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1.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879317

RESUMO

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Duplicação Gênica , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Taxa de Mutação , Metástase Neoplásica/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Análise de Célula Única , Sequenciamento Completo do Exoma
2.
Nat Commun ; 11(1): 4459, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900997

RESUMO

The origins of multicellular physiology are tied to evolution of gene expression. Genes can shift expression as organisms evolve, but how ancestral expression influences altered descendant expression is not well understood. To examine this, we amalgamate 1,903 RNA-seq datasets from 182 research projects, including 6 organs in 21 vertebrate species. Quality control eliminates project-specific biases, and expression shifts are reconstructed using gene-family-wise phylogenetic Ornstein-Uhlenbeck models. Expression shifts following gene duplication result in more drastic changes in expression properties than shifts without gene duplication. The expression properties are tightly coupled with protein evolutionary rate, depending on whether and how gene duplication occurred. Fluxes in expression patterns among organs are nonrandom, forming modular connections that are reshaped by gene duplication. Thus, if expression shifts, ancestral expression in some organs induces a strong propensity for expression in particular organs in descendants. Regardless of whether the shifts are adaptive or not, this supports a major role for what might be termed preadaptive pathways of gene expression evolution.


Assuntos
Evolução Molecular , Transcriptoma , Animais , Bases de Dados de Ácidos Nucleicos , Feminino , Duplicação Gênica , Humanos , Masculino , Modelos Genéticos , Família Multigênica , Especificidade de Órgãos , Filogenia , Proteínas/genética , RNA-Seq , Especificidade da Espécie , Vertebrados/classificação , Vertebrados/genética
3.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32938777

RESUMO

BACKGROUND AND OBJECTIVES: Genetic testing is recommended for individuals with autism spectrum disorder (ASD). Pathogenic yield varies by clinician and/or patient characteristics. Our objectives were to determine the pathogenic yield of genetic testing, the variability in rate of pathogenic results based on subject characteristics, and the percentage of pathogenic findings resulting in further medical recommendations in toddlers with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ASD. METHODS: We conducted a retrospective chart review of 500 toddlers, 18 to 36 months, diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (mean age: 25.8 months, 79% male). Subject demographics, medical and neuropsychological characteristics, and genetic test results were abstracted. Genetic results were divided into negative or normal, variants of unknown significance, and pathogenic. Subject characteristics were compared across results. Manual chart review determined if further recommendations were made after pathogenic results. RESULTS: Over half of subjects (59.8%, n = 299) completed genetic testing, and of those, 36 (12.0%) had pathogenic findings. There were no significant differences in Bayley Scales of Infant Development cognitive (P = .112), language (P = .898), or motor scores (P = .488) among children with negative or normal findings versus a variant of unknown significance versus pathogenic findings. Medical recommendations in response to the genetic finding were made for 72.2% of those with pathogenic results. CONCLUSIONS: Our findings reinforce the importance of genetic testing for toddlers diagnosed with ASD given the 12% yield and lack of phenotypic differences between subjects with and without pathogenic findings. The majority of pathogenic results lead to further medical recommendations.


Assuntos
Transtorno do Espectro Autista/genética , Testes Genéticos/estatística & dados numéricos , Transtorno do Espectro Autista/diagnóstico , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Pré-Escolar , Cromossomos Humanos 13-15 , Cognição , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Proteína do X Frágil de Retardo Mental/genética , Deleção de Genes , Duplicação Gênica , Testes Genéticos/métodos , Humanos , Lactente , Desenvolvimento da Linguagem , Masculino , Análise em Microsséries , Mosaicismo , Destreza Motora , Mutação , Fenótipo , Encaminhamento e Consulta , Estudos Retrospectivos
4.
Am J Bot ; 107(8): 1148-1164, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32830865

RESUMO

PREMISE: Whole-genome duplications (WGDs) are prevalent throughout the evolutionary history of plants. For example, dozens of WGDs have been phylogenetically localized across the order Brassicales, specifically, within the family Brassicaceae. A WGD event has also been identified in the Cleomaceae, the sister family to Brassicaceae, yet its placement, as well as that of WGDs in other families in the order, remains unclear. METHODS: Phylo-transcriptomic data were generated and used to infer a nuclear phylogeny for 74 Brassicales taxa. Genome survey sequencing was also performed on 66 of those taxa to infer a chloroplast phylogeny. These phylogenies were used to assess and confirm relationships among the major families of the Brassicales and within Brassicaceae. Multiple WGD inference methods were then used to assess the placement of WGDs on the nuclear phylogeny. RESULTS: Well-supported chloroplast and nuclear phylogenies for the Brassicales and the putative placement of the Cleomaceae-specific WGD event Th-ɑ are presented. This work also provides evidence for previously hypothesized WGDs, including a well-supported event shared by at least two members of the Resedaceae family, and a possible event within the Capparaceae. CONCLUSIONS: Phylogenetics and the placement of WGDs within highly polyploid lineages continues to be a major challenge. This study adds to the conversation on WGD inference difficulties by demonstrating that sampling is especially important for WGD identification and phylogenetic placement. Given its economic importance and genomic resources, the Brassicales continues to be an ideal group for assessing WGD inference methods.


Assuntos
Duplicação Gênica , Magnoliopsida/genética , Evolução Molecular , Genoma , Genoma de Planta/genética , Humanos , Filogenia , Poliploidia
6.
DNA Cell Biol ; 39(10): 1850-1861, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32790504

RESUMO

Strigolactones (SLs) are the major plant hormones that play important roles in regulating organ development and environmental stress tolerance in plants. Even though the SL-related genes have been identified and well characterized in some plants, the information of SL-related genes in soybean is not fully established yet, especially in response to salt and alkaline stresses. In this study, we identified nine SL biosynthetic genes that include two D27, two CCD7, two CCD8, and three MAX1, as well as seven SL signaling genes that comprised two D14, two MAX2, and three D53 in the soybean genome. We found that SL biosynthetic and signaling genes are evolutionary conserved among different species. Syntenic analysis of these genes revealed their location on nine chromosomes as well as the presence of 10 pairs of duplication genes. Moreover, plant hormone and stress-responsive elements were identified in the promoter regions of SL biosynthetic and signaling genes. By using reverse transcription quantitative real-time PCR, we confirmed that SL genes have different tissue expressions in roots, stems, and leaves. The expression profile of SL biosynthetic and signaling genes under salt and alkaline stresses further confirmed the regulatory roles of SL biosynthetic and signaling genes under stress. In conclusion, we identified and provided valuable information on the soybean SL biosynthetic and signaling genes, and established a foundation for further functional analysis of soybean SL-related genes in response to salt and alkaline stresses.


Assuntos
Compostos Heterocíclicos com 3 Anéis/metabolismo , Lactonas/metabolismo , Proteínas de Plantas/genética , Estresse Salino , Soja/genética , Cromossomos de Plantas/genética , Duplicação Gênica , Proteínas de Plantas/metabolismo , Transdução de Sinais , Soja/metabolismo , Sintenia
7.
Plant Mol Biol ; 104(1-2): 81-95, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621166

RESUMO

KEY MESSAGE: Genome-wide identification of WD40-like genes reveals a duplication of COP1-like genes, one of the key players involved in regulation of flowering time and photomorphogenesis, with strong functional diversification in Rosaceae. WD40 proteins play crucial roles in a broad spectrum of developmental and physiological processes. Here, we conducted a systematic characterization of this family of genes in Rosa chinensis 'Old Blush' (OB), a founder genotype for modern rose domestication. We identified 187 rose WD40 genes and classified them into 5 clusters and 15 subfamilies with 11 of RcWD40s presumably generated via tandem duplication. We found RcWD40 genes were expressed differentially following stages of vegetative and reproductive development. We detected a duplication of CONSTITUTIVE PHOTOMORPHOGENIC1-like genes in rose (RcCOP1 and RcCOP1L) and other Rosaceae plants. Featuring a distinct expression pattern and a different profile of cis-regulatory-elements in the transcriptional regulatory regions, RcCOP1 seemed being evolutionarily conserved while RcCOP1L did not dimerize with RcHY5 and RcSPA4. Our data thus reveals a functional diversification of COP1-like genes in Rosacaeae plants, and provides a valuable resource to explore the potential function and evolution of WD40-like genes in Rosaceae plants.


Assuntos
Genes de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Rosaceae/genética , Rosaceae/metabolismo , Ubiquitina-Proteína Ligases/genética , Sequência de Aminoácidos , Arabidopsis/genética , Arabidopsis/metabolismo , Cromossomos de Plantas/genética , Domesticação , Duplicação Gênica , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Filogenia , Plantas Geneticamente Modificadas , Rosa/genética , Rosa/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
8.
BMC Evol Biol ; 20(1): 91, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727363

RESUMO

BACKGROUND: The SIAMESE (SIM) locus is a cell-cycle kinase inhibitor (CKI) gene that has to date been identified only in plants; it encodes a protein that promotes transformation from mitosis to endoreplication. Members of the SIAMESE-RELATED (SMR) family have similar functions, and some are related to cell-cycle responses and abiotic stresses. However, the functions of SMRs are poorly understood in maize (Zea mays L.). RESULTS: In the present study, 12 putative SMRs were identified throughout the entire genome of maize, and these were clustered into six groups together with the SMRs from seven other plant species. Members of the ZmSMR family were divided into four groups according to their protein sequences. Various cis-acting elements in the upstream sequences of ZmSMRs responded to abiotic stresses. Expression analyses revealed that all ZmSMRs were upregulated at 5, 20, 25, and 35 days after pollination. In addition, we found that ZmSMR9/11/12 may have regulated the initiation of endoreplication in endosperm central cells. Additionally, ZmSMR2/10 may have been primarily responsible for the endoreplication regulation of outer endosperm or aleurone cells. The relatively high expression levels of almost all ZmSMRs in the ears and tassels also implied that these genes may function in seed development. The effects of treatments with ABA, heat, cold, salt, and drought on maize seedlings and expression of ZmSMR genes suggested that ZmSMRs were strongly associated with response to abiotic stresses. CONCLUSION: The present study is the first to conduct a genome-wide analysis of members of the ZmSMR family by investigating their locations in chromosomes, identifying regulatory elements in their promoter regions, and examining motifs in their protein sequences. Expression analysis of different endosperm developmental periods, tissues, abiotic stresses, and hormonal treatments suggests that ZmSMR genes may function in endoreplication and regulate the development of reproductive organs. These results may provide valuable information for future studies of the functions of the SMR family in maize.


Assuntos
Evolução Molecular , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Família Multigênica , Zea mays/genética , Sequência de Aminoácidos , Sequência de Bases , Cromossomos de Plantas/genética , Sequência Conservada/genética , Endosperma/genética , Duplicação Gênica , Genes de Plantas , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Regiões Promotoras Genéticas/genética , Análise de Regressão , Especificidade da Espécie , Estresse Fisiológico/efeitos dos fármacos , Sintenia/genética
9.
RNA ; 26(10): 1464-1480, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32631843

RESUMO

Many eukaryotes use RNA processing, including alternative splicing, to express multiple gene products from the same gene. The budding yeast Saccharomyces cerevisiae has been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. Alternative splicing of SKI7/HBS1 is widely conserved, but yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated, unspliced genes as part of a whole genome doubling (WGD). We show that other examples of alternative splicing known to have functional consequences are widely conserved within Saccharomycotina. A common mechanism by which alternative splicing has disappeared is by replacement of an alternatively spliced gene with duplicate unspliced genes. This loss of alternative splicing does not always take place soon after duplication, but can take place after sufficient time has elapsed for speciation. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently than S. cerevisiae, suggesting that WGD is a major reason for infrequent alternative splicing in yeast. We anticipate that WGDs in other lineages may have had the same effect. Having observed that two functionally distinct splice-isoforms are often replaced by duplicated genes allowed us to reverse the reasoning. We thereby identify several splice isoforms that are likely to produce two functionally distinct proteins because we find them replaced by duplicated genes in related species. We also identify some alternative splicing events that are not conserved in closely related species and unlikely to produce functionally distinct proteins.


Assuntos
Processamento Alternativo/genética , Proteoma/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Saccharomycetales/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Evolução Molecular , Duplicação Gênica/genética , Genoma/genética , Isoformas de Proteínas/genética
10.
PLoS Genet ; 16(6): e1008471, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32525879

RESUMO

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. We surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice: Mus caroli, M. cervicolor, and M. cookii. The presence of flanking repeats suggested it arose by LINE-mediated retroduplication within their most recent common ancestor. A high degree of natural variation was observed in both Fv1 and Fv7 and, on top of positive selection at certain residues, insertions and deletions were present that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes, with activities directed against gamma-, spuma-, and lentiviruses. It seems likely, at least in the case of M. caroli, that the observed gene duplication may expand the breadth of restriction beyond the capacity of Fv1 alone and that one or more such viruses have recently driven or continue to drive the evolution of the Fv1 and Fv7 genes.


Assuntos
Evolução Molecular , Duplicação Gênica , Camundongos/genética , Proteínas/genética , Infecções por Retroviridae/genética , Animais , Resistência à Doença/genética , Camundongos/virologia , Retroviridae/patogenicidade , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/virologia
11.
PLoS One ; 15(6): e0234411, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511257

RESUMO

The AINTEGUMENTA-like (AIL) proteins, which belong to the AP2 family, play important roles in regulating the growth and development of plant organs. The AIL family has not yet been comprehensively studied in rapeseed (Brassica napus), an allotetraploid and model organism for the study of polyploid evolution. In the present study, 99 AIL family genes were identified and characterized from B. rapa, B. oleracea, B. napus, B. juncea, and B. nigra using a comprehensive genome-wide study, including analyses of phylogeny, gene structure, chromosomal localization, and expression pattern. Using a phylogenetic analysis, the AIL genes were divided into eight groups, which were closely related to the eight AtAIL genes, and which shared highly conserved structural features within the same subfamily. The non-synonymous/synonymous substitution ratios of the paralogs and orthologs were less than 1, suggesting that the AIL genes mainly experienced purifying selection during evolution. In addition, the RNA sequencing data and qRT-PCR analysis revealed that the B. napus AIL genes exhibited organ- and developmental stage-specific expression patterns. Certain genes were highly expressed in the developing seeds (BnaAIL1, BnaAIL2, BnaAIL5, and BnaAIL6), the roots (BnaANT, BnaAIL5, and BnaAIL6), and the stem (BnaAIL7B). Our results provide valuable information for further functional analysis of the AIL family in B. napus and related Brassica species.


Assuntos
Brassica napus/genética , Brassica/genética , Genes de Plantas , Sequência de Aminoácidos , Proteínas de Arabidopsis/genética , Brassica/crescimento & desenvolvimento , Brassica napus/crescimento & desenvolvimento , Mapeamento Cromossômico , Sequência Conservada , Duplicação Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Proteínas de Homeodomínio/genética , Família Multigênica , Filogenia , Proteínas de Plantas/genética , Sintenia
12.
Science ; 368(6498): 1424-1425, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32587005
13.
Mol Genet Genomics ; 295(5): 1281-1294, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32564135

RESUMO

The tripartite motif (TRIM) gene family encodes diverse distinct proteins that play important roles in many biological processes. However, the molecular evolution and phylogenetic relationships of TRIM genes in primates are still elusive. We performed a genomic approach to identify and characterize TRIM genes in human and other six primate genomes. In total, 537 putative functional TRIM genes were identified and TRIM members varied among primates. A neighbor joining (NJ) tree based on the protein sequences of 82 human TRIM genes indicates seven TRIM groups, which is consistent with the results based on the architectural motifs. Many TRIM gene duplication events were identified, indicating a recent expansion of TRIM family in primate lineages. Interestingly, the chimpanzee genome shows the greatest TRIM gene expansion among the primates; however, its congeneric species, bonobo, has the least number of TRIM genes and no duplication event. Moreover, we identified a ~ 200 kb deletion on chromosome 11 of bonobos that results in a loss of cluster3 TRIM genes. The loss of TRIM genes might have occurred within the last 2 mys. Analysis of positive selection recovered 9 previously reported and 21 newly identified positively selected TRIM genes. In particular, most positive selected sites are located in the B30.2 domains. Our results have provided new insight into the evolution of primate TRIM genes and will broaden our understanding on the functions of the TRIM family.


Assuntos
Genômica/métodos , Primatas/genética , Proteínas com Motivo Tripartido/genética , Animais , Evolução Molecular , Duplicação Gênica , Gorilla gorilla/genética , Humanos , Macaca/genética , Família Multigênica , Pan paniscus/genética , Pan troglodytes/genética , Filogenia , Seleção Genética , Deleção de Sequência
14.
Gene ; 756: 144915, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32580009

RESUMO

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are key enzymes in the process of phosphatidylinositol signaling pathway and have essential functions in growth, development, and biotic and abiotic stresses responses in plants. However, the evolutionary history and patterns of PIP5K genes in plants have not been examined systematically. Here, we use whole-genome sequences from eight plant species of land plants and algae to define the evolutionary relationships between these proteins in plants. 85 PIP5K genes were identified and divided into two subfamilies based on phylogenetic analyses. PIP5K members in subfamily II underwent several duplication events in land plants, resulting in multiple gene copies in angiosperms, while PIP5K members in subfamily I displayed low-copy numbers and lost in eudicots. Furthermore, PIP5K genes within the same subfamily had similar motifs and intron/exon features. Nine duplicated soybean gene pairs, four duplicated Arabidopsis gene pairs and two rice duplicated gene pairs were identified and many of them localized in synteny genomic regions. These duplicate events were formed by Whole-genome duplication (WGD)/segmental duplications. In addition, the ratios of non-synonymous to synonymous substitutions (Ka/Ks) showed that the PIP5K family had undergone purifying selection in higher plants. Expression analysis showed that PIP5K genes had complex and variable expression patterns in different developmental stages. The specificity of these genes is utilized to provide evidence for selective expression in the evolutionary process.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)/genética , Plantas/enzimologia , Cromossomos de Plantas , Evolução Molecular , Duplicação Gênica , Especiação Genética , Genoma de Planta , Filogenia , Plantas/classificação , Plantas/genética
15.
Gene ; 754: 144818, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32485308

RESUMO

Plants are continuously exposed to agents that can generate DNA lesions. Nucleotide Excision Repair (NER) is one of the repair pathways employed by plants to protect their genome, including from sunlight. The Xeroderma Pigmentosum type B (XPB) protein is a DNA helicase shown to be involved in NER and is also an essential subunitof the Transcription Factor IIH (TFIIH) complex. XPB was found to be a single copy gene in eukaryotes, but found as a tandem duplication in the plant Arabidopsis thaliana, AtXPB1 and AtXPB2. We aimed to investigate whether the XPB in tandem duplication was common within members of the Brassicaceae. We analyzed genomic DNA of species from different tribes of the family and the results indicate that the tandem duplication occurred in Camelineae tribe ancestor, of which A. thaliana belongs, at approximately 8 million years ago. Further experiments were devised to study possible functional roles for the A. thaliana AtXPB paralogs. A non-coincident expression profile of the paralogs was observed in various plant organs, developmental and cell cycle stages. AtXPB2 expression was observed in proliferating cells and clustered with the transcription of other components of the TFIIH such as p44, p52 and XPD/UVH6 along the cell cycle. AtXPB1 gene transcription, on the other hand, was enhanced specifically after UV-B irradiation in leaf trichomes. Altogether, our results reported herein suggest a functional specialization for the AtXPB paralogs: while the AtXPB2 paralog may have a role in cell proliferation and repair as XPB of other eukaryotes, the AtXPB1 paralog is most likely implicated in repair functions in highly specialized A. thaliana cells.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Dano ao DNA , Reparo do DNA/genética , Duplicação Gênica , Fatores de Transcrição/metabolismo , Proteínas de Arabidopsis/genética , Ciclo Celular , Fator de Transcrição TFIIH/genética , Fator de Transcrição TFIIH/metabolismo , Fatores de Transcrição/genética , Raios Ultravioleta
16.
Gene ; 754: 144847, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32531456

RESUMO

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.


Assuntos
Anticonvulsivantes/efeitos adversos , Síndrome de Brugada/patologia , Epilepsia/tratamento farmacológico , Duplicação Gênica , Lamotrigina/efeitos adversos , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Adulto , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/genética , Epilepsia/genética , Epilepsia/patologia , Humanos , Masculino
17.
PLoS One ; 15(6): e0234782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559249

RESUMO

A functional Non-Tandem Duplicated Cluster (FNTDC) is a group of non-tandem-duplicated genes that are located closer than expected by mere chance and have a role in the same biological function. The identification of secondary-compounds-related FNTDC has gained increased interest in recent years, but little ab-initio attempts aiming to the identification of FNTDCs covering all biological functions, including primary metabolism compounds, have been carried out. We report an extensive FNTDC dataset accompanied by a detailed assessment on parameters used for genome scanning and their impact on FNTDC detection. We propose 70% identity and 70% alignment coverage as intermediate settings to exclude tandem duplicated genes and a dynamic scanning window of 24 genes. These settings were applied to rice, arabidopsis and grapevine genomes to call for FNTDCs. Besides the best-known secondary metabolism clusters, we identified many FNTDCs associated to primary metabolism ranging from macromolecules synthesis/editing, TOR signalling, ubiquitination, proton and electron transfer complexes. Using the intermediate FNTDC setting parameters (at P-value 1e-6), 130, 70 and 140 candidate FNTDCs were called in rice, arabidopsis and grapevine, respectively, and 20 to 30% of GO tags associated to called FNTDC were common among the 3 genomes. The datasets developed along with this work provide a rich framework for pinpointing candidate FNTDCs reflecting all GO-BP tags covering both primary and secondary metabolism with large macromolecular complexes/metabolons as the most represented FNTDCs. Noteworthy, several FNTDCs are tagged with GOs referring to organelle-targeted multi-enzyme complex, a finding that suggest the migration of endosymbiont gene chunks towards nuclei could be at the basis of these class of candidate FNTDCs. Most FNTDC appear to have evolved prior of genome duplication events. More than one-third of genes interspersed/adjacent to called FNTDCs lacked any functional annotation; however, their co-localization may provide hints towards a candidate biological role.


Assuntos
Arabidopsis/genética , Ontologia Genética , Genoma de Planta , Oryza/genética , Vitis/genética , Bases de Dados Genéticas , Diploide , Duplicação Gênica , Família Multigênica , Proteínas de Plantas/genética , Transdução de Sinais
18.
Hum Genet ; 139(11): 1417-1427, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32488466

RESUMO

An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent 8p inv-dup-del cases harbored a large copy-number-neutral region between the duplication and deletion in common. Although the other non-recurrent cases did not appear to have this copy-number-neutral region, refined sequencing analysis identified that they contained a small intervening region at the junction between the inverted and non-inverted segment. The size of this small intervening region ranged from 1741 to 3728 bp. Combined with a presence of microhomology at the junction, a resolution of the replication fork stalling through template switching within the same replication fork is suggested. We further observed two cases with mosaicism of the dicentric chromosome and various structural rearrangements related to the dicentric chromosome. Refined analysis allowed us to identify different breakpoints on the same chromosome in the same case, implicating multiple rounds of U-type formation and its breakage. From these results, we propose that a replication-based mechanism generates unstable dicentric chromosomes and that their breakage leads to the formation of inv-dup-dels and other related derivative chromosomes.


Assuntos
Transtornos Cromossômicos/genética , Inversão Cromossômica/genética , Cromossomos/genética , Duplicação Gênica/genética , Deleção de Sequência/genética , Deleção Cromossômica , Replicação do DNA/genética , Humanos , Mosaicismo
19.
Ann Bot ; 126(3): 363-376, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32504537

RESUMO

BACKGROUND AND AIMS: Whole-genome duplication is known to influence ecological interactions and plant physiology; however, despite abundant case studies, much is still unknown about the typical impact of genome duplication on plant secondary metabolites (PSMs). In this study, we assessed the impact of polyploidy events on PSM characteristics in non-cultivated plants. METHODS: We conducted a systematic review and meta-analysis to compare composition and concentration of PSMs among closely related plant species or species complexes differing in ploidy level. KEY RESULTS: We assessed 53 studies that focus on PSMs among multiple cytotypes, of which only 14 studies compared concentration quantitatively among cytotypes. We found that whole-genome duplication can have a significant effect on PSM concentration; however, these effects are highly inconsistent. CONCLUSION: Overall, there was no consistent effect of whole-genome duplication on PSM concentrations or profiles.


Assuntos
Duplicação Gênica , Genoma de Planta/genética , Humanos , Plantas/genética , Ploidias , Poliploidia
20.
Science ; 368(6498)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586993

RESUMO

Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.


Assuntos
Duplicação Gênica , Genes Duplicados , Genoma Fúngico , Mapas de Interação de Proteínas/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Deleção de Genes , Redes Reguladoras de Genes , Técnicas Genéticas , Proteínas de Membrana/genética , Peroxinas/genética
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