Giovanna Weykopf
@gweykopf.bsky.social
PhD student in the Bickmore lab at @MRC_hgu in Edinburgh | gene regulation, enhancer biology, genetic risk variants 🧬 | sport enthusiast 🏃🏼♀️🏋🏻♀️🏇
Thank you so much Christa!
November 15, 2025 at 8:08 AM
Thank you so much Christa!
Find more details in the pre-print:
https://www.biorxiv.org/content/10.1101/2025.07.24.666385v3.full.pdf
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https://www.biorxiv.org/content/10.1101/2025.07.24.666385v3.full.pdf
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July 30, 2025 at 11:09 AM
Find more details in the pre-print:
https://www.biorxiv.org/content/10.1101/2025.07.24.666385v3.full.pdf
14/
https://www.biorxiv.org/content/10.1101/2025.07.24.666385v3.full.pdf
14/
Huge thank you to my wonderful supervisors, all contributors and our fantastic collaborators who made this work possible. @wbickmor.bsky.social @simonbiddie.bsky.social @eliasfriman.bsky.social, @mbadonyi.bsky.social @leemurphy.bsky.social, Joe Marsh, Mark Gorrell, Jasmine Nguyen and others
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July 30, 2025 at 11:09 AM
Huge thank you to my wonderful supervisors, all contributors and our fantastic collaborators who made this work possible. @wbickmor.bsky.social @simonbiddie.bsky.social @eliasfriman.bsky.social, @mbadonyi.bsky.social @leemurphy.bsky.social, Joe Marsh, Mark Gorrell, Jasmine Nguyen and others
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Studying genetic risk variants? Make sure to check for alternative isoforms using long-read RNA-seq data!
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
July 30, 2025 at 11:09 AM
Studying genetic risk variants? Make sure to check for alternative isoforms using long-read RNA-seq data!
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
To recap, the DPP9 variant, previously thought to be non-coding, results in a likely structurally-damaging missense mutation in a lung-specific, functional, alternative DPP9 isoform. 11/
July 30, 2025 at 11:09 AM
To recap, the DPP9 variant, previously thought to be non-coding, results in a likely structurally-damaging missense mutation in a lung-specific, functional, alternative DPP9 isoform. 11/
What is the impact of the COVID-19 variant? It causes a leucine to proline missense mutation in an N-terminal extension formed by the alternative exon, whereby the variant is predicted to disrupt an alpha-helix. 10/
July 30, 2025 at 11:09 AM
What is the impact of the COVID-19 variant? It causes a leucine to proline missense mutation in an N-terminal extension formed by the alternative exon, whereby the variant is predicted to disrupt an alpha-helix. 10/
What do we know about DPP9’s function? It is a serine protease with diverse functions, including regulating the immune response by binding to and inhibiting the NLRP1 inflammasome. So is the alternative DPP9 isoform functional? Yes! It retains both enzymatic activity and NLRP1 binding. 9/
July 30, 2025 at 11:09 AM
What do we know about DPP9’s function? It is a serine protease with diverse functions, including regulating the immune response by binding to and inhibiting the NLRP1 inflammasome. So is the alternative DPP9 isoform functional? Yes! It retains both enzymatic activity and NLRP1 binding. 9/
Is this novel variant-harbouring DPP9 isoform translated? Yes! The isoform is expressed and highly lung-specific 8/
July 30, 2025 at 11:09 AM
Is this novel variant-harbouring DPP9 isoform translated? Yes! The isoform is expressed and highly lung-specific 8/
How can we be confident this isoform is expressed? We developed a protocol for target-enriched long-read RNA-sequencing to achieve high coverage of even rare transcripts. We find fl-DPP9-AFE is significantly expressed in multiple lung cell lines. 7/
July 30, 2025 at 11:09 AM
How can we be confident this isoform is expressed? We developed a protocol for target-enriched long-read RNA-sequencing to achieve high coverage of even rare transcripts. We find fl-DPP9-AFE is significantly expressed in multiple lung cell lines. 7/
How about examples? We intersected GWAS variants for severe COVID-19 with alternative exons to identify a common variant located in an alternative first exon of an unannotated DPP9 isoform (fl-DPP9-AFE). 6/
July 30, 2025 at 11:09 AM
How about examples? We intersected GWAS variants for severe COVID-19 with alternative exons to identify a common variant located in an alternative first exon of an unannotated DPP9 isoform (fl-DPP9-AFE). 6/
How can we assess the impact of variants on these alternative isoforms? We use AlphaFold structural modelling and variant effect prediction to estimate changes to the folding energy (ΔΔG), focusing on missense variants. 5/
July 30, 2025 at 11:09 AM
How can we assess the impact of variants on these alternative isoforms? We use AlphaFold structural modelling and variant effect prediction to estimate changes to the folding energy (ΔΔG), focusing on missense variants. 5/
Why do we think these are important? We find many of these isoforms are highly tissue-specific, more so than the corresponding reference isoform. For example, alternative isoforms harbouring respiratory trait-associated variants are frequently expressed in lung. 4/
July 30, 2025 at 11:09 AM
Why do we think these are important? We find many of these isoforms are highly tissue-specific, more so than the corresponding reference isoform. For example, alternative isoforms harbouring respiratory trait-associated variants are frequently expressed in lung. 4/
So how frequent are variants in alternative isoforms? More common than we thought! Variants are more frequent in alternative than reference exons, in agreement with reduced selection pressure. 3/
July 30, 2025 at 11:09 AM
So how frequent are variants in alternative isoforms? More common than we thought! Variants are more frequent in alternative than reference exons, in agreement with reduced selection pressure. 3/
Genetic variants are typically interpreted by considering only reference isoforms. Yet the vast majority of human genes has multiple isoforms. In fact, based on long-read transcriptomic data, there is 350k alternative exons, ~half of which are not annotated by reference databases (ENIC).
July 30, 2025 at 11:09 AM
Genetic variants are typically interpreted by considering only reference isoforms. Yet the vast majority of human genes has multiple isoforms. In fact, based on long-read transcriptomic data, there is 350k alternative exons, ~half of which are not annotated by reference databases (ENIC).
Studying genetic risk variants? Make sure to check for alternative isoforms using long-read RNA-seq data!
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
July 30, 2025 at 11:05 AM
Studying genetic risk variants? Make sure to check for alternative isoforms using long-read RNA-seq data!
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
Our findings highlight a largely unexplored mechanism where disease-associated genetic variants act by causing damaging mutations in tissue-specific alternative isoforms. 12/
To recap, the DPP9 variant, previously thought to be non-coding, results in a likely structurally-damaging missense mutation in a lung-specific, functional, alternative DPP9 isoform. 11/
July 30, 2025 at 11:05 AM
To recap, the DPP9 variant, previously thought to be non-coding, results in a likely structurally-damaging missense mutation in a lung-specific, functional, alternative DPP9 isoform. 11/
What is the impact of the COVID-19 variant? It causes a leucine to proline missense mutation in an N-terminal extension formed by the alternative exon, whereby the variant is predicted to disrupt an alpha-helix. 10/
July 30, 2025 at 11:05 AM
What is the impact of the COVID-19 variant? It causes a leucine to proline missense mutation in an N-terminal extension formed by the alternative exon, whereby the variant is predicted to disrupt an alpha-helix. 10/
What do we know about DPP9’s function? It is a serine protease with diverse functions, including regulating the immune response by binding to and inhibiting the NLRP1 inflammasome. So is the alternative DPP9 isoform functional? Yes! It retains both enzymatic activity and NLRP1 binding. 9/
July 30, 2025 at 11:05 AM
What do we know about DPP9’s function? It is a serine protease with diverse functions, including regulating the immune response by binding to and inhibiting the NLRP1 inflammasome. So is the alternative DPP9 isoform functional? Yes! It retains both enzymatic activity and NLRP1 binding. 9/
Is this novel variant-harbouring DPP9 isoform translated? Yes! The isoform is expressed and highly lung-specific 8/
July 30, 2025 at 11:05 AM
Is this novel variant-harbouring DPP9 isoform translated? Yes! The isoform is expressed and highly lung-specific 8/
How can we be confident this isoform is expressed? We developed a protocol for target-enriched long-read RNA-sequencing to achieve high coverage of even rare transcripts. We find fl-DPP9-AFE is significantly expressed in multiple lung cell lines. 7/
July 30, 2025 at 11:05 AM
How can we be confident this isoform is expressed? We developed a protocol for target-enriched long-read RNA-sequencing to achieve high coverage of even rare transcripts. We find fl-DPP9-AFE is significantly expressed in multiple lung cell lines. 7/
How about examples? We intersected GWAS variants for severe COVID-19 with alternative exons to identify a common variant located in an alternative first exon of an unannotated DPP9 isoform (fl-DPP9-AFE). 6/
July 30, 2025 at 11:05 AM
How about examples? We intersected GWAS variants for severe COVID-19 with alternative exons to identify a common variant located in an alternative first exon of an unannotated DPP9 isoform (fl-DPP9-AFE). 6/
How can we assess the impact of variants on these alternative isoforms? We use AlphaFold structural modelling and variant effect prediction to estimate changes to the folding energy (ΔΔG), focusing on missense variants. 5/
July 30, 2025 at 11:05 AM
How can we assess the impact of variants on these alternative isoforms? We use AlphaFold structural modelling and variant effect prediction to estimate changes to the folding energy (ΔΔG), focusing on missense variants. 5/
Why do we think these are important? We find many of these isoforms are highly tissue-specific, more so than the corresponding reference isoform. For example, alternative isoforms harbouring respiratory trait-associated variants are frequently expressed in lung. 4/
July 30, 2025 at 11:05 AM
Why do we think these are important? We find many of these isoforms are highly tissue-specific, more so than the corresponding reference isoform. For example, alternative isoforms harbouring respiratory trait-associated variants are frequently expressed in lung. 4/