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1.
PLoS Biol ; 16(7): e2006348, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30059545

RESUMO

While short-read sequencing technology has resulted in a sharp increase in the number of species with genome assemblies, these assemblies are typically highly fragmented. Repeats pose the largest challenge for reference genome assembly, and pericentromeric regions and the repeat-rich Y chromosome are typically ignored from sequencing projects. Here, we assemble the genome of Drosophila miranda using long reads for contig formation, chromatin interaction maps for scaffolding and short reads, and optical mapping and bacterial artificial chromosome (BAC) clone sequencing for consensus validation. Our assembly recovers entire chromosomes and contains large fractions of repetitive DNA, including about 41.5 Mb of pericentromeric and telomeric regions, and >100 Mb of the recently formed highly repetitive neo-Y chromosome. While Y chromosome evolution is typically characterized by global sequence loss and shrinkage, the neo-Y increased in size by almost 3-fold because of the accumulation of repetitive sequences. Our high-quality assembly allows us to reconstruct the chromosomal events that have led to the unusual sex chromosome karyotype in D. miranda, including the independent de novo formation of a pair of sex chromosomes at two distinct time points, or the reversion of a former Y chromosome to an autosome.


Assuntos
Cromatina/química , Drosophila/genética , Conformação de Ácido Nucleico , Análise de Sequência de DNA , Cromossomo Y/genética , Animais , Sequência de Bases , Centrômero/metabolismo , Evolução Molecular , Genes de Insetos , Cariótipo , Masculino , Sequências Repetitivas de Ácido Nucleico/genética , Reprodutibilidade dos Testes
2.
PLoS Genet ; 12(12): e1006464, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27935948

RESUMO

Alternative pre-mRNA splicing ("AS") greatly expands proteome diversity, but little is known about the evolutionary landscape of AS in Drosophila and how it differs between embryonic and adult stages or males and females. Here we study the transcriptomes from several tissues and developmental stages in males and females from four species across the Drosophila genus. We find that 20-37% of multi-exon genes are alternatively spliced. While males generally express a larger number of genes, AS is more prevalent in females, suggesting that the sexes adopt different expression strategies for their specialized function. While the number of total genes expressed increases during early embryonic development, the proportion of expressed genes that are alternatively spliced is highest in the very early embryo, before the onset of zygotic transcription. This indicates that females deposit a diversity of isoforms into the egg, consistent with abundant AS found in ovary. Cluster analysis by gene expression ("GE") levels shows mostly stage-specific clustering in embryonic samples, and tissue-specific clustering in adult tissues. Clustering embryonic stages and adult tissues based on AS profiles results in stronger species-specific clustering, suggesting that diversification of splicing contributes to lineage-specific evolution in Drosophila. Most sex-biased AS found in flies is due to AS in gonads, with little sex-specific splicing in somatic tissues.


Assuntos
Processamento Alternativo/genética , Proteínas de Drosophila/biossíntese , Drosophila/genética , Desenvolvimento Embrionário/genética , Evolução Molecular , Animais , Drosophila/classificação , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/genética , Éxons/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Masculino , Especificidade de Órgãos , Isoformas de Proteínas , Especificidade da Espécie
3.
Mol Brain ; 17(1): 26, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778381

RESUMO

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.


Assuntos
Neurônios , Doença de Parkinson , Agregados Proteicos , Proteômica , Proteostase , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Animais , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Mapas de Interação de Proteínas , Proteoma/metabolismo
4.
Sci Rep ; 11(1): 2879, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536571

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.


Assuntos
Doença de Alzheimer/genética , Autofagia/genética , Modelos Genéticos , Agregação Patológica de Proteínas/genética , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Engenharia Genética , Humanos , Aprendizado de Máquina , Mitocôndrias/genética , Mitocôndrias/patologia , Neurônios , Agregação Patológica de Proteínas/patologia , Transdução de Sinais/genética
5.
Nat Commun ; 11(1): 5537, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139741

RESUMO

Large portions of eukaryotic genomes consist of transposable elements (TEs), and the establishment of transcription-repressing heterochromatin during early development safeguards genome integrity in Drosophila. Repeat-rich Y chromosomes can act as reservoirs for TEs ('toxic' Y effect), and incomplete epigenomic defenses during early development can lead to deleterious TE mobilization. Here, we contrast the dynamics of early TE activation in two Drosophila species with vastly different Y chromosomes of different ages. Zygotic TE expression is elevated in male embryos relative to females in both species, mostly due to expression of Y-linked TEs. Interestingly, male-biased TE expression diminishes across development in D. pseudoobscura, but remains elevated in D. miranda, the species with the younger and larger Y chromosome. The repeat-rich Y of D. miranda still contains many actively transcribed genes, which compromise the formation of silencing heterochromatin. Elevated TE expression results in more de novo insertions of repeats in males compared to females. This lends support to the idea that the 'toxic' Y chromosome can create a mutational burden in males when genome-wide defense mechanisms are compromised, and suggests a previously unappreciated epigenetic conflict on evolving Y chromosomes between transcription of essential genes and silencing of selfish DNA.


Assuntos
Elementos de DNA Transponíveis/genética , Drosophila/genética , Inativação Gênica , Transcrição Gênica , Cromossomo Y/metabolismo , Animais , Feminino , Heterocromatina/metabolismo , Modelos Lineares , Masculino , Modelos Genéticos , Mutação , Fatores Sexuais , Zigoto
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