scholarly journals Molecular Analysis of Gli3, Ihh, Rab23, and Jag1 in a Rabbit Model of Craniosynostosis

2017 ◽  
Vol 55 (3) ◽  
pp. 375-382 ◽  
Author(s):  
James R. Gilbert ◽  
Gwen M. Taylor ◽  
Joseph E. Losee ◽  
Mark P. Mooney ◽  
Gregory M. Cooper
Keyword(s):  
Family Member ◽  
Genetic Basis ◽  
Rabbit Model ◽  
Craniofacial Development ◽  
Cranial Sutures ◽  
Nucleotide Polymorphisms ◽  
Ras Oncogene ◽  
Wild Type ◽  
Protein Coding ◽  
Coding Regions

Objective: Craniosynostosis (CS) involves the premature fusion of one or more cranial sutures. The etiology of CS is complex and mutations in more than 50 distinct genes have been causally linked to the disorder. Many of the genes that have been associated with CS in humans play an essential role in tissue patterning and early craniofacial development. Among these genes are members of the Hedgehog (HH) and Notch signal transduction pathways, including the GLI family member Gli3, Indian Hedgehog ( Ihh), the RAS oncogene family member Rab23, and the Notch ligand JAGGED1 ( Jag1). We have previously described a colony of rabbits with a heritable pattern of coronal suture synostosis, although the genetic basis for synostosis within this model remains unknown. The present study was performed to determine if coding errors in Gli3, Ihh, Rab23, or Jag1 could be causally linked to craniosynostosis in this unique animal model. Design: Sequencing of cDNA templates was performed using samples obtained from wild-type and craniosynostotic rabbits. Results: Several nucleotide polymorphisms were identified in Gli3, Ihh, and Rab23, although these variants failed to segregate by phenotype. No nucleotide polymorphisms were identified in Jag1. Conclusions: These data indicate that the causal locus for heritable craniosynostosis in this rabbit model is not located within the protein coding regions of Gli3, Ihh, Rab23, or Jag1.

scholarly journals Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1073
Author(s):  
Federica Tiberio ◽  
Ornella Parolini ◽  
Wanda Lattanzi
Keyword(s):  
Primary Cilium ◽  
Genetic Basis ◽  
Mendelian Inheritance ◽  
Craniofacial Development ◽  
Cranial Sutures ◽  
Craniofacial Malformation ◽  
Computational Annotation ◽  
Neural Crest Origin ◽  
Disease Associated Genes ◽  
Molecular Signals

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

scholarly journals Skip-mers: increasing entropy and sensitivity to detect conserved genic regions with simple cyclic q-grams

2017 ◽  
Author(s):  
Bernardo J. Clavijo ◽  
Gonzalo Garcia Accinelli ◽  
Luis Yanes ◽  
Katie Barr ◽  
Jonathan Wright
Keyword(s):  
Nucleotide Polymorphisms ◽  
Simple Task ◽  
Protein Coding ◽  
Sequencing Errors ◽  
Coding Regions ◽  
Spaced Seeds ◽  
A Genome ◽  
Increased Sensitivity ◽  
Genome Analyses ◽  
Multiple Samples

AbstractBioinformatic analyses and tools make extensive use of k-mers (fixed contiguous strings of k nucleotides) as an informational unit. K-mer analyses are both useful and fast, but are strongly affected by single nucleotide polymorphisms or sequencing errors, effectively hindering direct-analyses of whole regions and decreasing their usability between evolutionary distant samples. Q-grams or spaced seeds, subsequences generated with a pattern of used-and-skipped nucleotides, overcome many of these limitations but introduce larger complexity which hinders their wider adoption.We introduce a concept of skip-mers, a cyclic pattern of used-and-skipped positions of k nucleotides spanning a region of size S ≥ k, and show how analyses are improved by using this simple subset of q-grams as a replacement for k-mers. The entropy of skip-mers increases with the larger span, capturing information from more distant positions and increasing the specificity, and uniqueness, of larger span skip-mers within a genome. In addition, skip-mers constructed in cycles of 1 or 2 nucleotides in every 3 (or a multiple of 3) lead to increased sensitivity in the coding regions of genes, by grouping together the more conserved nucleotides of the protein-coding regions.We implemented a set of tools to count and intersect skip-mers between different datasets, a simple task given that the properties of skip-mers make them a direct substitute for k-mers. We used these tools to show how skip-mers have advantages over k-mers in terms of entropy and increased sensitivity to detect conserved coding sequence, allowing better identification of genic matches between evolutionarily distant species. We then show benefits for multi-genome analyses provided by increased and better correlated coverage of conserved skip-mers across multiple samples.Software availabilitythe skm-tools implementing the methods described in this manuscript are available under MIT license at http://github.com/bioinfologics/skm-tools/

scholarly journals Watch Out for a Second SNP: Focus on Multi-Nucleotide Variants in Coding Regions and Rescued Stop-Gained

2021 ◽  
Vol 12 ◽  
Author(s):  
Fabien Degalez ◽  
Frédéric Jehl ◽  
Kévin Muret ◽  
Maria Bernard ◽  
Frédéric Lecerf ◽  
...  
Keyword(s):  
Companion Paper ◽  
Potential Effect ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Coding Region ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Variant Annotation ◽  
Coding Regions ◽  
Reliable Genotypes

Most single-nucleotide polymorphisms (SNPs) are located in non-coding regions, but the fraction usually studied is harbored in protein-coding regions because potential impacts on proteins are relatively easy to predict by popular tools such as the Variant Effect Predictor. These tools annotate variants independently without considering the potential effect of grouped or haplotypic variations, often called “multi-nucleotide variants” (MNVs). Here, we used a large RNA-seq dataset to survey MNVs, comprising 382 chicken samples originating from 11 populations analyzed in the companion paper in which 9.5M SNPs— including 3.3M SNPs with reliable genotypes—were detected. We focused our study on in-codon MNVs and evaluate their potential mis-annotation. Using GATK HaplotypeCaller read-based phasing results, we identified 2,965 MNVs observed in at least five individuals located in 1,792 genes. We found 41.1% of them showing a novel impact when compared to the effect of their constituent SNPs analyzed separately. The biggest impact variation flux concerns the originally annotated stop-gained consequences, for which around 95% were rescued; this flux is followed by the missense consequences for which 37% were reannotated with a different amino acid. We then present in more depth the rescued stop-gained MNVs and give an illustration in the SLC27A4 gene. As previously shown in human datasets, our results in chicken demonstrate the value of haplotype-aware variant annotation, and the interest to consider MNVs in the coding region, particularly when searching for severe functional consequence such as stop-gained variants.

scholarly journals Identifying Liver Cancer-Related Enhancer SNPs by Integrating GWAS and Histone Modification ChIP-seq Data

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Tianjiao Zhang ◽  
Yang Hu ◽  
Xiaoliang Wu ◽  
Rui Ma ◽  
Qinghua Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Cancer ◽  
Histone Modification ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Protein Coding ◽  
Noncoding Regions ◽  
Coding Regions ◽  
Genome Wide

Many disease-related single nucleotide polymorphisms (SNPs) have been inferred from genome-wide association studies (GWAS) in recent years. Numerous studies have shown that some SNPs located in protein-coding regions are associated with numerous diseases by affecting gene expression. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. The SNPs located in enhancer elements may affect gene expression and lead to disease. We presented a method for identifying liver cancer-related enhancer SNPs through integrating GWAS and histone modification ChIP-seq data. We identified 22 liver cancer-related enhancer SNPs, 9 of which were regulatory SNPs involved in distal transcriptional regulation. The results highlight that these enhancer SNPs may play important roles in liver cancer.

scholarly journals Intra-individual heteroplasmy in the Gentiana tongolensis plastid genome (Gentianaceae)

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8025 ◽  
Author(s):  
Shan-Shan Sun ◽  
Xiao-Jun Zhou ◽  
Zhi-Zhong Li ◽  
Hong-Yang Song ◽  
Zhi-Cheng Long ◽  
...  
Keyword(s):  
Plastid Genome ◽  
Female Parent ◽  
Plastid Dna ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Plastid Inheritance ◽  
Coding Regions ◽  
Plastid Genomes ◽  
Biparental Plastid Inheritance

Chloroplasts are typically inherited from the female parent and are haploid in most angiosperms, but rare intra-individual heteroplasmy in plastid genomes has been reported in plants. Here, we report an example of plastome heteroplasmy and its characteristics in Gentiana tongolensis (Gentianaceae). The plastid genome of G. tongolensis is 145,757 bp in size and is missing parts of petD gene when compared with other Gentiana species. A total of 112 single nucleotide polymorphisms (SNPs) and 31 indels with frequencies of more than 2% were detected in the plastid genome, and most were located in protein coding regions. Most sites with SNP frequencies of more than 10% were located in six genes in the LSC region. After verification via cloning and Sanger sequencing at three loci, heteroplasmy was identified in different individuals. The cause of heteroplasmy at the nucleotide level in plastome of G. tongolensis is unclear from the present data, although biparental plastid inheritance and transfer of plastid DNA seem to be most likely. This study implies that botanists should reconsider the heredity and evolution of chloroplasts and be cautious with using chloroplasts as genetic markers, especially in Gentiana.

scholarly journals Complete chloroplast genomes of three important species, Abelmoschus moschatus, A. manihot and A. sagittifolius: Genome structures, mutational hotspots, comparative and phylogenetic analysis in Malvaceae

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242591
Author(s):  
Jie Li ◽  
Guang-ying Ye ◽  
Hai-lin Liu ◽  
Zai-hua Wang
Keyword(s):  
Phylogenetic Analysis ◽  
Chloroplast Genome ◽  
Intergenic Spacer ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Protein Coding ◽  
Important Species ◽  
Coding Regions ◽  
Chloroplast Genomes ◽  
Mutational Hotspots

Abelmoschus is an economically and phylogenetically valuable genus in the family Malvaceae. Owing to coexistence of wild and cultivated form and interspecific hybridization, this genus is controversial in systematics and taxonomy and requires detailed investigation. Here, we present whole chloroplast genome sequences and annotation of three important species: A. moschatus, A. manihot and A. sagittifolius, and compared with A. esculentus published previously. These chloroplast genome sequences ranged from 163121 bp to 163453 bp in length and contained 132 genes with 87 protein-coding genes, 37 transfer RNA and 8 ribosomal RNA genes. Comparative analyses revealed that amino acid frequency and codon usage had similarity among four species, while the number of repeat sequences in A. esculentus were much lower than other three species. Six categories of simple sequence repeats (SSRs) were detected, but A. moschatus and A. manihot did not contain hexanucleotide SSRs. Single nucleotide polymorphisms (SNPs) of A/T, T/A and C/T were the largest number type, and the ratio of transition to transversion was from 0.37 to 0.55. Abelmoschus species showed relatively independent inverted-repeats (IR) boundary traits with different boundary genes compared with the other related Malvaceae species. The intergenic spacer regions had more polymorphic than protein-coding regions and intronic regions, and thirty mutational hotpots (≥200 bp) were identified in Abelmoschus, such as start-psbA, atpB-rbcL, petD-exon2-rpoA, clpP-intron1 and clpP-exon2.These mutational hotpots could be used as polymorphic markers to resolve taxonomic discrepancies and biogeographical origin in genus Abelmoschus. Moreover, phylogenetic analysis of 33 Malvaceae species indicated that they were well divided into six subfamilies, and genus Abelmoschus was a well-supported clade within genus Hibiscus.

scholarly journals Genome Resequencing Reveals Genetic Variation between the Parents of An Elite Hybrid Upland Cotton

Agronomy ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 305
Author(s):  
Chengxiang Song ◽  
Wei Li ◽  
Zhenyu Wang ◽  
Xiaoyu Pei ◽  
Yangai Liu ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Development Stage ◽  
Fiber Development ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Polymorphic Snps ◽  
Gene Coding

Cotton is one of the most important economic crops worldwide. As the global demands rising, cotton yield improvement is the most important goal of cotton breeding. Hybrids have great potential for increasing yield, however, the genetic mechanism of hybrids is still not clear. To investigate the genetic basis of cotton hybrids, we resequenced 9053 and sGK9708 with 62.13x coverage depth, the parents of the elite hybrid cotton CCRI63 that has obvious heterosis in lint percentage (LP) and boll weight (BW). Based on the cotton reference genome (TM-1), 1,287,661 single nucleotide polymorphisms (SNPs) and 152,479 insertions/deletions (InDels) were identified in 9053, and 1,482,784 SNPs and 152,985 InDels in sGK9708. Among them, 8649 SNPs and 629 InDels in the gene coding regions showed polymorphism between parents. Moreover, these variations involved 5092 genes, and 3835 of these genes were divided into 10 clusters based on the gene expression profiles. The genes in Cluster 3 and 7 were specifically expressed in the ovule and fiber development stage, suggesting that they might relate to LP and BW. We further co-localized the polymorphic SNPs and InDels with the reported quantitative trait loci (QTLs) of LP and BW, and identified 68 genes containing the polymorphic SNPs or InDels within these QTL intervals and as being related to fiber development. This suggested that the outstanding traits of CCRI63 such as LP and BW might be generated by accumulating the favorable variations from the parents. The results generated herein provide a genetic basis for cotton hybrids and genetic markers for marker-assisted selection breeding of cotton.

scholarly journals Molecular Analysis of Ephrin A4 and Ephrin B1 in a Rabbit Model of Craniosynostosis

2018 ◽  
Vol 55 (7) ◽  
pp. 1020-1025 ◽  
Author(s):  
Gwen M. Taylor ◽  
Gregory M. Cooper ◽  
Joseph E. Losee ◽  
Mark P. Mooney ◽  
James Gilbert
Keyword(s):  
Tyrosine Kinases ◽  
Control Cell ◽  
Rabbit Model ◽  
Cell Lineage ◽  
Coronal Suture ◽  
Wild Type ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Membrane Bound ◽  
Model Sequencing

Craniosynostosis (CS) has a prevalence of approximately 1 in every 2000 live births and is characterized by the premature fusion of one or more cranial sutures. Failure to maintain the cell lineage boundary at the coronal suture is thought to be involved in the pathology of some forms of CS. The Ephrin family of receptor tyrosine kinases consists of membrane-bound receptors and ligands that control cell patterning and the formation of developmental boundaries. Mutations in the ephrin A4 (EFNA4) and ephrin B1 (EFNB1) ligands have been linked to nonsyndromic CS and craniofrontonasal syndrome, respectively, in patient samples. We have previously described a colony of rabbits with a heritable pattern of coronal suture synostosis, although the genetic basis for synostosis within this model remains unknown. The present study was performed to determine if EFNA4 or EFNB1 could be the loci of the causal mutation in this unique animal model. Sequencing of EFNA4 and EFNB1 was performed using templates obtained from wild-type (n = 4) and craniosynostotic (n = 4) rabbits. No structural coding errors were identified in either gene. A single-nucleotide transversion was identified in one wild-type rabbit within the third intron of EFNA4. These data indicate that the causal locus for heritable CS in this rabbit model is not located within the structural coding regions of either EFNA4 or EFNB1.

scholarly journals Prediction of Deleterious Nonsynonymous Single-Nucleotide Polymorphism for Human Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Jiaxin Wu ◽  
Rui Jiang
Keyword(s):  
Rare Variants ◽  
Fundamental Problem ◽  
Nucleotide Polymorphisms ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Inherited Diseases ◽  
Coding Regions ◽  
Typical Type ◽  
And Function

The identification of genetic variants that are responsible for human inherited diseases is a fundamental problem in human and medical genetics. As a typical type of genetic variation, nonsynonymous single-nucleotide polymorphisms (nsSNPs) occurring in protein coding regions may alter the encoded amino acid, potentially affect protein structure and function, and further result in human inherited diseases. Therefore, it is of great importance to develop computational approaches to facilitate the discrimination of deleterious nsSNPs from neutral ones. In this paper, we review databases that collect nsSNPs and summarize computational methods for the identification of deleterious nsSNPs. We classify the existing methods for characterizing nsSNPs into three categories (sequence based, structure based, and annotation based), and we introduce machine learning models for the prediction of deleterious nsSNPs. We further discuss methods for identifying deleterious nsSNPs in noncoding variants and those for dealing with rare variants.

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