The landscape of expression and alternative splicing variation across human traits.

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.

Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing.

Nanopore RNA sequencing shows promise as a method for discriminating and identifying different RNA modifications in native RNA. Expanding on the ability of nanopore sequencing to detect N6-methyladenosine, we show that other modifications, in particular pseudouridine (Ψ) and 2'-O-methylation (Nm), also result in characteristic base-calling 'error' signatures in the nanopore data. Focusing on Ψ modification sites, we detected known and uncovered previously unreported Ψ sites in mRNAs, non-coding RNAs and rRNAs, including a Pus4-dependent Ψ modification in yeast mitochondrial rRNA. To explore the dynamics of pseudouridylation, we treated yeast cells with oxidative, cold and heat stresses and detected heat-sensitive Ψ-modified sites in small nuclear RNAs, small nucleolar RNAs and mRNAs. Finally, we developed a software, nanoRMS, that estimates per-site modification stoichiometries by identifying single-molecule reads with altered current intensity and trace profiles. This work demonstrates that Nm and Ψ RNA modifications can be detected in cellular RNAs and that their modification stoichiometry can be quantified by nanopore sequencing of native RNA.

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures.

BACKGROUND: RNA modifications play central roles in cellular fate and differentiation. However, the machinery responsible for placing, removing, and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modification-related proteins (RMPs) may be dysregulated in each cancer type. RESULTS: Here, we perform a comprehensive annotation and evolutionary analysis of human RMPs, as well as an integrative analysis of their expression patterns across 32 tissues, 10 species, and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testis-specific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. We uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO are not significantly upregulated in most cancer types, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers. CONCLUSIONS: Our analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviors that are orchestrated by RNA modifications.

Accurate detection of m6A RNA modifications in native RNA sequences.

The epitranscriptomics field has undergone an enormous expansion in the last few years; however, a major limitation is the lack of generic methods to map RNA modifications transcriptome-wide. Here, we show that using direct RNA sequencing, N6-methyladenosine (m6A) RNA modifications can be detected with high accuracy, in the form of systematic errors and decreased base-calling qualities. Specifically, we find that our algorithm, trained with m6A-modified and unmodified synthetic sequences, can predict m6A RNA modifications with ~90% accuracy. We then extend our findings to yeast data sets, finding that our method can identify m6A RNA modifications in vivo with an accuracy of 87%. Moreover, we further validate our method by showing that these 'errors' are typically not observed in yeast ime4-knockout strains, which lack m6A modifications. Our results open avenues to investigate the biological roles of RNA modifications in their native RNA context.

[Atrial functional mitral regurgitation. Three-dimensional echocardiographic study]. / Insuficiencia mitral funcional auricular. Estudio ecocardiográfico tridimensional.

INTRODUCTION AND OBJECTIVES: Atrial fibrillation can lead to left atrium remodelling and induce functional mitral regurgitation. The aim of this study is to establish those features of the mitral annulus that are related to atrial functional mitral regurgitation. METHODS: A total of 29 patients with persistent atrial fibrillation and 36 controls in sinus rhythm were retrospectively enrolled. The characteristics of the mitral annulus were analysed by three-dimensional transoesophageal echocardiography in both groups. The 2D and 3D echocardiographic parameters were correlated with the effective regurgitant orifice. RESULTS: Patients with atrial fibrillation had a larger left atrium volume, anteroposterior diameter at end-diastole, and lower percentage of change in this diameter (P=.015, P=.019 and P<.001, respectively). In the multiple regression analysis, the ellipticity index (ß: -0.756, P=.004) and height-anterolateral-posteromedial diameter ratio (ß: -0704, P=.003) were independent parameters that correlated with the effective regurgitant orifice (R2: 0.699, P=.019) in patients with atrial fibrillation. CONCLUSIONS: Atrial fibrillation leads to atrial dilation and alterations in the size and dynamics of the anteroposterior diameter, producing a circular mitral annulus. The independent determining factors of atrial functional mitral regurgitation in the atrial fibrillation group were the ellipticity index and the height-anterolateral-posteromedial diameter ratio.

Insuficiencia mitral funcional auricular. Estudio ecocardiográfico tridimensional / Atrial functional mitral regurgitation. Three-dimensional echocardiographic study

Resumen Introducción y objetivos: La fibrilación auricular puede producir remodelado de la aurícula izquierda e inducir insuficiencia mitral funcional. El objetivo de este estudio es establecer qué características del anillo mitral están relacionadas con la regurgitación mitral funcional auricular. Método: Restrospectivamente se reclutaron 29 pacientes en fibrilación auricular persistente y 36 en ritmo sinusal. Las características del anillo mitral mediante ecocardiografía transesofágica tridimensional fueron analizadas en ambos grupos. Los parámetros ecocardiográficos 2D y 3D fueron correlacionados con el orificio regurgitante efectivo. Resultados: Los pacientes con fibrilación auricular presentaron mayor volumen de aurícula izquierda, diámetro anteroposterior al final de la diástole y disminución de su porcentaje de cambio (p: 0.015, 0.019 y < 0.001 respectivamente). En el análisis de regresión multivariante el índice de elipticidad (ˇ: −0.756, p: 0.004) y el ratio altura/diámetro anterolateral posteromedial (ˇ: −0.704, p: 0.003) fueron parámetros independientes correlacionados con el orificio regurgitante efectivo (R2: 0.699, p: 0.019) en pacientes con fibrilación auricular. Conclusiones: La fibrilación auricular produce cambios en el tamaño y dinámica del diámetro anteroposterior, lo que provoca un anillo mitral circular. Los mayores determinantes de la insuficiencia mitral funcional auricular en el grupo de fibrilación auricular resultaron el índice de elipticidad y el ratio altura/diámetro anterolateral-posteromedial.

Abstract Introduction and objectives: Atrial fibrillation can lead to left atrium remodelling and induce functional mitral regurgitation. The aim of this study is to establish those features of the mitral annulus that are related to atrial functional mitral regurgitation. Methods: A total of 29 patients with persistent atrial fibrillation and 36 controls in sinus rhythm were retrospectively enrolled. The characteristics of the mitral annulus were analysed by three-dimensional transoesophageal echocardiography in both groups. The 2D and 3D echocardiographic parameters were correlated with the effective regurgitant orifice. Results: Patients with atrial fibrillation had a larger left atrium volume, anteroposterior diameter at end-diastole, and lower percentage of change in this diameter (P = .015, P = .019 and P < .001, respectively). In the multiple regression analysis, the ellipticity index (ˇ: −0.756, P = .004) and height-anterolateral-posteromedial diameter ratio (ˇ: −0704, P = .003) were independent parameters that correlated with the effective regurgitant orifice (R2: 0.699, P = .019) in patients with atrial fibrillation. Conclusions: Atrial fibrillation leads to atrial dilation and alterations in the size and dynamics of the anteroposterior diameter, producing a circular mitral annulus. The independent determining factors of atrial functional mitral regurgitation in the atrial fibrillation group were the ellipticity index and the height-anterolateral-posteromedial diameter ratio.

First complete mitochondrial genome data from ancient South American camelids - The mystery of the chilihueques from Isla Mocha (Chile).

In South American societies, domesticated camelids were of great cultural importance and subject to trade and translocation. South American camelids were even found on remote and hard to reach islands, emphasizing their importance to historic and pre-historic South American populations. Isla Mocha, a volcanic island 35 km offshore of Central-South Chile, is an example of such an island. When Dutch and Spanish explorers reached the island in the early 17th century, they found that domesticated camelids called "chilihueque" played a major role in the island's society. The origin and taxonomy of these enigmatic camelids is unclear and controversial. This study aims to resolve this controversy through genetic analyses of Isla Mocha camelid remains dating from pre-Columbian to early historic times. A recent archaeological excavation of site P21-3 on Isla Mocha yielded a number of camelid remains. Three complete mitochondrial genomes were successfully recovered and analysed. Phylogenetic analyses suggest that "chilihueque" was a local term for a domesticated guanaco. Results from phylogeographic analyses are consistent with Isla Mocha camelids being sourced from Southern Chilean guanaco populations. Our data highlights the capability of ancient DNA to answer questions about extinct populations which includes species identity, potential translocation events and origins of founding individuals.

Radiocarbon and DNA evidence for a pre-Columbian introduction of Polynesian chickens to Chile.

Two issues long debated among Pacific and American prehistorians are (i) whether there was a pre-Columbian introduction of chicken (Gallus gallus) to the Americas and (ii) whether Polynesian contact with South America might be identified archaeologically, through the recovery of remains of unquestionable Polynesian origin. We present a radiocarbon date and an ancient DNA sequence from a single chicken bone recovered from the archaeological site of El Arenal-1, on the Arauco Peninsula, Chile. These results not only provide firm evidence for the pre-Columbian introduction of chickens to the Americas, but strongly suggest that it was a Polynesian introduction.