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1.
Life Sci Alliance ; 6(7)2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37137707

RESUMEN

Recursive splicing is a non-canonical splicing mechanism in which an intron is removed in segments via multiple splicing reactions. Relatively few recursive splice sites have been identified with high confidence in human introns, and more comprehensive analyses are needed to better characterize where recursive splicing happens and whether or not it has a regulatory function. In this study, we use an unbiased approach using intron lariats to search for recursive splice sites in constitutive introns and alternative exons in the human transcriptome. We find evidence for recursive splicing in a broader range of intron sizes than previously reported and detail a new location for recursive splicing at the distal ends of cassette exons. In addition, we identify evidence for the conservation of these recursive splice sites among higher vertebrates and the use of these sites to influence alternative exon exclusion. Together, our data demonstrate the prevalence of recursive splicing and its potential influence on gene expression through alternatively spliced isoforms.


Asunto(s)
Sitios de Empalme de ARN , Empalme del ARN , Animales , Humanos , Sitios de Empalme de ARN/genética , Empalme del ARN/genética , Isoformas de Proteínas/genética , Intrones/genética , Análisis de Secuencia de ARN
2.
Blood Cancer Discov ; 2(5): 500-517, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34568833

RESUMEN

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.


Asunto(s)
Hematopoyesis Clonal , Síndromes Mielodisplásicos , Animales , Hematopoyesis/genética , Células Madre Hematopoyéticas , Humanos , Ratones , Síndromes Mielodisplásicos/genética , Empalme del ARN/genética , Factores de Transcripción/genética
3.
Nat Genet ; 52(1): 84-94, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31911676

RESUMEN

While RNA-seq has enabled comprehensive quantification of alternative splicing, no correspondingly high-throughput assay exists for functionally interrogating individual isoforms. We describe pgFARM (paired guide RNAs for alternative exon removal), a CRISPR-Cas9-based method to manipulate isoforms independent of gene inactivation. This approach enabled rapid suppression of exon recognition in polyclonal settings to identify functional roles for individual exons, such as an SMNDC1 cassette exon that regulates pan-cancer intron retention. We generalized this method to a pooled screen to measure the functional relevance of 'poison' cassette exons, which disrupt their host genes' reading frames yet are frequently ultraconserved. Many poison exons were essential for the growth of both cultured cells and lung adenocarcinoma xenografts, while a subset had clinically relevant tumor-suppressor activity. The essentiality and cancer relevance of poison exons are likely to contribute to their unusually high conservation and contrast with the dispensability of other ultraconserved elements for viability.


Asunto(s)
Adenocarcinoma del Pulmón/patología , Empalme Alternativo , Exones/genética , Genes Supresores de Tumor , Isoformas de ARN/genética , Factores de Empalme de ARN/genética , ARN Mensajero/genética , Proteínas del Complejo SMN/genética , Adenocarcinoma del Pulmón/genética , Animales , Proliferación Celular , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Science ; 360(6393)2018 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-29880660

RESUMEN

Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly and full-length complementary DNA sequencing with a multiplatform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. By comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single- to mega-base pair-sized variants. We identified ~17,000 fixed human-specific structural variants identifying genic and putative regulatory changes that have emerged in humans since divergence from nonhuman apes. Interestingly, these variants are enriched near genes that are down-regulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.


Asunto(s)
Evolución Molecular , Genoma Humano , Hominidae/genética , Animales , Mapeo Contig , Variación Genética , Humanos , Anotación de Secuencia Molecular , Análisis de Secuencia de ADN
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