Pilar Alvarez Jerez
@pilaralvjer
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PhD Student NIH/UCL 🧬 Long-read technologies for structural variation
Joined December 2019
Delighted to comment on the paper explaining the role of a new GBA variant in Parkinson's risk in Africa in Nature Structural and Molecular Biology by @pilaralvjer
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Proud of the team!
1/ 🧵 So excited to finally share our preprint! Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation (SV) on gene expression and DNA methylation- A new genomic resource for brain research! 🧠✨ https://t.co/vYcbGIJWXU
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Out now! Excited to share and grateful for all the work and collaboration on this one. 🎉
New paper from @pilaralvjer @cornelisblauw & GP2 colleagues reports the functional effect of the African ancestry-specific GBA1 non-coding #Parkinsons risk variant; It interfers with splicing of functional GBA1 transcripts; =⬇️protein &⬇️GCase activity https://t.co/MVQRa1V8iU
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Collaborating with colleagues from Sweden ( https://t.co/xiVO9w52To) & leveraging @nanopore targeted #longreadsequencing, we showed that the #SCA4 GGC repeat expansion haplotype arose from a common founder ~2,000 years ago https://t.co/2v6CqLqz43.
@LRS_UCL
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The @GenomeInABottle genomic stratifications resource is published in @NatureComms: https://t.co/Ar1Dx3I1yK Stratifications reveal key insights into precision and recall of variant calling across different genomic contexts! Great team work by Nate Dwarshuis, Justin Zook & others
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Great overview of our CARD long-read project! We’re sequencing thousands of human brains to better understand the genetics of ADRDs across diverse populations 🧬🧠 🌎 This wouldn’t be possible without our amazing sequencing dream team 😎 Big data release coming soon!
Hear how researchers at the Centre for Alzheimer’s & Related Dementias are gaining a better understanding of the genetics behind neurodegenerative diseases. Discover how using the #PromethION they scaled-up their workflow to sequence thousands of samples rapidly.
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Join our @DEMONNetworkUK #Genetics and #Omics meeting on THURSDAY 12th September @ 2.30 PM (UK Time). Delighted to have @pilaralvjer as invited speaker – “African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1” Join network or DM for more info
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Proud of these guys ✨
Trying to do @nanopore Long-read sequencing and only have old DNA samples available? Check out our new protocol aimed at getting the best N50s and coverage possible for that input 🧬 (Note: HMW extractions from tissue always preferred) feedback welcome
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New paper from @pilaralvjer @KimberleyBill10 et al investigates prevalence of RFC1 (AAGGG) expansions in #Parkinsons patients of non-Finnish European ancestry in 1609 cases from the @MichaelJFoxOrg PPMI study; 4 PD = biallelic RFC1 expansion (controls=0) https://t.co/Xjj0JpvFLh
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Other authors on this platform include: @em_ka_gu, @mbmakarious, @KimberleyBill10, @kendaida, @huwmorris, @HamptonLLeonard, @mike_nalls, @sarabandres1, @EstebanBurchard, @Linda_Kachuri, @SingletonNeuro, @Michael_E_Ward_. Plus many others who are not on the socials!
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Lastly, a huge thank you to everyone that participated in this work, especially @peter_wc and @cornelisblauw as well as GP2 ( @ASAP_research) and the team at the University of Lagos!
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All scripts and code for this project can be found at:
github.com
This is the online repository for the manuscript titled "African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1" - GP2code/GBA1-rs3115534-branchpoint
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Summary statistics for cis-eQTLs and a catalog of ancestry-specific eQTLs from Kachuri et al. were obtained from https://t.co/xLkiI3EPjQ.
zenodo.org
We explored the role of genetic ancestry in shaping the genetic architecture of whole blood gene expression using whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino...
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1000 Genomes project data is publicly available at https://t.co/oRRMRfJbey. All generated brain tissue bulk RNAseq data (ONT) is currently being submitted to the NIMH data sharing platform at https://t.co/bdqO9FbKAs.
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All generated LCL Coriell ONT DNAseq, CAGEseq and RNAseq data (Illumina and ONT) is available at https://t.co/w9CHOeob9n via GP2 tier 2 access. AMP-PD Illumina blood based RNAseq is available at https://t.co/w9CHOeob9n after signing the data usage agreement.
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This work was limited by a small amount of ancestrally diverse genetic datasets, and thus ongoing recruitment efforts of diverse samples will be crucial in further follow ups of rs3115534.
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We report the functional effect of a GBA1 non-coding risk variant, which interferes with splicing of functional transcripts, resulting in reduced protein levels and reduced enzyme activity. This understanding reveals a novel therapeutic target in an underrepresented population.
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Follow-up analysis showed that rs3115534 is in a key intronic branchpoint sequence and therefore has important implications in splicing and disease. Additionally, when measuring glucocerebrosidase activity we identified a dose-dependent reduction in risk variant carriers.
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CRISPR editing of the reported index variant (rs3115534) confirmed that this is the responsible sequence alteration driving production of these intron 8 containing transcripts.
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Using long-read RNA sequencing, we identified intron 8 expression in risk variant carriers (G) absent in non-variant carriers (T). This was then replicated in short-read datasets.
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