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1.
Phys Rev Lett ; 126(3): 038102, 2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-33543960

RESUMEN

-1 programmed ribosomal frameshifting (-1 PRF) is stimulated by structures in messenger RNA (mRNA), but the factors determining -1 PRF efficiency are unclear. We show that -1 PRF efficiency varies directly with the conformational heterogeneity of the stimulatory structure, quantified as the Shannon entropy of the state occupancy, for a panel of stimulatory structures with efficiencies from 2% to 80%. The correlation is force dependent and vanishes at forces above those applied by the ribosome. These results support the hypothesis that heterogeneous conformational dynamics are a key factor in stimulating -1 PRF.


Asunto(s)
Sistema de Lectura Ribosómico , Modelos Genéticos , ARN Mensajero/química , ARN Mensajero/genética , Simulación por Computador , Entropía , Humanos , Microscopía de Fuerza Atómica/métodos , Conformación de Ácido Nucleico
2.
BMC Bioinformatics ; 22(1): 50, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33546598

RESUMEN

BACKGROUND: In the last decade, Genome-wide Association studies (GWASs) have contributed to decoding the human genome by uncovering many genetic variations associated with various diseases. Many follow-up investigations involve joint analysis of multiple independently generated GWAS data sets. While most of the computational approaches developed for joint analysis are based on summary statistics, the joint analysis based on individual-level data with consideration of confounding factors remains to be a challenge. RESULTS: In this study, we propose a method, called Coupled Mixed Model (CMM), that enables a joint GWAS analysis on two independently collected sets of GWAS data with different phenotypes. The CMM method does not require the data sets to have the same phenotypes as it aims to infer the unknown phenotypes using a set of multivariate sparse mixed models. Moreover, CMM addresses the confounding variables due to population stratification, family structures, and cryptic relatedness, as well as those arising during data collection such as batch effects that frequently appear in joint genetic studies. We evaluate the performance of CMM using simulation experiments. In real data analysis, we illustrate the utility of CMM by an application to evaluating common genetic associations for Alzheimer's disease and substance use disorder using datasets independently collected for the two complex human disorders. Comparison of the results with those from previous experiments and analyses supports the utility of our method and provides new insights into the diseases. The software is available at https://github.com/HaohanWang/CMM .


Asunto(s)
Estudio de Asociación del Genoma Completo , Fenotipo , Programas Informáticos , Algoritmos , Humanos , Modelos Genéticos , Polimorfismo de Nucleótido Simple
3.
J Anim Sci ; 99(2)2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33544869

RESUMEN

The stability of genomic evaluations depends on the amount of data and population parameters. When the dataset is large enough to estimate the value of nearly all independent chromosome segments (~10K in American Angus cattle), the accuracy and persistency of breeding values will be high. The objective of this study was to investigate changes in estimated breeding values (EBV) and genomic EBV (GEBV) across monthly evaluations for 1 yr in a large genotyped population of beef cattle. The American Angus data used included 8.2 million records for birth weight, 8.9 for weaning weight, and 4.4 for postweaning gain. A total of 10.1 million animals born until December 2017 had pedigree information, and 484,074 were genotyped. A truncated dataset included animals born until December 2016. To mimic a scenario with monthly evaluations, 2017 data were added 1 mo at a time to estimate EBV using best linear unbiased prediction (BLUP) and GEBV using single-step genomic BLUP with the algorithm for proven and young (APY) with core group fixed for 1 yr or updated monthly. Predictions from monthly evaluations in 2017 were contrasted with the predictions of the evaluation in December 2016 or the previous month for all genotyped animals born until December 2016 with or without their own phenotypes or progeny phenotypes. Changes in EBV and GEBV were similar across traits, and only results for weaning weight are presented. Correlations between evaluations from December 2016 and the 12 consecutive evaluations were ≥0.97 for EBV and ≥0.99 for GEBV. Average absolute changes for EBV were about two times smaller than for GEBV, except for animals with new progeny phenotypes (≤0.12 and ≤0.11 additive genetic SD [SDa] for EBV and GEBV). The maximum absolute changes for EBV (≤2.95 SDa) were greater than for GEBV (≤1.59 SDa). The average(maximum) absolute GEBV changes for young animals from December 2016 to January and December 2017 ranged from 0.05(0.25) to 0.10(0.53) SDa. Corresponding ranges for animals with new progeny phenotypes were from 0.05(0.88) to 0.11(1.59) SDa for GEBV changes. The average absolute change in EBV(GEBV) from December 2016 to December 2017 for sires with ≤50 progeny phenotypes was 0.26(0.14) and for sires with >50 progeny phenotypes was 0.25(0.16) SDa. Updating the core group in APY without adding data created an average absolute change of 0.07 SDa in GEBV. Genomic evaluations in large genotyped populations are as stable and persistent as the traditional genetic evaluations, with less extreme changes.


Asunto(s)
Genoma , Modelos Genéticos , Animales , Bovinos/genética , Femenino , Genómica , Genotipo , Linaje , Fenotipo , Embarazo
4.
Nat Commun ; 12(1): 1050, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594080

RESUMEN

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.


Asunto(s)
Genoma Humano , Filogenia , Adulto , Anciano , Bancos de Muestras Biológicas , Índice de Masa Corporal , Escolaridad , Humanos , Patrón de Herencia/genética , Desequilibrio de Ligamiento , Persona de Mediana Edad , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Carácter Cuantitativo Heredable , Análisis de Regresión , Reino Unido
5.
BMC Bioinformatics ; 22(1): 5, 2021 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-33407064

RESUMEN

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) enables the possibility of many in-depth transcriptomic analyses at a single-cell resolution. It's already widely used for exploring the dynamic development process of life, studying the gene regulation mechanism, and discovering new cell types. However, the low RNA capture rate, which cause highly sparse expression with dropout, makes it difficult to do downstream analyses. RESULTS: We propose a new method SCC to impute the dropouts of scRNA-seq data. Experiment results show that SCC gives competitive results compared to two existing methods while showing superiority in reducing the intra-class distance of cells and improving the clustering accuracy in both simulation and real data. CONCLUSIONS: SCC is an effective tool to resolve the dropout noise in scRNA-seq data. The code is freely accessible at https://github.com/nwpuzhengyan/SCC .


Asunto(s)
Perfilación de la Expresión Génica/métodos , ARN Citoplasmático Pequeño/genética , Análisis de la Célula Individual/métodos , Regulación de la Expresión Génica/genética , Genómica/métodos , Modelos Genéticos
6.
Nat Commun ; 12(1): 315, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436613

RESUMEN

Although it is well established that the Polycomb Group (PcG) complexes maintain gene repression through the incorporation of H2AK121ub and H3K27me3, little is known about the effect of these modifications on chromatin accessibility, which is fundamental to understand PcG function. Here, by integrating chromatin accessibility, histone marks and expression analyses in different Arabidopsis PcG mutants, we show that PcG function regulates chromatin accessibility. We find that H2AK121ub is associated with a less accessible but still permissive chromatin at transcriptional regulation hotspots. Accessibility is further reduced by EMF1 acting in collaboration with PRC2 activity. Consequently, H2AK121ub/H3K27me3 marks are linked to inaccessible although responsive chromatin. In contrast, only-H3K27me3-marked chromatin is less responsive, indicating that H2AK121ub-marked hotspots are required for transcriptional responses. Nevertheless, despite the loss of PcG activities leads to increased chromatin accessibility, this is not necessarily accompanied by transcriptional activation, indicating that accessible chromatin is not always predictive of gene expression.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Cromatina/metabolismo , Regulación de la Expresión Génica de las Plantas , Transcripción Genética , Proteínas de Arabidopsis/genética , Modelos Genéticos , Mutación/genética , Proteínas del Grupo Polycomb/metabolismo , Análisis de Componente Principal , Plantones/metabolismo , Ubiquitina/metabolismo , Ubiquitinación
7.
Nat Commun ; 12(1): 33, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397927

RESUMEN

The Origin Recognition Complex (ORC) is an evolutionarily conserved six-subunit protein complex that binds specific sites at many locations to coordinately replicate the entire eukaryote genome. Though highly conserved in structure, ORC's selectivity for replication origins has diverged tremendously between yeasts and humans to adapt to vastly different life cycles. In this work, we demonstrate that the selectivity determinant of ORC for DNA binding lies in a 19-amino acid insertion helix in the Orc4 subunit, which is present in yeast but absent in human. Removal of this motif from Orc4 transforms the yeast ORC, which selects origins based on base-specific binding at defined locations, into one whose selectivity is dictated by chromatin landscape and afforded with plasticity, as reported for human. Notably, the altered yeast ORC has acquired an affinity for regions near transcriptional start sites (TSSs), which the human ORC also favors.


Asunto(s)
Complejo de Reconocimiento del Origen/metabolismo , Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión , ADN de Hongos/metabolismo , Fase G2/genética , Genoma Fúngico , Humanos , Modelos Genéticos , Mutación/genética , Nucleosomas/metabolismo , Motivos de Nucleótidos/genética , Complejo de Reconocimiento del Origen/química , Fase S , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Procesos Estocásticos , Sitio de Iniciación de la Transcripción
8.
Nat Commun ; 12(1): 41, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397980

RESUMEN

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.


Asunto(s)
Drosophila melanogaster/genética , Genoma de los Insectos , Conformación de Ácido Nucleico , Animales , Biopolímeros/metabolismo , Cromatina/genética , Bases de Datos Genéticas , Epigénesis Genética , Haploidia , Modelos Genéticos , Procesos Estocásticos , Cromosoma X/genética
9.
Nat Commun ; 12(1): 130, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420076

RESUMEN

Homeostasis of protein concentrations in cells is crucial for their proper functioning, requiring steady-state concentrations to be stable to fluctuations. Since gene expression is regulated by proteins such as transcription factors (TFs), the full set of proteins within the cell constitutes a large system of interacting components, which can become unstable. We explore factors affecting stability by coupling the dynamics of mRNAs and proteins in a growing cell. We find that mRNA degradation rate does not affect stability, contrary to previous claims. However, global structural features of the network can dramatically enhance stability. Importantly, a network resembling a bipartite graph with a lower fraction of interactions that target TFs has a higher chance of being stable. Scrambling the E. coli transcription network, we find that the biological network is significantly more stable than its randomized counterpart, suggesting that stability constraints may have shaped network structure during the course of evolution.


Asunto(s)
Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Redes Reguladoras de Genes , Modelos Genéticos , Proteínas de Escherichia coli/metabolismo , ARN Mensajero/metabolismo , Factores de Transcripción/metabolismo
10.
Nat Commun ; 12(1): 537, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483487

RESUMEN

Targeting chromatin regulators to specific genomic locations for gene control is emerging as a powerful method in basic research and synthetic biology. However, many chromatin regulators are large, making them difficult to deliver and combine in mammalian cells. Here, we develop a strategy for gene control using small nanobodies that bind and recruit endogenous chromatin regulators to a gene. We show that an antiGFP nanobody can be used to simultaneously visualize GFP-tagged chromatin regulators and control gene expression, and that nanobodies against HP1 and DNMT1 can silence a reporter gene. Moreover, combining nanobodies together or with other regulators, such as DNMT3A or KRAB, can enhance silencing speed and epigenetic memory. Finally, we use the slow silencing speed and high memory of antiDNMT1 to build a signal duration timer and recorder. These results set the basis for using nanobodies against chromatin regulators for controlling gene expression and epigenetic memory.


Asunto(s)
Cromatina/inmunología , Epigénesis Genética/inmunología , Regulación de la Expresión Génica/inmunología , Regiones Promotoras Genéticas/inmunología , Anticuerpos de Dominio Único/inmunología , Algoritmos , Animales , Cromatina/genética , Silenciador del Gen/inmunología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/inmunología , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Modelos Genéticos , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Anticuerpos de Dominio Único/metabolismo
11.
Nat Commun ; 12(1): 555, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483498

RESUMEN

The ever-expanding set of CRISPR technologies and their programmable RNA-guided nucleases exhibit remarkable flexibility in DNA targeting. However, this flexibility comes with an ever-present constraint: the requirement for a protospacer adjacent motif (PAM) flanking each target. While PAMs play an essential role in self/nonself discrimination by CRISPR-Cas immune systems, this constraint has launched a far-reaching expedition for nucleases with relaxed PAM requirements. Here, we review ongoing efforts toward realizing PAM-free nucleases through natural ortholog mining and protein engineering. We also address potential consequences of fully eliminating PAM recognition and instead propose an alternative nuclease repertoire covering all possible PAM sequences.


Asunto(s)
Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas , Edición Génica/métodos , Motivos de Nucleótidos , ARN Guia/metabolismo , Sitios de Unión/genética , Proteína 9 Asociada a CRISPR/clasificación , Proteína 9 Asociada a CRISPR/genética , Modelos Genéticos , Filogenia , Ingeniería de Proteínas/métodos , ARN Guia/genética
12.
Nat Commun ; 12(1): 520, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483506

RESUMEN

The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5'-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals alternative splicing as an important component of transcriptome re-organization in leukemia by an aberrant transcriptional regulator.


Asunto(s)
Empalme Alternativo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide/genética , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Enfermedad Aguda , Línea Celular Tumoral , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Leucemia Mieloide/patología , Modelos Genéticos , Proteínas de Fusión Oncogénica/metabolismo , Interferencia de ARN , Isoformas de ARN/genética , Isoformas de ARN/metabolismo , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Sitio de Iniciación de la Transcripción
13.
Am J Hum Genet ; 108(1): 68-83, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33385324

RESUMEN

The proportion of samples with one or more close relatives in a genetic dataset increases rapidly with sample size, necessitating relatedness modeling and enabling pedigree-based analyses. Despite this, relatives are generally unreported and current inference methods typically detect only the degree of relatedness of sample pairs and not pedigree relationships. We developed CREST, an accurate and fast method that identifies the pedigree relationships of close relatives. CREST utilizes identity by descent (IBD) segments shared between a pair of samples and their mutual relatives, leveraging the fact that sharing rates among these individuals differ across pedigree configurations. Furthermore, CREST exploits the profound differences in sex-specific genetic maps to classify pairs as maternally or paternally related-e.g., paternal half-siblings-using the locations of autosomal IBD segments shared between the pair. In simulated data, CREST correctly classifies 91.5%-100% of grandparent-grandchild (GP) pairs, 80.0%-97.5% of avuncular (AV) pairs, and 75.5%-98.5% of half-siblings (HS) pairs compared to PADRE's rates of 38.5%-76.0% of GP, 60.5%-92.0% of AV, 73.0%-95.0% of HS pairs. Turning to the real 20,032 sample Generation Scotland (GS) dataset, CREST identified seven pedigrees with incorrect relationship types or maternal/paternal parent sexes, five of which we confirmed as mistakes, and two with uncertain relationships. After correcting these, CREST correctly determines relationship types for 93.5% of GP, 97.7% of AV, and 92.2% of HS pairs that have sufficient mutual relative data; the parent sex in 100% of HS and 99.6% of GP pairs; and it completes this analysis in 2.8 h including IBD detection in eight threads.


Asunto(s)
Genoma Humano/genética , Femenino , Ligamiento Genético/genética , Genotipo , Humanos , Masculino , Modelos Genéticos , Linaje , Escocia
14.
Nat Commun ; 12(1): 223, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431820

RESUMEN

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.


Asunto(s)
Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Transcripción Genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Glicoles/farmacología , Histonas/metabolismo , Humanos , Leucemia/genética , Leucemia/patología , Modelos Genéticos , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética/efectos de los fármacos
15.
Nucleic Acids Res ; 49(2): 879-890, 2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33406239

RESUMEN

Programmed DNA double-strand breaks (DSBs) made during meiosis are repaired by recombination with the homologous chromosome to generate, at selected sites, reciprocal crossovers that are critical for the proper separation of homologs in the first meiotic division. Backup repair processes can compensate when the normal meiotic recombination processes are non-functional. We describe a novel backup repair mechanism that occurs when the homologous chromosome is not available in Drosophila melanogaster meiosis. In the presence of a previously described mutation (Mcm5A7) that disrupts chromosome pairing, DSB repair is initiated by homologous recombination but is completed by non-homologous end joining (NHEJ). Remarkably, this process yields precise repair products. Our results provide support for a recombination intermediate recently proposed in mouse meiosis, in which an oligonucleotide bound to the Spo11 protein that catalyzes DSB formation remains bound after resection. We propose that this oligonucleotide functions as a primer for fill-in synthesis to allow scarless repair by NHEJ. We argue that this is a conserved repair mechanism that is likely to be invoked to overcome occasional challenges in normal meiosis.


Asunto(s)
Proteínas de Ciclo Celular/fisiología , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/genética , Proteínas de Drosophila/fisiología , Drosophila melanogaster/genética , Meiosis/genética , Oligonucleótidos/genética , Animales , Proteínas de Ciclo Celular/genética , Simulación por Computador , Intercambio Genético , ADN Ligasa (ATP)/fisiología , Proteínas de Drosophila/genética , Endodesoxirribonucleasas/fisiología , Femenino , Masculino , Modelos Genéticos , Mutación Missense , Mutación Puntual , Polimorfismo de Nucleótido Simple , Recombinasa Rad51/fisiología , Alineación de Secuencia , Eliminación de Secuencia , Secuenciación Completa del Genoma
16.
Nucleic Acids Res ; 49(2): 847-863, 2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33410915

RESUMEN

Well-differentiated liposarcoma (WDLPS) is a malignant neoplasia hard to diagnose and treat. Its main molecular signature is amplification of the MDM2-containing genomic region. The MDM2 oncogene is the master regulator of p53: its overexpression enhances p53 degradation and inhibits apoptosis, leading to the tumoral phenotype. Here, we show that the MDM2 inducible promoter G-rich region folds into stable G-quadruplexes both in vitro and in vivo and it is specifically recognized by cellular helicases. Cell treatment with G-quadruplex-ligands reduces MDM2 expression and p53 degradation, thus stimulating cancer cell cycle arrest and apoptosis. Structural characterization of the MDM2 G-quadruplex revealed an extraordinarily stable, unique four-tetrad antiparallel dynamic conformation, amenable to selective targeting. These data indicate the feasibility of an out-of-the-box G-quadruplex-targeting approach to defeat WDLPS and all tumours where restoration of wild-type p53 is sought. They also point to G-quadruplex-dependent genomic instability as possible cause of MDM2 expansion and WDLPS tumorigenesis.


Asunto(s)
G-Cuádruplex , Regulación Neoplásica de la Expresión Génica/genética , Liposarcoma/terapia , Terapia Molecular Dirigida , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Neoplasias de los Tejidos Blandos/terapia , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Simulación por Computador , Humanos , Ligandos , Modelos Genéticos , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Mapeo de Interacción de Proteínas , Proteolisis , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , Proteína p53 Supresora de Tumor/metabolismo
17.
Nat Commun ; 12(1): 355, 2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33441561

RESUMEN

The implementation of Boolean logic circuits in cells have become a very active field within synthetic biology. Although these are mostly focussed on the genetic components alone, the context in which the circuit performs is crucial for its outcome. We characterise 20 genetic NOT logic gates in up to 7 bacterial-based contexts each, to generate 135 different functions. The contexts we focus on are combinations of four plasmid backbones and three hosts, two Escherichia coli and one Pseudomonas putida strains. Each gate shows seven different dynamic behaviours, depending on the context. That is, gates can be fine-tuned by changing only contextual parameters, thus improving the compatibility between gates. Finally, we analyse portability by measuring, scoring, and comparing gate performance across contexts. Rather than being a limitation, we argue that the effect of the genetic background on synthetic constructs expands functionality, and advocate for considering context as a fundamental design parameter.


Asunto(s)
Algoritmos , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Modelos Genéticos , Pseudomonas putida/genética , Escherichia coli/citología , Redes Reguladoras de Genes , Lógica , Pseudomonas putida/citología , Especificidad de la Especie , Biología Sintética/métodos
18.
J Anim Sci ; 99(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33507280

RESUMEN

In the pig industry, purebred animals are raised in nucleus herds and selected to produce crossbred progeny to perform in commercial environments. Crossbred and purebred performances are different, correlated traits. All purebreds in a pen have their performance assessed together at the end of a performance test. However, only selected crossbreds are removed (based on visual inspection) and measured at different times creating many small contemporary groups (CGs). This may reduce estimated breeding value (EBV) prediction accuracies. Considering this sequential recording of crossbreds, the objective was to investigate the impact of different CG definitions on genetic parameters and EBV prediction accuracy for crossbred traits. Growth rate (GP) and ultrasound backfat (BFP) records were available for purebreds. Lifetime growth (GX) and backfat (BFX) were recorded on crossbreds. Different CGs were tested: CG_all included farm, sex, birth year, and birth week; CG_week added slaughter week; and CG_day used slaughter day instead of week. Data of 124,709 crossbreds were used. The purebred phenotypes (62,274 animals) included three generations of purebred ancestors of these crossbreds and their CG mates. Variance components for four-trait models with different CG definitions were estimated with average information restricted maximum likelihood. Purebred traits' variance components remained stable across CG definitions and varied slightly for BFX. Additive genetic variances (and heritabilities) for GX fluctuated more: 812 ± 36 (0.28 ± 0.01), 257 ± 15 (0.17 ± 0.01), and 204 ± 13 (0.15 ± 0.01) for CG_all, CG_week, and CG_day, respectively. Age at slaughter (AAS) and hot carcass weight (HCW) adjusted for age were investigated as alternatives for GX. Both have potential for selection but lower heritabilities compared with GX: 0.21 ± 0.01 (0.18 ± 0.01), 0.16 ± 0.02 (0.16 + 0.01), and 0.10 ± 0.01 (0.14 ± 0.01) for AAS (HCW) using CG_all, CG_week, and CG_day, respectively. The predictive ability, linear regression (LR) accuracy, bias, and dispersion of crossbred traits in crossbreds favored CG_day, but correlations with unadjusted phenotypes favored CG_all. In purebreds, CG_all showed the best LR accuracy, while showing small relative differences in bias and dispersion. Different CG scenarios showed no relevant impact on BFX EBV. This study shows that different CG definitions may affect evaluation stability and animal ranking. Results suggest that ignoring slaughter dates in CG is more appropriate for estimating crossbred trait EBV for purebred animals.


Asunto(s)
Hibridación Genética , Modelos Genéticos , Animales , Fenotipo , Porcinos/genética
19.
J Anim Sci ; 99(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33507285

RESUMEN

Tail length and tail lesions are the major triggers for tail biting in pigs. Against this background, 2 datasets were analyzed to estimate genetic parameters for tail characteristics and growth traits. Dataset 1 considered measurements for trait tail length (T-LEN) and for the growth traits birth weight (BW), weaning weight (WW), postweaning weight (PWW), and average daily gain (ADG) from 9,348 piglets. Piglets were born in the period from 2015 to 2018 and kept on the university Gießen research station. Dataset 2 included 4,943 binary observations from 1,648 pigs from the birth years 2016 to 2019 for tail lesions (T-LES) as indicators for nail necrosis, tail abnormalities, or tail biting. T-LES were recorded at 30 ± 7 d after entry for rearing (T-Les-1), at 50 ± 7 d after entry for rearing (end of the rearing period, T-LES-2), and 130 ± 20 d after entry for rearing (end of fattening period, T-LES-3). Genetic statistical model evaluation for dataset 1 based on Akaike's information criterion and likelihood ration tests suggested multiple-trait animal models considering covariances between direct and maternal genetic effects. The direct heritability for T-LEN was 0.42 (±0.03), indicating the potential for genetic selection on short tails. The maternal genetic heritability for T-LEN was 0.05 (±0.04), indicating the influence of uterine characteristics on morphological traits. The negative correlation between direct and maternal effects for T-LEN of -0.35 (±0.13), as well as the antagonistic relationships (i.e., positive direct genetic correlations in the range from 0.03 to 0.40) between T-LEN with the growth traits BW, WW, PWW, and ADG, complicate selection strategies and breeding goal definitions. The correlations between direct effects for T-LEN and maternal effects for breeding goal traits, and vice versa, were positive but associated with a quite large SE. The heritability for T-LES when considering the 3 repeated measurements was 0.23 (±0.04) from the linear (repeatability of 0.30) and 0.21 (±0.06; repeatability of 0.29) from the threshold model. The breeding value correlations between T-LES-3 with breeding values from the repeatability models were quite large (0.74 to 0.90), suggesting trait lesion recording at the end of the rearing period. To understand all genetic mechanisms in detail, ongoing studies are focusing on association analyses between T-LEN and T-LES, and the identification of tail biting from an actor's perspective.


Asunto(s)
Cola (estructura animal) , Aumento de Peso , Animales , Peso al Nacer/genética , Peso Corporal , Femenino , Modelos Genéticos , Fenotipo , Embarazo , Porcinos/genética , Destete
20.
J Anim Sci ; 99(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33515470

RESUMEN

Tail length and tail lesions are the major triggers for tail biting in pigs. Against this background, 2 datasets were analyzed to estimate genetic parameters for tail characteristics and growth traits. Dataset 1 considered measurements for trait tail length (T-LEN) and for the growth traits birth weight (BW), weaning weight (WW), postweaning weight (PWW), and average daily gain (ADG) from 9,348 piglets. Piglets were born in the period from 2015 to 2018 and kept on the university Gießen research station. Dataset 2 included 4,943 binary observations from 1,648 pigs from the birth years 2016 to 2019 for tail lesions (T-LES) as indicators for nail necrosis, tail abnormalities, or tail biting. T-LES were recorded at 30 ± 7 d after entry for rearing (T-Les-1), at 50 ± 7 d after entry for rearing (end of the rearing period, T-LES-2), and 130 ± 20 d after entry for rearing (end of fattening period, T-LES-3). Genetic statistical model evaluation for dataset 1 based on Akaike's information criterion and likelihood ration tests suggested multiple-trait animal models considering covariances between direct and maternal genetic effects. The direct heritability for T-LEN was 0.42 (±0.03), indicating the potential for genetic selection on short tails. The maternal genetic heritability for T-LEN was 0.05 (±0.04), indicating the influence of uterine characteristics on morphological traits. The negative correlation between direct and maternal effects for T-LEN of -0.35 (±0.13), as well as the antagonistic relationships (i.e., positive direct genetic correlations in the range from 0.03 to 0.40) between T-LEN with the growth traits BW, WW, PWW, and ADG, complicate selection strategies and breeding goal definitions. The correlations between direct effects for T-LEN and maternal effects for breeding goal traits, and vice versa, were positive but associated with a quite large SE. The heritability for T-LES when considering the 3 repeated measurements was 0.23 (±0.04) from the linear (repeatability of 0.30) and 0.21 (±0.06; repeatability of 0.29) from the threshold model. The breeding value correlations between T-LES-3 with breeding values from the repeatability models were quite large (0.74 to 0.90), suggesting trait lesion recording at the end of the rearing period. To understand all genetic mechanisms in detail, ongoing studies are focusing on association analyses between T-LEN and T-LES, and the identification of tail biting from an actor's perspective.


Asunto(s)
Cola (estructura animal) , Aumento de Peso , Animales , Peso al Nacer/genética , Peso Corporal , Femenino , Modelos Genéticos , Fenotipo , Embarazo , Porcinos/genética , Destete
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