While we can’t possibly capture all the exciting work happening in genomics right now, we’ve put together a short list of papers that stood out to our team this week. These selections reflect some of our staff’s current favorites across genomics and related areas of research. Here are five papers worth a look.
StringTie3 Improves Total RNA-seq Assembly by Resolving Nascent and Mature Transcripts
An updated assembler from Johns Hopkins University, StringTie3, improves transcriptome assembly from total RNA-seq by distinguishing nascent from mature transcripts and correcting misassemblies caused by partially spliced RNA. Its nascent mode models co-transcriptional splicing and removes poly(A)-priming artifacts, boosting precision and sensitivity across short-read, long-read, and hybrid datasets. In studies of Argonaute protein knockouts and breast cancer, StringTie3 showed transcriptional and post-transcriptional regulation patterns that are typically obscured in standard RNA-seq analysis.
Paper Details: Ida Shinder, Geo Pertea, Richard Hu, Zoe Rudnick, Mihaela Pertea. StringTie3 Improves Total RNA-seq Assembly by Resolving Nascent and Mature Transcripts. bioRxiv 2025.05.21.655404; doi: https://doi.org/10.1101/2025.05.21.655404
Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice
A new study published in Nature Genetics shows that base editing can reduce harmful DNA repeat expansions linked to Huntington’s disease and Friedreich’s ataxia. Researchers used cytosine and adenine base editors to introduce interruptions in repetitive CAG and GAA sequences in patient cells and mice. These edits mimic naturally occurring stable variants, reducing somatic repeat expansion in the brain. Treated cells and animals showed less genetic instability and signs of disease. The findings suggest that base editing is a promising therapeutic strategy for trinucleotide repeat disorders by stabilizing disease-causing genomic regions.
Paper Details: Matuszek, Z., Arbab, M., Kesavan, M. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02172-8
Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation
Researchers from the Broad Institute and their collaborators have developed Expansion in situ Genome Sequencing (ExIGS), a technique that combines high-resolution imaging and DNA sequencing within individual cell nuclei. Using this method on cells from Hutchinson-Gilford progeria syndrome patients, they linked nuclear shape abnormalities to local disruptions in euchromatin organization and transcriptional repression. These disruptions occurred in hotspots rather than across the entire genome. The study further found similar abnormalities in aged cells and tissues, suggesting that lamin mislocalization may drive transcriptional heterogeneity during aging and disease. In summary, ExIGS offers a powerful new platform for studying spatial genome regulation in diverse biological contexts.
Paper Details: Ajay S. Labade et al., Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation. Science 0, eadt2781 DOI:10.1126/science.adt2781
SAVANA: reliable analysis of somatic structural variants and copy number aberrations using long-read sequencing
A team of researchers has developed SAVANA, a machine learning–based algorithm for detecting somatic structural variants (SVs) and copy number aberrations (SCNAs) from long-read sequencing data. SAVANA accurately identifies SVs at single-haplotype resolution, even without a matched normal sample, and estimates tumor purity and ploidy. In benchmarking tests using 99 tumor-normal pairs, SAVANA showed significantly higher sensitivity and specificity than existing methods. It also reduces false positives, particularly in repetitive regions, and aligns well with results from short-read sequencing. This work establishes SAVANA as a powerful tool for cancer genome analysis and clinical applications using long-read sequencing technologies.
Paper Details: Elrick, H., Sauer, C.M., Espejo Valle-Inclan, J. et al. SAVANA: reliable analysis of somatic structural variants and copy number aberrations using long-read sequencing. Nat Methods (2025). https://doi.org/10.1038/s41592-025-02708-0
SNP calling, haplotype phasing and allele-specific analysis with long RNA-seq reads
Last, but certainly not least, we have another great preprint from Heng Li and colleagues. Together, they have developed longcallR, a tool that uses long-read RNA sequencing data to jointly perform SNP calling, haplotype phasing, and allele-specific analysis with high accuracy. Validated on benchmark datasets, longcallR outperformed existing methods in precision and revealed 88 allele-specific splicing events per sample across 202 human samples. Notably, 46% of these events involved previously unannotated splice junctions. Overall, this study highlights the utility of long-read RNA-seq for uncovering genetic variation and splicing dynamics and suggests that allele-specific splicing correlates with population structure. Future work aims to extend longcallR to single-cell RNA-seq for higher-resolution insights.
Paper Details: Neng Huang, Human Pangenome Reference Consortium, Heng Li. NP calling, haplotype phasing and allele-specific analysis with long RNA-seq reads. bioRxiv 2025.05.26.656191; doi: https://doi.org/10.1101/2025.05.26.656191
StringTie3 Improves Total RNA-seq Assembly by Resolving Nascent and Mature Transcripts
An updated assembler from Johns Hopkins University, StringTie3, improves transcriptome assembly from total RNA-seq by distinguishing nascent from mature transcripts and correcting misassemblies caused by partially spliced RNA. Its nascent mode models co-transcriptional splicing and removes poly(A)-priming artifacts, boosting precision and sensitivity across short-read, long-read, and hybrid datasets. In studies of Argonaute protein knockouts and breast cancer, StringTie3 showed transcriptional and post-transcriptional regulation patterns that are typically obscured in standard RNA-seq analysis.
Paper Details: Ida Shinder, Geo Pertea, Richard Hu, Zoe Rudnick, Mihaela Pertea. StringTie3 Improves Total RNA-seq Assembly by Resolving Nascent and Mature Transcripts. bioRxiv 2025.05.21.655404; doi: https://doi.org/10.1101/2025.05.21.655404
Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice
A new study published in Nature Genetics shows that base editing can reduce harmful DNA repeat expansions linked to Huntington’s disease and Friedreich’s ataxia. Researchers used cytosine and adenine base editors to introduce interruptions in repetitive CAG and GAA sequences in patient cells and mice. These edits mimic naturally occurring stable variants, reducing somatic repeat expansion in the brain. Treated cells and animals showed less genetic instability and signs of disease. The findings suggest that base editing is a promising therapeutic strategy for trinucleotide repeat disorders by stabilizing disease-causing genomic regions.
Paper Details: Matuszek, Z., Arbab, M., Kesavan, M. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02172-8
Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation
Researchers from the Broad Institute and their collaborators have developed Expansion in situ Genome Sequencing (ExIGS), a technique that combines high-resolution imaging and DNA sequencing within individual cell nuclei. Using this method on cells from Hutchinson-Gilford progeria syndrome patients, they linked nuclear shape abnormalities to local disruptions in euchromatin organization and transcriptional repression. These disruptions occurred in hotspots rather than across the entire genome. The study further found similar abnormalities in aged cells and tissues, suggesting that lamin mislocalization may drive transcriptional heterogeneity during aging and disease. In summary, ExIGS offers a powerful new platform for studying spatial genome regulation in diverse biological contexts.
Paper Details: Ajay S. Labade et al., Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation. Science 0, eadt2781 DOI:10.1126/science.adt2781
SAVANA: reliable analysis of somatic structural variants and copy number aberrations using long-read sequencing
A team of researchers has developed SAVANA, a machine learning–based algorithm for detecting somatic structural variants (SVs) and copy number aberrations (SCNAs) from long-read sequencing data. SAVANA accurately identifies SVs at single-haplotype resolution, even without a matched normal sample, and estimates tumor purity and ploidy. In benchmarking tests using 99 tumor-normal pairs, SAVANA showed significantly higher sensitivity and specificity than existing methods. It also reduces false positives, particularly in repetitive regions, and aligns well with results from short-read sequencing. This work establishes SAVANA as a powerful tool for cancer genome analysis and clinical applications using long-read sequencing technologies.
Paper Details: Elrick, H., Sauer, C.M., Espejo Valle-Inclan, J. et al. SAVANA: reliable analysis of somatic structural variants and copy number aberrations using long-read sequencing. Nat Methods (2025). https://doi.org/10.1038/s41592-025-02708-0
SNP calling, haplotype phasing and allele-specific analysis with long RNA-seq reads
Last, but certainly not least, we have another great preprint from Heng Li and colleagues. Together, they have developed longcallR, a tool that uses long-read RNA sequencing data to jointly perform SNP calling, haplotype phasing, and allele-specific analysis with high accuracy. Validated on benchmark datasets, longcallR outperformed existing methods in precision and revealed 88 allele-specific splicing events per sample across 202 human samples. Notably, 46% of these events involved previously unannotated splice junctions. Overall, this study highlights the utility of long-read RNA-seq for uncovering genetic variation and splicing dynamics and suggests that allele-specific splicing correlates with population structure. Future work aims to extend longcallR to single-cell RNA-seq for higher-resolution insights.
Paper Details: Neng Huang, Human Pangenome Reference Consortium, Heng Li. NP calling, haplotype phasing and allele-specific analysis with long RNA-seq reads. bioRxiv 2025.05.26.656191; doi: https://doi.org/10.1101/2025.05.26.656191