Computational and Experimental Analysis of Genetic Variants

Prokop, Jeremy W.; Jdanov, Vladislav; Savage, Linda; Morris, Michele; Lamb, Neil E.; VanSickle, Elizabeth; Stenger, Cynthia L.; Rajasekaran, Surender; Bupp, Caleb

doi:10.1002/cphy.c210012

Cited by 7 publications

(7 citation statements)

References 171 publications

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“…NMD thus contributes heavily to human health genetics ( Holbrook et al, 2004 ), including cancer ( Lindeboom et al, 2016 ). Through the use of total RNAseq and variant screening in the RNA, our group has previously discovered that NMD inhibition through viral infections can result in the accumulation of NMD-based transcripts that change cellular outcomes ( Prokop et al, 2020 ), where a dominant negative variant can be reactivated by virus to cause a rare transient disease within the cells of viral infection, termed viral-induced genetics ( Prokop et al, 2022 ). Many of the blood samples with the highest levels of NMD transcripts throughout this study had bacterial or viral infections, suggesting that environmental factors may modify NMD transcript levels of small GTPase genes.…”

Section: Resultsmentioning

confidence: 99%

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The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Das

Sherry

Vaughan

et al. 2022

Front. Cell Dev. Biol.

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The small GTPase family is well-studied in cancer and cellular physiology. With 162 annotated human genes, the family has a broad expression throughout cells of the body. Members of the family have multiple exons that require splicing. Yet, the role of splicing within the family has been underexplored. We have studied the splicing dynamics of small GTPases throughout 41,671 samples by integrating Nanopore and Illumina sequencing techniques. Within this work, we have made several discoveries. 1). Using the GTEx long read data of 92 samples, each small GTPase gene averages two transcripts, with 83 genes (51%) expressing two or more isoforms. 2). Cross-tissue analysis of GTEx from 17,382 samples shows 41 genes (25%) expressing two or more protein-coding isoforms. These include protein-changing transcripts in genes such as RHOA, RAB37, RAB40C, RAB4B, RAB5C, RHOC, RAB1A, RAN, RHEB, RAC1, and KRAS. 3). The isolation and library technique of the RNAseq influences the abundance of non-sense-mediated decay and retained intron transcripts of small GTPases, which are observed more often in genes than appreciated. 4). Analysis of 16,243 samples of “Blood PAXgene” identified seven genes (3.7%; RHOA, RAB40C, RAB4B, RAB37, RAB5B, RAB5C, RHOC) with two or more transcripts expressed as the major isoform (75% of the total gene), suggesting a role of genetics in altering splicing. 5). Rare (ARL6, RAB23, ARL13B, HRAS, NRAS) and common variants (GEM, RHOC, MRAS, RAB5B, RERG, ARL16) can influence splicing and have an impact on phenotypes and diseases. 6). Multiple genes (RAB9A, RAP2C, ARL4A, RAB3A, RAB26, RAB3C, RASL10A, RAB40B, and HRAS) have sex differences in transcript expression. 7). Several exons are included or excluded for small GTPase genes (RASEF, KRAS, RAC1, RHEB, ARL4A, RHOA, RAB30, RHOBTB1, ARL16, RAP1A) in one or more forms of cancer. 8). Ten transcripts are altered in hypoxia (SAR1B, IFT27, ARL14, RAB11A, RAB10, RAB38, RAN, RIT1, RAB9A) with RHOA identified to have a transient 3′UTR RNA base editing at a conserved site found in all of its transcripts. Overall, we show a remarkable and dynamic role of splicing within the small GTPase family that requires future explorations.

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Section: Resultsmentioning

confidence: 99%

“…The human genome encodes >250,000 transcripts represented by diverse biotypes ( Prokop et al, 2022 ). Of these transcripts, 37% are polyadenylated and code for proteins (protein coding), which account for most studied/published transcripts.…”

Section: Introductionmentioning

confidence: 99%

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Das

Sherry

Vaughan

et al. 2022

Front. Cell Dev. Biol.

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“…The bioinformatics of WAC were assessed using a combination of previously published tools [ 18 , 19 ]. In short, sequences of vertebrate WAC protein were extracted from NCBI Gene Ortholog [ 20 ] during October 2022 and aligned with NCBI Cobalt [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto–Shinawi Syndrome

Rudolph

Stafford

Hwang

et al. 2023

Biology

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Dysfunction of the WW domain-containing adaptor with coiled-coil, WAC, gene underlies a rare autosomal dominant disorder, DeSanto–Shinawi syndrome (DESSH). DESSH is associated with facial dysmorphia, hypotonia, and cognitive alterations, including attention deficit hyperactivity disorder and autism. How the WAC protein localizes and functions in neural cells is critical to understanding its role during development. To understand the genotype–phenotype role of WAC, we developed a knowledgebase of WAC expression, evolution, human genomics, and structural/motif analysis combined with human protein domain deletions to assess how conserved domains guide cellular distribution. Then, we assessed localization in a cell type implicated in DESSH, cortical GABAergic neurons. WAC contains conserved charged amino acids, phosphorylation signals, and enriched nuclear motifs, suggesting a role in cellular signaling and gene transcription. Human DESSH variants are found within these regions. We also discovered and tested a nuclear localization domain that impacts the cellular distribution of the protein. These data provide new insights into the potential roles of this critical developmental gene, establishing a platform to assess further translational studies, including the screening of missense genetic variants in WAC. Moreover, these studies are essential for understanding the role of human WAC variants in more diverse neurological phenotypes, including autism spectrum disorder.

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“…The bioinformatics of WAC was assessed using a combination of previously published tools [18,19]. In short, sequences of vertebrate WAC protein were extracted from NCBI Gene Ortholog [20] during Oct 2022 and aligned with NCBI Cobalt [21].…”

Section: Bioinformaticsmentioning

confidence: 99%

Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto-Shinawi Syndrome

Rudolph¹,

Stafford²,

Hwang³

et al. 2023

Preprint

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Dysfunction of the WW domain-containing adaptor with coiled-coil, WAC, gene underlies a rare autosomal dominant disorder, DeSanto-Shinawi syndrome (DESSH). DESSH is associated with facial dysmorphia, hypotonia, and cognitive alterations, including attention deficit hyperactivity disorder and autism. How the WAC protein localizes and functions in neural cells is critical to understanding its role during development. To understand the genotype-phenotype role of WAC, we developed a knowledgebase of WAC expression, evolution, human genomics, and structural/motif analysis combined with human protein domain deletions to assess how conserved domains guide cellular distribution. Then assessed in a cell type implicated in DESSH, cortical GABAergic neurons. WAC contains conserved charged amino acids, phosphorylation signals, and enriched nuclear motifs, suggesting a role in cellular signaling and gene transcription. Human DESSH variants are found within these regions. We also discovered and tested a nuclear localaization domain that impacts the cellular distribution of the protein. These data provide new insights into the potential roles of this critical developmental gene, establishing a platform to assess further translational studies, including the screening of missense genetic variants in WAC. Moreover, these studies are essential for understanding the role of human WAC variants in more diverse neurological phenotypes, including autism spectrum disorder.

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Computational and Experimental Analysis of Genetic Variants

Cited by 7 publications

References 171 publications

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto–Shinawi Syndrome

Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto-Shinawi Syndrome

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