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Article ; Online: Transposable Elements: Classification, Identification, and Their Use As a Tool For Comparative Genomics.

Makałowski, Wojciech / Gotea, Valer / Pande, Amit / Makałowska, Izabela

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1910, Page(s) 177–207

Abstract: Most genomes are populated by hundreds of thousands of sequences originated from mobile elements. On the one hand, these sequences present a real challenge in the process of genome analysis and annotation. On the other hand, they are very interesting ... ...

Abstract	Most genomes are populated by hundreds of thousands of sequences originated from mobile elements. On the one hand, these sequences present a real challenge in the process of genome analysis and annotation. On the other hand, they are very interesting biological subjects involved in many cellular processes. Here we present an overview of transposable elements biodiversity, and we discuss different approaches to transposable elements detection and analyses.
MeSH term(s)	Bacteria/genetics ; Computational Biology/methods ; DNA Transposable Elements ; Eukaryota/genetics ; Evolution, Molecular ; Genetic Association Studies ; Genome ; Genomics/methods ; High-Throughput Nucleotide Sequencing ; Mutagenesis, Insertional ; Repetitive Sequences, Nucleic Acid
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2019-07-05
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9074-0_6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: CAGI experiments: Modeling sequence variant impact on gene splicing using predictions from computational tools.

Gotea, Valer / Margolin, Gennady / Elnitski, Laura

Human mutation

2019 Volume 40, Issue 9, Page(s) 1252–1260

Abstract: Improving predictions of phenotypic consequences for genomic variants is part of ongoing efforts in the scientific community to gain meaningful insights into genomic function. Within the framework of the critical assessment of genome interpretation ... ...

Abstract	Improving predictions of phenotypic consequences for genomic variants is part of ongoing efforts in the scientific community to gain meaningful insights into genomic function. Within the framework of the critical assessment of genome interpretation experiments, we participated in the Vex-seq challenge, which required predicting the change in the percent spliced in measure (ΔΨ) for 58 exons caused by more than 1,000 genomic variants. Experimentally determined through the Vex-seq assay, the Ψ quantifies the fraction of reads that include an exon of interest. Predicting the change in Ψ associated with specific genomic variants implies determining the sequence changes relevant for splicing regulators, such as splicing enhancers and silencers. Here we took advantage of two computational tools, SplicePort and SPANR, that incorporate relevant sequence features in their models of splice sites and exon-inclusion level, respectively. Specifically, we used the SplicePort and SPANR outputs to build mathematical models of the experimental data obtained for the variants in the training set, which we then used to predict the ΔΨ associated with the mutations in the test set. We show that the sequence changes captured by these computational tools provide a reasonable foundation for modeling the impact on splicing associated with genomic variants.
MeSH term(s)	Computational Biology/methods ; Exons ; Genetic Variation ; Humans ; Models, Genetic ; RNA Splicing ; Software
Language	English
Publishing date	2019-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.23782
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Article ; Online: Characterization and clustering of kinase isoform expression in metastatic melanoma.

Holland, David O / Gotea, Valer / Fedkenheuer, Kevin / Jaiswal, Sushil K / Baugher, Catherine / Tan, Hua / Fedkenheuer, Michael / Elnitski, Laura

PLoS computational biology

2022 Volume 18, Issue 5, Page(s) e1010065

Abstract: Mutations to the human kinome are known to play causal roles in cancer. The kinome regulates numerous cell processes including growth, proliferation, differentiation, and apoptosis. In addition to aberrant expression, aberrant alternative splicing of ... ...

Abstract	Mutations to the human kinome are known to play causal roles in cancer. The kinome regulates numerous cell processes including growth, proliferation, differentiation, and apoptosis. In addition to aberrant expression, aberrant alternative splicing of cancer-driver genes is receiving increased attention as it could lead to loss or gain of functional domains, altering a kinase's downstream impact. The present study quantifies changes in gene expression and isoform ratios in the kinome of metastatic melanoma cells relative to primary tumors. We contrast 538 total kinases and 3,040 known kinase isoforms between 103 primary tumor and 367 metastatic samples from The Cancer Genome Atlas (TCGA). We find strong evidence of differential expression (DE) at the gene level in 123 kinases (23%). Additionally, of the 468 kinases with alternative isoforms, 60 (13%) had significant difference in isoform ratios (DIR). Notably, DE and DIR have little correlation; for instance, although DE highlights enrichment in receptor tyrosine kinases (RTKs), DIR identifies altered splicing in non-receptor tyrosine kinases (nRTKs). Using exon junction mapping, we identify five examples of splicing events favored in metastatic samples. We demonstrate differential apoptosis and protein localization between SLK isoforms in metastatic melanoma. We cluster isoform expression data and identify subgroups that correlate with genomic subtypes and anatomic tumor locations. Notably, distinct DE and DIR patterns separate samples with BRAF hotspot mutations and (N/K/H)RAS hotspot mutations, the latter of which lacks effective kinase inhibitor treatments. DE in RAS mutants concentrates in CMGC kinases (a group including cell cycle and splicing regulators) rather than RTKs as in BRAF mutants. Furthermore, isoforms in the RAS kinase subgroup show enrichment for cancer-related processes such as angiogenesis and cell migration. Our results reveal a new approach to therapeutic target identification and demonstrate how different mutational subtypes may respond differently to treatments highlighting possible new driver events in cancer.
MeSH term(s)	Cell Line, Tumor ; Cluster Analysis ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Protein Isoforms/genetics ; Proto-Oncogene Proteins B-raf ; Tyrosine
Chemical Substances	Protein Isoforms ; Tyrosine (42HK56048U) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2022-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010065
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Article ; Online: Characterization and clustering of kinase isoform expression in metastatic melanoma.

David O Holland / Valer Gotea / Kevin Fedkenheuer / Sushil K Jaiswal / Catherine Baugher / Hua Tan / Michael Fedkenheuer / Laura Elnitski

PLoS Computational Biology, Vol 18, Iss 5, p e

2022 Volume 1010065

Abstract	Mutations to the human kinome are known to play causal roles in cancer. The kinome regulates numerous cell processes including growth, proliferation, differentiation, and apoptosis. In addition to aberrant expression, aberrant alternative splicing of cancer-driver genes is receiving increased attention as it could lead to loss or gain of functional domains, altering a kinase's downstream impact. The present study quantifies changes in gene expression and isoform ratios in the kinome of metastatic melanoma cells relative to primary tumors. We contrast 538 total kinases and 3,040 known kinase isoforms between 103 primary tumor and 367 metastatic samples from The Cancer Genome Atlas (TCGA). We find strong evidence of differential expression (DE) at the gene level in 123 kinases (23%). Additionally, of the 468 kinases with alternative isoforms, 60 (13%) had significant difference in isoform ratios (DIR). Notably, DE and DIR have little correlation; for instance, although DE highlights enrichment in receptor tyrosine kinases (RTKs), DIR identifies altered splicing in non-receptor tyrosine kinases (nRTKs). Using exon junction mapping, we identify five examples of splicing events favored in metastatic samples. We demonstrate differential apoptosis and protein localization between SLK isoforms in metastatic melanoma. We cluster isoform expression data and identify subgroups that correlate with genomic subtypes and anatomic tumor locations. Notably, distinct DE and DIR patterns separate samples with BRAF hotspot mutations and (N/K/H)RAS hotspot mutations, the latter of which lacks effective kinase inhibitor treatments. DE in RAS mutants concentrates in CMGC kinases (a group including cell cycle and splicing regulators) rather than RTKs as in BRAF mutants. Furthermore, isoforms in the RAS kinase subgroup show enrichment for cancer-related processes such as angiogenesis and cell migration. Our results reveal a new approach to therapeutic target identification and demonstrate how different mutational subtypes may respond ...
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Ascertaining regions affected by GC-biased gene conversion through weak-to-strong mutational hotspots.

Gotea, Valer / Elnitski, Laura

Genomics

2014 Volume 103, Issue 5-6, Page(s) 349–356

Abstract: A major objective for evolutionary biology is to identify regions affected by positive selection. High dN/dS values for proteins and accelerated lineage-specific substitution rates for non-coding regions are considered classic signatures of positive ... ...

Abstract	A major objective for evolutionary biology is to identify regions affected by positive selection. High dN/dS values for proteins and accelerated lineage-specific substitution rates for non-coding regions are considered classic signatures of positive selection. However, these could also be the result of non-adaptive phenomena, such as GC-biased gene conversion (gBGC), which favors the fixation of strong (C/G) over weak (A/T) nucleotides. Recent estimates indicate that gBGC affected up to 20% of regions with signatures of positive selection. Here we evaluate the impact of gBGC through its molecular signature of weak-to-strong mutational hotspots. We implemented specific modifications to the test proposed by Tang and Lewontin (1999) for identifying regions of differential variability and applied it to regions previously investigated for the influence of gBGC. While we found significant agreement with previous reports, our results suggest a smaller influence of gBGC than previously estimated, warranting further development of methods for its detection.
MeSH term(s)	Algorithms ; Animals ; Base Composition ; Base Sequence ; Computer Simulation ; Consensus Sequence ; DNA Mutational Analysis ; Gene Conversion ; Genome, Human ; Humans ; Models, Genetic ; Molecular Sequence Data ; Mutation Rate ; Pituitary Adenylate Cyclase-Activating Polypeptide/genetics ; Sequence Alignment
Chemical Substances	ADCYAP1 protein, human ; Pituitary Adenylate Cyclase-Activating Polypeptide
Language	English
Publishing date	2014-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2014.04.001
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Article: Ascertaining regions affected by GC-biased gene conversion through weak-to-strong mutational hotspots

Gotea, Valer / Laura Elnitski

Genomics. 2014 May, June, v. 103

2014

Abstract	A major objective for evolutionary biology is to identify regions affected by positive selection. High dN/dS values for proteins and accelerated lineage-specific substitution rates for non-coding regions are considered classic signatures of positive selection. However, these could also be the result of non-adaptive phenomena, such as GC-biased gene conversion (gBGC), which favors the fixation of strong (C/G) over weak (A/T) nucleotides. Recent estimates indicate that gBGC affected up to 20% of regions with signatures of positive selection. Here we evaluate the impact of gBGC through its molecular signature of weak-to-strong mutational hotspots. We implemented specific modifications to the test proposed by Tang and Lewontin (1999) for identifying regions of differential variability and applied it to regions previously investigated for the influence of gBGC. While we found significant agreement with previous reports, our results suggest a smaller influence of gBGC than previously estimated, warranting further development of methods for its detection.
Keywords	gene conversion ; nucleotides ; proteins
Language	English
Dates of publication	2014-06
Size	p. 349-356.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2014.04.001
Database	NAL-Catalogue (AGRICOLA)

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Article: CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies.

Sánchez-Vega, Francisco / Gotea, Valer / Chen, Yun-Ching / Elnitski, Laura

World journal of gastrointestinal oncology

2017 Volume 9, Issue 3, Page(s) 105–120

Abstract: Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed ...

Abstract	Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as
Language	English
Publishing date	2017-03-23
Publishing country	China
Document type	Editorial
ZDB-ID	2573696-6
ISSN	1948-5204
ISSN	1948-5204
DOI	10.4251/wjgo.v9.i3.105
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Article ; Online: A novel role for nucleolin in splice site selection

Shefer, Kinneret / Boulos, Ayub / Gotea, Valer / Arafat, Maram / Ben Chaim, Yair / Muharram, Aya / Isaac, Sara / Eden, Amir / Sperling, Joseph / Elnitski, Laura / Sperling, Ruth

RNA Biology. 2022 Dec. 31, v. 19, no. 1 p.333-352

2022

Abstract: Latent 5ʹ splice sites, not normally used, are highly abundant in human introns, but are activated under stress and in cancer, generating thousands of nonsense mRNAs. A previously proposed mechanism to suppress latent splicing was shown to be independent ...

Abstract	Latent 5ʹ splice sites, not normally used, are highly abundant in human introns, but are activated under stress and in cancer, generating thousands of nonsense mRNAs. A previously proposed mechanism to suppress latent splicing was shown to be independent of NMD, with a pivotal role for initiator-tRNA independent of protein translation. To further elucidate this mechanism, we searched for nuclear proteins directly bound to initiator-tRNA. Starting with UV-crosslinking, we identified nucleolin (NCL) interacting directly and specifically with initiator-tRNA in the nucleus, but not in the cytoplasm. Next, we show the association of initiator-tRNA and NCL with pre-mRNA. We further show that recovery of suppression of latent splicing by initiator-tRNA complementation is NCL dependent. Finally, upon nucleolin knockdown we show activation of latent splicing in hundreds of coding transcripts having important cellular functions. We thus propose nucleolin, a component of the endogenous spliceosome, through its direct binding to initiator-tRNA and its effect on latent splicing, as the first protein of a nuclear quality control mechanism regulating splice site selection to protect cells from latent splicing that can generate defective mRNAs.
Keywords	RNA ; humans ; introns ; quality control ; spliceosomes ; 5ʹ splice site selection ; suppression of splicing ; alternative splicing ; endogenous spliceosome ; latent splice sites ; latent splicing ; splicing regulation ; mass spectrometry ; RNA sequencing ; bioinformatics analysis
Language	English
Dates of publication	2022-1231
Size	p. 333-352.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	2159587-2
ISSN	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2021.2020455
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Significant associations between driver gene mutations and DNA methylation alterations across many cancer types.

Chen, Yun-Ching / Gotea, Valer / Margolin, Gennady / Elnitski, Laura

PLoS computational biology

2017 Volume 13, Issue 11, Page(s) e1005840

Abstract: Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer. In light of these findings, we hypothesized that the landscapes of tumor genomes and epigenomes are tightly interconnected. We ... ...

Abstract	Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer. In light of these findings, we hypothesized that the landscapes of tumor genomes and epigenomes are tightly interconnected. We measured this relationship using principal component analyses and methylation-mutation associations applied at the nucleotide level and with respect to genome-wide trends. We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types. In addition, we identified associations between 737 mutated driver genes and site-specific methylation changes. Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes. The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways. These results establish that driver gene mutations are associated with methylation alterations capable of shaping regulatory network functions. In addition, the methodology presented here can be used to subdivide tumors into more homogeneous subsets corresponding to underlying molecular characteristics, which could improve treatment efficacy.
MeSH term(s)	Computational Biology ; CpG Islands/genetics ; DNA Methylation/genetics ; Genetic Association Studies ; Genome/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics ; Principal Component Analysis ; Signal Transduction/genetics
Language	English
Publishing date	2017-11-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1005840
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Article ; Online: Significant associations between driver gene mutations and DNA methylation alterations across many cancer types.

Yun-Ching Chen / Valer Gotea / Gennady Margolin / Laura Elnitski

PLoS Computational Biology, Vol 13, Iss 11, p e

2017 Volume 1005840

Abstract	Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer. In light of these findings, we hypothesized that the landscapes of tumor genomes and epigenomes are tightly interconnected. We measured this relationship using principal component analyses and methylation-mutation associations applied at the nucleotide level and with respect to genome-wide trends. We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types. In addition, we identified associations between 737 mutated driver genes and site-specific methylation changes. Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes. The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways. These results establish that driver gene mutations are associated with methylation alterations capable of shaping regulatory network functions. In addition, the methodology presented here can be used to subdivide tumors into more homogeneous subsets corresponding to underlying molecular characteristics, which could improve treatment efficacy.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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