Biology subjects

Rodriguez-Martinez, J. A.

Publications and source records attributed to Rodriguez-Martinez, J. A..

3 recordsLinked to original sources

bioRxiv2022

Disease-Associated Non-Coding Variants Alter NKX2-5 DNA-Binding Affinity

1.Genome-wide association studies (GWAS) have mapped over 90% of disease- or trait-associated variants within the non-coding genome, like cis-regulatory elements (CREs). Non-coding single nucleotide polymorphisms (SNPs) are genomic variants that can change how DNA-binding regulatory proteins, like transcription factors (TFs), interact with the genome and regulate gene expression. NKX2-5 is a TF essential for proper heart development, and mutations affecting its function have been associated with congenital heart diseases (CHDs). However, establishing a causal mechanism between non-coding genomic variants and human disease remains challenging. To address this challenge, we identified 8,475 SNPs predicted to alter NKX2-5 DNA- binding using a position weight matrix (PWM)-based predictive model. Five variants were prioritized for in vitro validation; four of them are associated with traits and diseases that impact cardiovascular health. The impact of these variants on NKX2-5 binding was evaluated with electrophoretic mobility shift assay (EMSA) using recombinantly expressed and purified human NKX2-5 homeodomain. Binding curves were constructed to determine changes in binding between variant and reference alleles. Variants rs7350789, rs7719885, rs747334, and rs3892630 increased binding affinity, whereas rs61216514 decreased binding by NKX2-5 when compared to the reference genome. Our findings suggest that differential TF-DNA binding affinity can be key in establishing a causal mechanism of pathogenic variants. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/518772v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@c5091dorg.highwire.dtl.DTLVardef@1d96d0forg.highwire.dtl.DTLVardef@18723eborg.highwire.dtl.DTLVardef@147517a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

CREPE: A Shiny App for Transcription Factor Cataloguing

Transcription factors (TFs) are proteins that directly interpret the genome to regulate gene expression and determine cellular phenotypes. TF identification is a common first step in unravelling gene regulatory networks. We present CREPE, an R Shiny app to catalogue and annotate TFs. CREPE was benchmarked against curated human transcription factor datasets. Next, we use CREPE to explore the TF repertoires of Heliconius erato and Heliconius melpomene butterflies. CREPE is available as a Shiny app package available at GitHub (github.com/dirostri/CREPE).

bioinformatics↗

bioRxiv2022

A butterfly pan-genome reveals a large amount of structural variation underlies the evolution of chromatin accessibility

Despite insertions and deletions being the most common structural variants (SVs) found across genomes, not much is known about how much these SVs vary within populations and between closely related species, nor their significance in evolution. To address these questions, we characterized the evolution of indel SVs using genome assemblies of three closely related Heliconius butterfly species. Over the relatively short evolutionary timescales investigated, up to 18.0% of the genome was composed of indels between two haplotypes of an individual H. charithonia butterfly and up to 62.7% included lineage-specific SVs between the genomes of the most distant species (11 Mya). Lineage-specific sequences were mostly characterized as transposable elements (TEs) inserted at random throughout the genome and their overall distribution was similarly affected by linked selection as single nucleotide substitutions. Using chromatin accessibility profiles (i.e., ATAC-seq) of head tissue in caterpillars to identify sequences with potential cis-regulatory function, we found that out of the 31,066 identified differences in chromatin accessibility between species, 30.4% were within lineage-specific SVs and 9.4% were characterized as TE insertions. These TE insertions were localized closer to gene transcription start sites than expected at random and were enriched for several transcription factor binding site candidates with known function in neuron development in Drosophila. We also identified 24 TE insertions with head-specific chromatin accessibility. Our results show high rates of structural genome evolution that were previously overlooked in comparative genomic studies and suggest a high potential for structural variation to serve as raw material for adaptive evolution.

genomics↗