Biology subjects

Quinones-Valdez, G.

Publications and source records attributed to Quinones-Valdez, G..

8 recordsLinked to original sources

bioRxiv2026

Allele-specific splicing modulates protein isoforms and Alzheimer's risk

Despite growing catalogs of genetic variation linked to human traits and diseases, the functional impact of most genetic variants remains poorly understood. Alternative splicing, particularly in the human brain, represents a key layer of post-transcriptional regulation that may mediate genetic effects on gene expression and protein diversity. In this study, we systematically map allele-specific alternative splicing (ASAS) events in postmortem brain tissues from the Mount Sinai Brain Bank cohort, identifying hundreds of genetically regulated splicing events across four brain regions. Using a concordance-based method, we nominate over 500 putative functional SNPs associated with ASAS, many of which overlap splicing QTLs (sQTLs), RNA-binding protein binding sites, and GWAS loci for Alzheimers disease (AD), brain traits, and immune phenotypes. ASAS events are enriched in genes involved in mitochondrial function and frequently occur in 5' untranslated regions (5' UTRs), where they are associated with protein quantitative trait loci (pQTLs), alternative start codons, and isoform-specific domain changes - highlighting an underappreciated mechanism through which noncoding variants can influence translation and proteome complexity. Importantly, we also identify a subset of ASAS events exhibiting disease-specific splicing patterns in AD brains, including functional SNPs with opposing splicing effects between AD and control groups in genes implicated in mitochondrial function and neuronal signaling. Together, our results provide a brain-specific, splicing-resolved map of regulatory variation and uncover novel mechanisms linking genetic variation to transcript and protein-level changes in AD. This work highlights the importance of allele-specific splicing analysis for interpreting noncoding variation in complex human disorders.

genomics↗

bioRxiv2026

Allele-specific alternative polyadenylation links noncoding genetic variation to Alzheimer's disease risk

BackgroundAlternative polyadenylation (APA) is a crucial post-transcriptional mechanism generating isoform diversity in the nervous system. While genetic variants significantly influence gene expression, the extent to which they regulate 3 UTR usage in the human brain remains underexplored. We aimed to characterize the landscape of allele-specific alternative polyadenylation (asAPA) and investigate its role in neurodevelopmental and neurodegenerative disorders. ResultsAnalyzing 1,047 RNA-seq data from 293 Alzheimers disease (AD) and control donors across four brain regions, we identified 4,462 asAPA events involving 3,432 SNPs. We prioritized a core set of putative functional variants that drive consistent cis-regulatory effects across individuals. These functional SNPs are enriched for RNA-binding protein motifs, particularly those recognized by FMRP. In Fragile X Syndrome brains lacking FMRP, we observed widespread 3 UTR shortening, with FMRP motifs enriched in the 3 UTR extension regions of shortened transcripts, suggesting FMRP normally protects against proximal site usage. Integrating these data with population genetics, we found that asAPA SNPs significantly overlap GWAS risk loci for autism spectrum disorder (ASD), ADHD, and AD. Furthermore, comparing AD to control brains within our cohort revealed 77 asAPA genes exhibiting condition-specific shifts in allelic bias, affecting key synaptic genes including CAMK2G. ConclusionsOur study uncovers a pervasive layer of cis-regulatory variation in the human brain that links noncoding genetics to transcript structure via RBP interactions. We identify FMRP as a key regulator of this process and demonstrate that asAPA provides a mechanistic bridge connecting genetic risk to neuronal pathology in both neurodevelopment and neurodegeneration.

genomics↗

bioRxiv2024

Long-read RNA-seq demarcates cis- and trans-directed alternative RNA splicing

Genetic regulation of alternative splicing constitutes an important link between genetic variation and disease. Nonetheless, RNA splicing is regulated by both cis-acting elements and trans-acting splicing factors. Determining splicing events that are directed primarily by the cis- or trans-acting mechanisms will greatly inform our understanding of the genetic basis of disease. Here, we show that long-read RNA-seq, combined with our new method isoLASER, enables a clear segregation of cis- and trans-directed splicing events for individual samples. The genetic linkage of splicing is largely individual-specific, in stark contrast to the tissue-specific pattern of splicing profiles. Analysis of long-read RNA-seq data from human and mouse revealed thousands of cis-directed splicing events susceptible to genetic regulation. We highlight such events in the HLA genes whose analysis was challenging with short-read data. We also highlight novel cis-directed splicing events in Alzheimers disease-relevant genes such as MAPT and BIN1. Together, the clear demarcation of cis- and trans-directed splicing paves ways for future studies of the genetic basis of disease.

bioinformatics↗

bioRxiv2023

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

genomics↗

bioRxiv2022

scAllele: a versatile tool for the detection and analysis of variants in scRNA-seq

Single-cell RNA sequencing (scRNA-seq) data contain rich information at the gene, transcript, and nucleotide levels. Most analyses of scRNA-seq have focused on gene expression profiles, and it remains challenging to extract nucleotide variants and isoform-specific information. Here, we present scAllele, an integrative approach that detects single nucleotide variants, insertions, deletions, and their allelic linkage with splicing patterns in scRNA-seq. We demonstrate that scAllele achieves better performance in identifying nucleotide variants than other commonly used tools. In addition, the read-specific variant calls by scAllele enables allele-specific splicing analysis, a unique feature not afforded by other methods. Applied to a lung cancer scRNA-seq data set, scAllele identified variants with strong allelic linkage to alternative splicing, some of which being cancer-specific. scAllele represents a versatile tool to uncover multi-layer information and novel biological insights from scRNA-seq data.

bioinformatics↗

bioRxiv2022

L-GIREMI uncovers RNA editing sites in long-read RNA-seq

Using third-generation sequencers, long-read RNA-seq is increasingly applied in transcriptomic studies given its major advantage in characterizing full-length transcripts. A number of methods have been developed to analyze this new type of data for transcript isoforms and their abundance. Another application, which is significantly under-explored, is to identify and analyze single nucleotide variants (SNVs) in the RNA. Identification of SNVs, such as genetic mutations or RNA editing sites, is fundamental to many biomedical questions. In long-read RNA-seq, SNV analysis presents significant challenges, due to the well-known relatively high error rates of the third-generation sequencers. Here, we present the first study to detect and analyze RNA editing sites in long-read RNA-seq. Our new method, L-GIREMI, effectively handles sequencing errors and biases in the reads, and uses a model-based approach to score RNA editing sites. Applied to PacBio long-read RNA-seq data, L-GIREMI affords a high accuracy in RNA editing identification. In addition, the unique advantage of long reads allowed us to uncover novel insights about RNA editing occurrences in single molecules and double-stranded RNA (dsRNA) structures. L-GIREMI provides a valuable means to study RNA nucleotide variants in long-read RNA-seq.

bioinformatics↗

bioRxiv2020

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

Recent studies revealed global shifts in RNA editing, the modification of RNA sequences, across many cancers. Besides a few sites implicated in tumorigenesis or metastasis, most tumor-associated sites, predominantly in noncoding regions, have unknown function. Here, we characterize editing profiles between epithelial (E) and mesenchymal (M) phenotypes in seven cancer types, as epithelial-mesenchymal transition (EMT) is a key paradigm for metastasis. We observe distinct editing patterns between E and M tumors and EMT induction upon loss of ADAR enzymes in cultured cells. E-M differential sites are highly enriched in genes involved in immune and viral processes, some of which regulate mRNA abundance of their respective genes. We identify a novel mechanism in which ILF3 preferentially stabilizes edited transcripts. Among editing-dependent ILF3 targets is the transcript encoding PKR, a crucial player in immune response. Our study demonstrates the broad impact of RNA editing in cancer and relevance of editing to cancer-related immune pathways.

cancer biology↗

bioRxiv2018

Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants influencing RNA processing and gene expression phenotypes. Recently, genome-wide detection of in vivo binding sites of RNA binding proteins (RBPs) is greatly facilitated by the enhanced UV crosslinking and immunoprecipitation (eCLIP) protocol. Hundreds of eCLIP-Seq data sets were generated from HepG2 and K562 cells during the ENCODE3 phase. These data afford a valuable opportunity to examine allele-specific binding (ASB) of RBPs. To this end, we developed a new computational algorithm, called BEAPR (Binding Estimation of Allele-specific Protein-RNA interaction). In identifying statistically significant ASB sites, BEAPR takes into account UV cross-linking induced sequence propensity and technical variations between replicated experiments. Using simulated data and actual eCLIP-Seq data, we show that BEAPR largely outperforms often-used methods Chi-Squared test and Fishers Exact test. Importantly, BEAPR overcomes the inherent over-dispersion problem of the other methods. Complemented by experimental validations, we demonstrate that ASB events are significantly associated with genetic regulation of splicing and mRNA abundance, supporting the usage of this method to pinpoint functional genetic variants in post-transcriptional gene regulation. Many variants with ASB patterns of RBPs were found as genetic variants with cancer or other disease relevance. About 38% of ASB variants were in linkage disequilibrium with single nucleotide polymorphisms from genome-wide association studies. Overall, our results suggest that BEAPR is an effective method to reveal ASB patterns in eCLIP and can inform functional interpretation of disease-related genetic variants.

bioinformatics↗