Biology subjects

Magno, R.

Publications and source records attributed to Magno, R..

7 recordsLinked to original sources

bioRxiv2023

SPATIO-TEMPORAL DYNAMICS OF EARLY SOMITE SEGMENTATION IN THE CHICKEN EMBRYO

During vertebrate embryo development, the body is progressively segmented along the anterior-posterior (A-P) axis early in development. The rate of somite formation is controlled by the somitogenesis embryo clock (EC), which was first described as gene expression oscillations of hairy1 (hes4) in the presomitic mesoderm of chick embryos with 15-20 somites. Here, the EC displays the same periodicity as somite formation, 90 min, whereas the posterior-most somites (44-52) only arise every 150 minutes, matched by a corresponding slower pace of the EC. Evidence suggests that the rostral-most somites are formed faster, however, their periodicity and the EC expression dynamics in these early stages are unknown. In this study, we used time-lapse imaging of chicken embryos from primitive streak to somitogenesis stages with high temporal resolution (3-minute intervals). We measured the length between the anterior-most and the last formed somitic clefts in each captured frame and developed a simple algorithm to automatically infer both the length and time of formation of each somite. We found that the occipital somites (up to somite 5) form at an average rate of 75 minutes, while somites 6 onwards are formed approximately every 90 minutes. We also assessed the expression dynamics of hairy1 using half-embryo explants cultured for different periods of time. This showed that EC hairy1 expression is highly dynamic prior to somitogenesis and assumes a clear oscillatory behaviour as the first somites are formed. Importantly, using ex ovo culture and live-imaging techniques, we showed that the hairy1 expression pattern recapitulates with the formation of each new pair of somites, indicating that somite segmentation is coupled with EC oscillations since the onset of somitogenesis. HighlightsO_LITime of early somite formation can be inferred from sequential length measurements C_LIO_LIThe cranial-most somites are formed faster than trunk somites C_LIO_LIOscillations of hairy1 expression are temporally coupled with early somite formation C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/535703v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@f643aborg.highwire.dtl.DTLVardef@1d4a9b0org.highwire.dtl.DTLVardef@d085a1org.highwire.dtl.DTLVardef@1f51399_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Preferential allelic expression of PIK3CA mutations is frequent in breast cancer and is prognostically significant

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found allelic imbalances in the expression of PIK3CA in normal breast tissue and mapped a germline candidate regulatory variant. An imbalance was also frequently observed in the expression of the missense mutant and wild-type PIK3CA alleles in breast tumors from METABRIC and TCGA projects. Moreover, although 60% of tumors preferentially expressed the mutant allele, 10% did preferentially express the wild-type allele. Mechanistically, we show that these imbalances are more frequently due to regulatory variants in cis than altered copy-number and predict that somatic variants have a more significant role than germline ones. We further found that imbalanced allelic expression between mutant and wild-type alleles due to cis-regulatory variants associated with poor prognosis (p=0.0081). Interestingly, ER+, PR+, and Her2- tumors expressing very low levels of the mutant allele had the poorest prognosis (DSS <7.5yrs for ER+ and PR+ tumors and <5yrs for Her2- tumors). Hence, our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying this cohort of low mutant allele expressing patients of poorer prognosis, who will unlikely benefit from PI3K inhibitors. Furthermore, our work establishes a new model of differential regulation of critical cancer-promoting genes.

cancer biology↗

bioRxiv2021

FrozenChicken: Promoting the meta-analysis of chicken microarray data

The FrozenChicken RData package, contains the frozen vectors for the commercially available (in situ oligonucleotide) Affymetrix Chicken Genome Array (GEO platform id GPL3213). This package will promote, simplify, and ease the meta-analysis of chicken microarray data by the research community studying vertebrate development using the chick model organism. The package is freely available in https://github.com/iduarte/FrozenChicken. (*Equal contribution.)

bioinformatics↗

bioRxiv2021

quincunx: an R package to query, download and wrangle PGS Catalog data

MotivationThe Polygenic Score (PGS) Catalog is a recently established open database of published polygenic scores that, to date, has collected, curated, and made available 721 polygenic scores from over 133 publications. The PGS Catalog REST API is the only method allowing programmatic access to this resource. ResultsHere, we describe quincunx, an R package that provides the first client interface to the PGS Catalog REST API. quincunx enables users to query and quickly retrieve, filter and integrate metadata associated with polygenic scores, as well as polygenic scoring files in tidy table format. Availabilityquincunx is freely available under an MIT License, and can be accessed from https://github.com/maialab/quincunx.

bioinformatics↗

bioRxiv2019

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated variants (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting miRNA genes and/or miRNA-binding. To test this we adapted two miRNA-binding prediction algorithms -- TargetScan and miRanda -- to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant (P [≤] 5 x 10-8) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3UTRs of putative miRNA target genes were predicted to alter miRNA::mRNA pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and re-inforce the role of miRNA mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.

cancer biology↗

bioRxiv2019

Alternative splicing regulation by GWAS risk loci for breast cancer

Recent genome-wide association studies (GWAS) have revealed the association of hundreds of single nucleotide polymorphisms (SNPs) with breast cancer (BC) risk, which mostly locate in non-coding regions, suggesting regulatory roles to the causal variants. Functional characterisation of GWAS loci has been biased towards the effect of regulatory SNPs on transcription factor binding. Here we set out to determine the extent of the contribution of breast cancer risk-associated SNPs to alternative splicing (AS).\n\nWe screened genome-wide significant (P [≤] 5 x 10-8) BC risk SNPs for association with AS, using expression and genotype data from normal breast samples, from the GTEx project. We identified four splicing quantitative trait loci (sQTL). In locus 6p22.1, rs6456883 is a significant cis-sQTL for the expression of ZNF311 gene isoforms. Three SNPs in locus 8p23.3, rs6682326, rs3008282 and rs2906324, were also identified as significant cis-sQTLs/svQTLs for the expression of RPL23AP53 gene isoforms. In-silico functional analysis revealed that these variants can potentially alter enhancer splicing elements within the target genes.\n\nOur work shows that BC risk-associated variants at two loci are associated with AS isoforms in normal breast tissue, thus demonstrating that AS plays an important role in breast cancer susceptibility. Furthermore, it supports that all cis-regulatory mechanisms should be considered in the functional characterisation of risk loci.

cancer biology↗

bioRxiv2019

gwasrapidd: an R package to query, download and wrangle GWAS Catalog data

MotivationThe NHGRI Catalog of Published Genome-Wide Association Studies (GWAS) Catalog has collected, curated, and made available data from over 3 900 studies. The recently developed GWAS Catalog REST API is the only method allowing programmatic access to this resource.\n\nResultsHere, we describe gwasrapidd, an R package that provides a client interface to the GWAS Catalog REST API, representing an important software counterpart to the server-side component. gwasrapidd enables users to quickly retrieve, filter and integrate data with comprehensive bioinformatics analysis tools, which is particularly critical for those looking into functional characterisation of risk loci.\n\nAvailabilitygwasrapidd is freely available under an MIT License, and can be accessed from https://github.com/ramiromagno/gwasrapidd.

bioinformatics↗