Biology subjects

Xue, J. R.

Publications and source records attributed to Xue, J. R..

3 recordsLinked to original sources

bioRxiv2025

Long-range mRNA folding shapes expression and sequence of bacterial genes

Accessibility of the ribosome binding site (RBS) plays an outsized role in bacterial mRNA decay and translation. Antagonistic mRNA sequences that reduce accessibility and regulate expression have been widely documented near the RBS. To determine whether such sequences are also the primary effectors of expression when placed far from the RBS, we measured impacts of all possible 8-nucleotide substitutions (65,536 variants) at different positions in mRNA in Bacillus subtilis. While the vast majority of substitutions negligibly affect RNA levels, pyrimidine-rich substitutions resembling the anti-Shine-Dalgarno (aSD) sequence exhibit strong inhibitory effects. Even several hundred nucleotides downstream of the RBS, these aSD-like sequences base-pair with the RBS, promote RNA decay, and inhibit translation initiation. We find aSD-like sequences to be depleted throughout endogenous genes, likely due to selective pressure for expression. Taken together, our findings reveal widespread long-range RNA intramolecular interactions in vivo and uncover a key constraint on gene sequence evolution. HIGHLIGHTSO_LILong-range mRNA folding tunes accessibility of the ribosome binding site (RBS) C_LIO_LIShort anti-RBS sequences are major mRNA repressors across the transcript body C_LIO_LIAnti-RBSs, even distally located, can promote RNA decay and inhibit translation C_LIO_LIAnti-RBS sequences are depleted throughout endogenous bacterial coding sequences C_LI

molecular biology↗

bioRxiv2023

Title: Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

genomics↗

bioRxiv2021

Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution

3 untranslated region (3UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3UTRs (MPRAu) to sensitively assay 12,173 3UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3UTR function, suggesting that low-complexity sequences predominately explain 3UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an AU-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14, and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

genetics↗