) genome organization by applying Hi-C to adult and fetal brain cortex with concomitant RNA-seq, open chromatin (ATAC-seq), and ChIP-seq data (H3K27ac, H3K4me3, and CTCF). Extensive analyses established the quality, information content, and salience of these new Hi-C data. We used these data to connect 938 significant genetic loci for schizophrenia, intelligence, ADHD, alcohol dependence, Alzheimer's disease, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depression, and educational attainment to 8,595 genes (with 42.1% of these genes implicated more than once). We show that assigning genes to traits based on proximity provides a limited view of the complexity of GWAS findings and that gene set analyses based on functional genomic data provide an expanded view of the biological processes involved in the etiology of schizophrenia and other complex brain traits.

scholarly journals Analysis of Major Depression Risk Genes Reveals Evolutionary Conservation, Shared Phenotypes, and Extensive Genetic Interactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Saveen Sall ◽  
Willie Thompson ◽  
Aurianna Santos ◽  
Donard S. Dwyer
Keyword(s):  
Association Studies ◽  
Network Connectivity ◽  
Evolutionary Conservation ◽  
Model Organisms ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
C Elegans ◽  
Gene Sets ◽  
Increased Risk ◽  
Phenotype Analysis

Major depressive disorder (MDD) affects around 15% of the population at some stage in their lifetime. It can be gravely disabling and it is associated with increased risk of suicide. Genetics play an important role; however, there are additional environmental contributions to the pathogenesis. A number of possible risk genes that increase liability for developing symptoms of MDD have been identified in genome-wide association studies (GWAS). The goal of this study was to characterize the MDD risk genes with respect to the degree of evolutionary conservation in simpler model organisms such as Caenorhabditis elegans and zebrafish, the phenotypes associated with variation in these genes and the extent of network connectivity. The MDD risk genes showed higher conservation in C. elegans and zebrafish than genome-to-genome comparisons. In addition, there were recurring themes among the phenotypes associated with variation of these risk genes in C. elegans. The phenotype analysis revealed enrichment for essential genes with pleiotropic effects. Moreover, the MDD risk genes participated in more interactions with each other than did randomly-selected genes from similar-sized gene sets. Syntenic blocks of risk genes with common functional activities were also identified. By characterizing evolutionarily-conserved counterparts to the MDD risk genes, we have gained new insights into pathogenetic processes relevant to the emergence of depressive symptoms in man.

An algorithm for estimation of chromosome motion in Four-Dimensional microscopic images

1994 ◽  
Vol 52 ◽  
pp. 930-931
Author(s):  
Wallace Marshall ◽  
David Agard ◽  
John Sedat
Keyword(s):  
Nuclear Organization ◽  
Three Dimensional ◽  
Estimation Algorithm ◽  
Structural Features ◽  
Random Motion ◽  
Structural Representation ◽  
Functional Roles ◽  
The Face ◽  
Chromosome Motion

Analysis of the three-dimensional organization of chromosomes within the nucleus has revealed a number of characteristic structural features. Yet imaging of living nuclei indicate that chromosomes undergo considerable random motion. Maintenance of nuclear organization in the face of such motion is thought to involve the attachment of chromosomes to the nuclear envelope or matrix. Yet while such attachments have been proposed to play a variety of functional roles as well as maintain nuclear organization, direct evidence for the existence of these mechanical interactions in vivo has been lacking. One way to demonstrate such attachment directly would be to estimate the motion of chromosomes and attempt thereby to demonstrate the presence of fixed points, which would indicate attachment of chromatin to some fixed superstructure.We have previously presented a motion estimation algorithm that is designed for tracking the motion of nonrigid and featureless objects such as chromosomes. This algorithm starts with a structural representation for the set of chromosomes at each time point, and then finds a correspondence between elements of the representations at successive time points.

scholarly journals Implicating candidate genes at GWAS signals by leveraging topologically associating domains

2016 ◽  
Author(s):  
Gregory P. Way ◽  
Daniel W. Youngstrom ◽  
Kurt D. Hankenson ◽  
Casey S. Greene ◽  
Struan F. A. Grant
Keyword(s):  
Candidate Genes ◽  
Complex Disease ◽  
System Development ◽  
Association Studies ◽  
Three Dimensional ◽  
Computational Method ◽  
Causal Mechanism ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Topologically Associating Domains

AbstractGenome wide association studies (GWAS) have contributed significantly to the understanding of complex disease genetics. However, GWAS only report associated signals and do not necessarily identify culprit genes. As most signals occur in non-coding regions of the genome, it is often challenging to assign genomic variants to the underlying causal mechanism(s). Topologically associating domains (TADs) are primarily cell-type independent genomic regions that define interactome boundaries and can aid in the designation of limits within which an association most likely impacts gene function. We describe and validate a computational method that uses the genic content of TADs to discover candidate genes. Our method, called “TAD_Pathways,” performs a Gene Ontology (GO) analysis over genes that reside within TAD boundaries corresponding to GWAS signals for a given trait or disease. We applied our pipeline to the GWAS catalog entries associated with bone mineral density (BMD), identifying ‘Skeletal System Development’ (Benjamini-Hochberg adjusted p=1.02x10−5) as the top ranked pathway. In many cases, our method implicated a gene other than the nearest gene. Our molecular experiments describe a novel example: ACP2, implicated at the canonical ‘ARHGAP1’ locus. We found ACP2 to be an important regulator of osteoblast metabolism, whereas ARHGAP1 was not supported. Our results via the example of BMD demonstrate how basic principles of three-dimensional genome organization can define biologically informed association windows.

scholarly journals Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

2019 ◽  
Vol 25 (1) ◽  
pp. 6-18 ◽  
Author(s):  
Anja Barešić ◽  
Alexander Jolyon Nash ◽  
Tarik Dahoun ◽  
Oliver Howes ◽  
Boris Lenhard
Keyword(s):  
Long Range ◽  
Developmental Disorders ◽  
Target Genes ◽  
Association Studies ◽  
Three Dimensional ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Genome Wide Association Studies ◽  
Genomic Context ◽  
Coding Regions

Abstract Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders—autism spectrum disorder and bipolar disorder—to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer–promoter associations can be browsed for each schizophrenia-associated SNP.

scholarly journals Wnt Signaling Drives Correlated Changes in Facial Morphology and Brain Shape

2021 ◽  
Vol 9 ◽  
Author(s):  
Marta Marchini ◽  
Diane Hu ◽  
Lucas Lo Vercio ◽  
Nathan M. Young ◽  
Nils D. Forkert ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Three Dimensional ◽  
Facial Morphology ◽  
Ontogenetic Changes ◽  
Expression Domain ◽  
Head Development ◽  
Facial Shape ◽  
Close Relationship ◽  
The Face ◽  
Canonical Wnt

Canonical Wnt signaling plays multiple roles critical to normal craniofacial development while its dysregulation is known to be involved in structural birth defects of the face. However, when and how Wnt signaling influences phenotypic variation, including those associated with disease, remains unclear. One potential mechanism is via Wnt signaling’s role in the patterning of an early facial signaling center, the frontonasal ectodermal zone (FEZ), and its subsequent regulation of early facial morphogenesis. For example, Wnt signaling may directly alter the shape and/or magnitude of expression of the sonic hedgehog (SHH) domain in the FEZ. To test this idea, we used a replication-competent avian sarcoma retrovirus (RCAS) encoding Wnt3a to modulate its expression in the facial mesenchyme. We then quantified and compared ontogenetic changes in treated to untreated embryos in the three-dimensional (3D) shape of both the SHH expression domain of the FEZ, and the morphology of the facial primordia and brain using iodine-contrast microcomputed tomography imaging and 3D geometric morphometrics (3DGM). We found that increased Wnt3a expression in early stages of head development produces correlated variation in shape between both structural and signaling levels of analysis. In addition, altered Wnt3a activation disrupted the integration between the forebrain and other neural tube derivatives. These results show that activation of Wnt signaling influences facial shape through its impact on the forebrain and SHH expression in the FEZ, and highlights the close relationship between morphogenesis of the forebrain and midface.

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