Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape

Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait-craniofacial shape - in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.

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Shapes and Genescapes: Mapping Multivariate Phenotype-Biological Process Associations for Craniofacial Shape

10.1101/2020.11.12.378513 ◽

2020 ◽

Author(s):

J. David Aponte ◽

David C. Katz ◽

Wei Liu ◽

Fernando Andrade ◽

Charles C. Roseman ◽

...

Keyword(s):

Regulatory Networks ◽

Biological Process ◽

Association Studies ◽

Complex Trait ◽

Joint Effect ◽

Genome Wide Association Studies ◽

Shape Variation ◽

Gene Effects ◽

Online Application ◽

Pathway Gene

AbstractThe importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. However, genome wide association studies identify and localize the contribution of individual genes to phenotypic variation, seldom targeting the coordinated influence of multiple genes on phenotypes. Here, we explicitly model the joint effect of biologically coherent collections of genes on craniofacial shape in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. Our process-centered view of cranial shape variation allows us to consider fundamental issues that are difficult to address with existing methods, such as the extent to which variation in different processes relevant to the same phenotype correspond to similar axes of shape variation, and whether the direction of the effect of experimental mutations to a pathway gene is similar to the primary axis of shape variation associated with that pathway. Finally, we introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.

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Contrasting roles of GmNAC065 and GmNAC085 in natural senescence, plant development, multiple stresses and cell death responses

Scientific Reports ◽

10.1038/s41598-021-90767-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bruno Paes Melo ◽

Isabela Tristan Lourenço-Tessutti ◽

Otto Teixeira Fraga ◽

Luanna Bezerra Pinheiro ◽

Camila Barrozo de Jesus Lins ◽

...

Keyword(s):

Cell Death ◽

Plant Development ◽

Stress Responses ◽

Regulatory Networks ◽

Lower Stress ◽

Multiple Stresses ◽

Gene Sets ◽

Ros Accumulation ◽

Stress Dependent ◽

Senescence Associated Genes

AbstractNACs are plant-specific transcription factors involved in controlling plant development, stress responses, and senescence. As senescence-associated genes (SAGs), NACs integrate age- and stress-dependent pathways that converge to programmed cell death (PCD). In Arabidopsis, NAC-SAGs belong to well-characterized regulatory networks, poorly understood in soybean. Here, we interrogated the soybean genome and provided a comprehensive analysis of senescence-associated Glycine max (Gm) NACs. To functionally examine GmNAC-SAGs, we selected GmNAC065, a putative ortholog of Arabidopsis ANAC083/VNI2 SAG, and the cell death-promoting GmNAC085, an ANAC072 SAG putative ortholog, for analyses. Expression analysis of GmNAC065 and GmNAC085 in soybean demonstrated (i) these cell death-promoting GmNACs display contrasting expression changes during age- and stress-induced senescence; (ii) they are co-expressed with functionally different gene sets involved in stress and PCD, and (iii) are differentially induced by PCD inducers. Furthermore, we demonstrated GmNAC065 expression delays senescence in Arabidopsis, a phenotype associated with enhanced oxidative performance under multiple stresses, higher chlorophyll, carotenoid and sugar contents, and lower stress-induced PCD compared to wild-type. In contrast, GmNAC085 accelerated stress-induced senescence, causing enhanced chlorophyll loss, ROS accumulation and cell death, decreased antioxidative system expression and activity. Accordingly, GmNAC065 and GmNAC085 targeted functionally contrasting sets of downstream AtSAGs, further indicating that GmNAC85 and GmNAC065 regulators function inversely in developmental and environmental PCD.

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Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

PLoS ONE ◽

10.1371/journal.pone.0233377 ◽

2020 ◽

Vol 15 (6) ◽

pp. e0233377

Author(s):

David C. Katz ◽

J. David Aponte ◽

Wei Liu ◽

Rebecca M. Green ◽

Jessica M. Mayeux ◽

...

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Facial Shape ◽

Diversity Outbred ◽

Outbred Mouse ◽

Trait Locus ◽

Facial Development

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Genetics of cleft lip and palate revisited

Journal of Clinical Pediatric Dentistry ◽

10.17796/jcpd.27.4.k7j3628944237392 ◽

2003 ◽

Vol 27 (4) ◽

pp. 311-320 ◽

Cited By ~ 3

Author(s):

Puneet Batra ◽

Ritu Duggal ◽

Hari Parkash

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Speech Therapy ◽

Cleft Lip And Palate ◽

Gene List ◽

Complex Trait ◽

Case Control Studies ◽

Systematic Screening ◽

Complex Interactions ◽

Facial Development

Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects, with treatment including multiple surgeries, speech therapy, and dental and orthodontic treatments over the first 18 years of life. Providing care for these patients and families includes educating patients and parents about the genetics of CL/CP, as well as meeting the immediate medical needs.Attempts at identifying susceptibility loci via family and case-control studies have proved inconsistent. It is likely that initial predictions of the complex interactions involved in facial development were underestimated. The candidate gene list for CL/P is getting longer and the need for an impartial, systematic screening technique, to implicate or refute the inclusion of particular loci, is apparent. So we are faced with the question "Can this complex trait be too complex?"The aim of this review is to make the dentist aware of the differences between syndromic and non-syndromic cleft as well as understanding the etiological variation in cleft lip with and without cleft palate. This will aid the dentist in diagnosis and give proper genetic counseling to parents and patients of cleft lip and palate.

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GATA3 is essential for separating patterning domains during facial morphogenesis

Development ◽

10.1242/dev.199534 ◽

2021 ◽

Author(s):

Makoto Abe ◽

Timothy C. Cox ◽

Anthony B. Firulli ◽

Stanley M. Kanai ◽

Jacob Dalhka ◽

...

Keyword(s):

Gene Regulatory Networks ◽

Regulatory Networks ◽

Mouse Embryos ◽

Pharyngeal Arch ◽

Bony Fusion ◽

Craniofacial Microsomia ◽

Crucial Component ◽

Gene Regulatory ◽

Facial Development ◽

Gata Family

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the Hinge and Caps model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues while the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.

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Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder

Frontiers in Genetics ◽

10.3389/fgene.2021.690537 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ting Li ◽

He Li ◽

Yue Li ◽

Shu-An Dong ◽

Ming Yi ◽

...

Keyword(s):

Genome Wide Association Study ◽

Biological Process ◽

Susceptibility Gene ◽

Susceptibility Genes ◽

Cellular Component ◽

Molecular Function ◽

Risk Genes ◽

Kegg Pathways ◽

Gene Sets ◽

Genome Wide

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system and it is understandable that environmental and genetic factors underlie the etiology of NMOSD. However, the susceptibility genes and associated pathways of NMOSD patients who are AQP4-Ab positive and negative have not been elucidated.MethodsSecondary analysis from a NMOSD Genome-wide association study (GWAS) dataset originally published in 2018 (215 NMOSD cases and 1244 controls) was conducted to identify potential susceptibility genes and associated pathways in AQP4-positive and negative NMOSD patients, respectively (132 AQP4-positive and 83 AQP4-negative).ResultsIn AQP4-positive NMOSD cases, five shared risk genes were obtained at chromosome 6 in AQP4-positive NMOSD cases by using more stringent p-Values in both methods (p < 0.05/16,532), comprising CFB, EHMT2, HLA-DQA1, MSH5, and SLC44A4. Fifty potential susceptibility gene sets were determined and 12 significant KEGG pathways were identified. Sixty-seven biological process pathways, 32 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained from the GO annotations of the 128 pathways identified. In the AQP4 negative NMOSD group, no significant genes were obtained by using more stringent p-Values in both methods (p < 0.05/16,485). The 22 potential susceptibility gene sets were determined. There were no shared potential susceptibility genes between the AQP4-positive and negative groups, furthermore, four significant KEGG pathways were also identified. Of the GO annotations of the 165 pathways identified, 99 biological process pathways, 37 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained.ConclusionThe potential molecular mechanism underlying NMOSD may be related to proteins encoded by these novel genes in complements, antigen presentation, and immune regulation. The new results may represent an improved comprehension of the genetic and molecular mechanisms underlying NMOSD.

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IDENTIFICATION OF GRANGER CAUSALITY BETWEEN GENE SETS

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720010004860 ◽

2010 ◽

Vol 08 (04) ◽

pp. 679-701 ◽

Cited By ~ 12

Author(s):

ANDRÉ FUJITA ◽

JOÃO RICARDO SATO ◽

KANAME KOJIMA ◽

LUCIANA RODRIGUES GOMES ◽

MASAO NAGASAKI ◽

...

Keyword(s):

Granger Causality ◽

Information Flow ◽

Gene Networks ◽

Regulatory Networks ◽

Complete Information ◽

Gene Expressions ◽

Vector Autoregressive ◽

Gene Sets ◽

Intuitive Concept ◽

Flow Of Information

Wiener and Granger have introduced an intuitive concept of causality (Granger causality) between two variables which is based on the idea that an effect never occurs before its cause. Later, Geweke generalized this concept to a multivariate Granger causality, i.e. n variables Granger-cause another variable. Although Granger causality is not "effective causality" in the Aristothelic sense, this concept is useful to infer directionality and information flow in observational data. Granger causality is usually identified by using VAR (Vector Autoregressive) models due to their simplicity. In the last few years, several VAR-based models were presented in order to model gene regulatory networks. Here, we generalize the multivariate Granger causality concept in order to identify Granger causalities between sets of gene expressions, i.e. whether a set of n genes Granger-causes another set of m genes, aiming at identifying the flow of information between gene networks (or pathways). The concept of Granger causality for sets of variables is presented. Moreover, a method for its identification with a bootstrap test is proposed. This method is applied in simulated and also in actual biological gene expression data in order to model regulatory networks. This concept may be useful for the understanding of the complete information flow from one network or pathway to the other, mainly in regulatory networks. Linking this concept to graph theory, sink and source can be generalized to node sets. Moreover, hub and centrality for sets of genes can be defined based on total information flow. Another application is in annotation, when the functionality of a set of genes is unknown, but this set is Granger-caused by another set of genes which is well studied. Therefore, this information may be useful to infer or construct some hypothesis about the unknown set of genes.

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HB-PLS: An algorithm for identifying biological process or pathway regulators by integrating Huber loss and Berhu penalty with partial least squares regression

10.1101/2020.05.16.089623 ◽

2020 ◽

Author(s):

Wenping Deng ◽

Kui Zhang ◽

Zhigang Wei ◽

Lihu Wang ◽

Cheng He ◽

...

Keyword(s):

Least Squares ◽

Partial Least Squares ◽

Regulatory Networks ◽

Biological Process ◽

Ordinary Least Squares ◽

Descent Method ◽

High Dimensional ◽

Gradient Descent Method ◽

Least Squares Regression ◽

Non Gaussian

AbstractGene expression data features high dimensionality, multicollinearity, and the existence of outlier or non-Gaussian distribution noise, which make the identification of true regulatory genes controlling a biological process or pathway difficult. In this study, we embedded the Huber-Berhu (HB) regression into the partial least squares (PLS) framework and created a new method called HB-PLS for predicting biological process or pathway regulators through construction of regulatory networks. PLS is an alternative to ordinary least squares (OLS) for handling multicollinearity in high dimensional data. The Huber loss is more robust to outliers than square loss, and the Berhu penalty can obtain a better balance between the ℓ2 penalty and the ℓ1 penalty. HB-PLS therefore inherits the advantages of the Huber loss, the Berhu penalty, and PLS. To solve the Huber-Berhu regression, a fast proximal gradient descent method was developed; the HB regression runs much faster than CVX, a Matlab-based modeling system for convex optimization. Implementation of HB-PLS to real transcriptomic data from Arabidopsis and maize led to the identification of many pathway regulators that had previously been identified experimentally. In terms of its efficiency in identifying positive biological process or pathway regulators, HB-PLS is comparable to sparse partial least squares (SPLS), a very efficient method developed for variable selection and dimension reduction in handling multicollinearity in high dimensional genomic data. However, HB-PLS is able to identify some distinct regulators, and in one case identify more positive regulators at the top of output list, which can reduce the burden for experimental test of the identified candidate targets. Our study suggests that HB-PLS is instrumental for identifying biological process and pathway genes.

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Network-Based Approaches Reveal Potential Therapeutic Targets for Host-Directed Antileishmanial Therapy Driving Drug Repurposing

Microbiology Spectrum ◽

10.1128/spectrum.01018-21 ◽

2021 ◽

Author(s):

J. Eduardo Martinez-Hernandez ◽

Zaynab Hammoud ◽

Alessandra Mara de Sousa ◽

Frank Kramer ◽

Rubens L. do Monte-Neto ◽

...

Keyword(s):

Gene Regulatory Networks ◽

Regulatory Networks ◽

Biological Process ◽

Expression Profiles ◽

Therapeutic Targets ◽

Drug Repurposing ◽

Novel Approach ◽

Gene Regulatory ◽

Molecular Functions ◽

Approved Drugs

This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles.

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The NAD+-dependent deacetylase Sir2 enables evolution of new traits by regulating distinct gene sets in two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis

10.1101/734608 ◽

2019 ◽

Author(s):

Kristen M. Humphrey ◽

Lisha Zhu ◽

Meleah A. Hickman ◽

Shirin Hasan ◽

Haniam Maria ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Regulatory Networks ◽

Environmental Changes ◽

Yeast Species ◽

Kluyveromyces Lactis ◽

Carbon Sources ◽

Adaptive Responses ◽

Gene Sets ◽

Conserved Genes ◽

Heavy Metal Efflux

ABSTRACTEvolutionary adaptation increases the fitness of an organism in its environment. It can occur through rewiring of gene regulatory networks, such that an organism responds appropriately to environmental changes. We investigated whether sirtuin deacetylases, which repress transcription and require NAD+ for activity, could facilitate the evolution of potentially adaptive responses by serving as transcriptional rewiring points. If so, bringing genes under the control of sirtuins could enable organisms to mount appropriate responses to stresses that decrease NAD+ levels. To explore how the genomic targets of sirtuins shift over evolutionary time, we compared two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis that display differences in cellular metabolism and lifecycle timing in response to nutrient availability. We identified sirtuin-regulated genes through a combination of chromatin immunoprecipitation and RNA expression. In both species, regulated genes were associated with NAD+ homeostasis, mating, and sporulation, but the specific genes differed. In addition, regulated genes in K. lactis were associated with other processes, including utilization of non-glucose carbon sources, heavy metal efflux, DNA synthesis, and production of the siderophore pulcherrimin. Consistent with the species-restricted regulation of these genes, sirtuin deletion impacted relevant phenotypes in K. lactis but not S. cerevisiae. Finally, sirtuin-regulated gene sets were depleted for broadly-conserved genes, consistent with sirtuins regulating processes restricted to a few species. Taken together, these results are consistent with the notion that sirtuins serve as rewiring points that allow species to evolve distinct responses to low NAD+ stress.

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