Human y chromosome variation and the peopling of the African continent

The analysis, by Next Generation Sequencing, of 1.5 Mb of the Male-Specific region of the Y chromosome (MSY), in a sample carefully selected to represent a wide range of diversity and antiquity among MSY lineages, led to the identification of 2,386 variable positions, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome- wide de novo events, suggesting that in the MSY a large proportion of newly arisen alleles have survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. We used these markers to reconstruct a phylogenetic tree, which showed remarkable differences with the one known in literature, although recapitulating the previously known topology. The relative lengths of the tree branches have been notably altered, and the time estimates associated with the tree nodes have moved towards more ancient times. Keeping into account the present day distribution of patrilineages, and the fossil remains of Homo sapiens found to date, our data enabled us to draw hypotheses on the evolutionary events that involved the human species, since its origin, up to its migration out of the African continent

Human y chromosome variation and the peopling of the African continent

The analysis, by Next Generation Sequencing, of 1.5 Mb of the Male-Specific region of the Y chromosome (MSY), in a sample carefully selected to represent a wide range of diversity and antiquity among MSY lineages, led to the identification of 2,386 variable positions, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome- wide de novo events, suggesting that in the MSY a large proportion of newly arisen alleles have survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. We used these markers to reconstruct a phylogenetic tree, which showed remarkable differences with the one known in literature, although recapitulating the previously known topology. The relative lengths of the tree branches have been notably altered, and the time estimates associated with the tree nodes have moved towards more ancient times. Keeping into account the present day distribution of patrilineages, and the fossil remains of Homo sapiens found to date, our data enabled us to draw hypotheses on the evolutionary events that involved the human species, since its origin, up to its migration out of the African continent

A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility

Purpose: To verify the capability of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. Methods: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin\u2019s disease (DXR dose: 40\u201350 mg/m2 per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. Results: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. Conclusions: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting

Birth, expansion, and death of VCY -containing palindromes on the human Y chromosome

Abstract: Background: Large palindromes (inverted repeats) make up substantial proportions of mammalian sex chromosomes, often contain genes, and have high rates of structural variation arising via ectopic recombination. As a result, they underlie many genomic disorders. Maintenance of the palindromic structure by gene conversion between the arms has been documented, but over longer time periods, palindromes are remarkably labile. Mechanisms of origin and loss of palindromes have, however, received little attention. Results: Here, we use fiber-FISH, 10x Genomics Linked-Read sequencing, and breakpoint PCR sequencing to characterize the structural variation of the P8 palindrome on the human Y chromosome, which contains two copies of the VCY (Variable Charge Y) gene. We find a deletion of almost an entire arm of the palindrome, leading to death of the palindrome, a size increase by recruitment of adjacent sequence, and other complex changes including the formation of an entire new palindrome nearby. Together, these changes are found in ~ 1% of men, and we can assign likely molecular mechanisms to these mutational events. As a result, healthy men can have 1–4 copies of VCY. Conclusions: Gross changes, especially duplications, in palindrome structure can be relatively frequent and facilitate the evolution of sex chromosomes in humans, and potentially also in other mammalian species

Single Cell Gene Expression to Understand the Dynamic Architecture of the Heart.

The recent development of single cell gene expression technologies, and especially single cell transcriptomics, have revolutionized the way biologists and clinicians investigate organs and organisms, allowing an unprecedented level of resolution to the description of cell demographics in both healthy and diseased states. Single cell transcriptomics provide information on prevalence, heterogeneity, and gene co-expression at the individual cell level. This enables a cell-centric outlook to define intracellular gene regulatory networks and to bridge toward the definition of intercellular pathways otherwise masked in bulk analysis. The technologies have developed at a fast pace producing a multitude of different approaches, with several alternatives to choose from at any step, including single cell isolation and capturing, lysis, RNA reverse transcription and cDNA amplification, library preparation, sequencing, and computational analyses. Here, we provide guidelines for the experimental design of single cell RNA sequencing experiments, exploring the current options for the crucial steps. Furthermore, we provide a complete overview of the typical data analysis workflow, from handling the raw sequencing data to making biological inferences. Significantly, advancements in single cell transcriptomics have already contributed to outstanding exploratory and functional studies of cardiac development and disease models, as summarized in this review. In conclusion, we discuss achievable outcomes of single cell transcriptomics' applications in addressing unanswered questions and influencing future cardiac clinical applications

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.Peer reviewe