Base by Base

Peters R et al., The American Journal of Human Genetics - This episode reviews a nationwide survey of 2,509 Australian adults using two discrete choice experiments to quantify public preferences and the monetary value placed on genomic newborn screening (gNBS), and to identify preferred implementation features such as consent model and result delivery. Key terms: genomic newborn screening, discrete choice experiment, public preferences, health policy, Australia.

Study Highlights:
Two discrete choice experiments with 2,509 Australian participants reveal a broad public preference for gNBS, with cost identified as the strongest influence on uptake. Higher accuracy and more additional diagnoses increase public utility, but including conditions with limited or no treatments and reduced penetrance reduces value. The public values a gNBS program that yields 10–50 additional diagnoses per 1,000 newborns at AU$4,600–5,700 per newborn for restrictive models. Most respondents preferred an opt-in consent model and favored initial information from GPs or obstetricians and high-chance results returned by genetics professionals.

Conclusion:
Australian public preferences support implementation of gNBS if programs balance cost, accuracy, and condition selection, and if service delivery prioritizes trusted clinicians and genetics professionals for complex results; findings should inform economic evaluations and implementation planning.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Public preferences for the value and implementation of genomic newborn screening: Insights from two discrete choice experiments in Australia

First author:
Peters R

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.05.001

Reference:
Peters R., Best S., Lynch F., et al. Public preferences for the value and implementation of genomic newborn screening: Insights from two discrete choice experiments in Australia. The American Journal of Human Genetics. 112:1–13, July 3, 2025. https://doi.org/10.1016/j.ajhg.2025.05.001

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/gnbs-public-preferences-australia

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and quantitative results described in the transcript: public interest and uptake, cost as a driver, monetary valuation for restrictive vs non-restrictive gNBS, four latent classes, implementation preferences (delivery and return of results), and policy/workforce implications.
- transcript topics: Genomic newborn screening concept and ethical considerations; Discrete choice experiments (DCE) methodology and latent class analysis; Public value results: uptake, trade-offs, and monetary valuation; Implementation preferences: who informs and who returns results, delivery modes; Policy implications: workforce training and service-delivery models; Study limitations and design considerations

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Public interest in gNBS (~90%) and uptake (>87%)
- Cost is the primary driver of uptake
- Monetary value: AU$4,600–5,700 per newborn for 10–50 additional diagnoses per 1,000 (restrictive); AU$5,400 per newborn for non-restrictive
- Four latent classes with proportions: Class1 ~13%, Class2 ~28%, Class3 ~42%, Class4 ~17%

QC result: Pass.

Provided PDF (truncated source text) et al., Cell - This episode reviews a study that examines SLC7A11 (7A11) localization to lysosomes and its impact on lysosomal acidification, cystine/cysteine balance, lysosomal function, and cell viability using genetic and pharmacologic tools and isolated lysosome assays. Key terms: SLC7A11, lysosome, lysosomal pH, cystine, ferroptosis.

Study Highlights:
The authors localize SLC7A11/7A11 to lysosomes (LAMP1 colocalization, tagged knock‑ins/overexpression) and measure juxta‑lysosomal pH changes with genetically encoded and dye‑based pH reporters. Loss, inhibition, or mutation of 7A11 alters lysosomal acidification, cystine/cysteine handling and downstream readouts including cathepsin activity, lipid peroxidation markers, and cell viability under ferroptosis‑related perturbations. Experiments include isolated lysosome assays, pharmacologic modulators (erastin, RSL3, bafilomycin, chloroquine, ferrostatin‑1), multiple cell lines (HT1080, HeLa, HAP1, MEFs), and analyses of patient‑derived neurons from PD cohorts.

Conclusion:
SLC7A11 associates with lysosomes and modulates lysosomal pH and amino‑acid flux; altering its function changes lysosomal enzyme activity and cellular stress responses in experimental models, suggesting lysosomal amino‑acid handling is an important regulator of lysosomal physiology.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
SLC7A11 is an unconventional H+ transporter in lysosomes

First author:
Provided PDF (truncated source text)

Journal:
Cell

DOI:
10.1016/j.cell.2025.04.004

Reference:
Provided PDF (truncated source text)

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/base-by-base-40-slc7a11-lysosomes

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-09.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive content describing lysosomal localization of SLC7A11, the proposed H+ shuttle/vent mechanism, the pH change from ~4.6 to ~4.2 upon valve disruption, downstream lysosomal dysfunction and ferroptosis, chloroquine rescue at low dose, AAS trafficking mutation validation, and Parkinson's disease relevanc
- transcript topics: Lysosomal localization of SLC7A11 and LAMP1 colocalization; Proton shuttle mechanism and lysosomal H+ leak; Effect of SLC7A11 loss on lysosomal pH and enzyme activity; Lipofuscin accumulation and ferroptosis in neurons; Chloroquine low-dose rescue of lysosomal pH and ferroptosis; AAS trafficking mutation confirms lysosomal localization

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- SLC7A11 localizes to lysosomes and colocalizes with LAMP1
- SLC7A11 modulates lysosomal juxta‑lysosomal pH via a proton shuttle mechanism
- Loss/inhibition of SLC7A11 leads to lysosomal overacidification and dysfunction (pH ~4.2; enzymes impaired; lipofuscin accumulation; ferroptosis)
- Low-dose chloroquine (1 µM) buffers lysosomal pH from ~4.2 to ~4.6 and rescues lipofuscin accumulation and ferroptosis
- AAS trafficking mutation demonstrates lysosomal localization as the site of the proton leak
- Parkinson's disease relevance evidenced by alpha-synuclein aggregation and patient-derived neuronal models

QC result: Pass.

Zabad S et al., The American Journal of Human Genetics - This episode covers Zabad et al.'s methods to scale summary-statistics-based polygenic risk score (PRS) inference to millions of variants. The authors introduce compressed LD storage, memory-efficient coordinate-ascent variational algorithms, and multi-level parallelism to cut storage, runtime, and RAM by orders of magnitude while retaining competitive prediction accuracy. Key terms: polygenic risk scores, linkage disequilibrium, variational inference, LD compression, VIPRS.

Study Highlights:
The authors design a compact LD-matrix format (CSR stored in Zarr with quantization) and algorithmic optimizations that reduce LD storage by over 50-fold. They reimplement coordinate-ascent variational updates in C/C++ using single-precision floats, triangular-LD updates, dequantize-on-the-fly, and two layers of parallelism to cut runtime and memory use by orders of magnitude. VIPRS v0.1 can run variational Bayesian regression on 1.1M HapMap3 variants in under a minute and converges genome wide on up to 18M variants in tens of minutes using <15 GB RAM. The paper also analyzes spectral causes of numerical instability in LD matrices and gives practical recommendations to improve stability and prediction accuracy.

Conclusion:
The updated VIPRS toolkit enables fast, memory-efficient whole-genome PRS inference at biobank scale with competitive accuracy and provides storage formats and numerical safeguards to improve reproducibility and portability.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Toward whole-genome inference of polygenic scores with fast and memory-efficient algorithms

First author:
Zabad S

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.05.002

Reference:
Zabad S., Haryan C.A., Gravel S., Misra S., Li Y. (2025). Toward whole-genome inference of polygenic scores with fast and memory-efficient algorithms. The American Journal of Human Genetics 112, 1–19. https://doi.org/10.1016/j.ajhg.2025.05.002

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/viprs-whole-genome-prs

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's presentation of VIPRS architecture (LD storage, quantization, DQF, triangular LD), memory/performance benchmarks, parallelism, numerical stability guards, and cross-ancestry/cross-biobank findings against the original article.
- transcript topics: Polygenic risk scores and LD challenges; LD matrix compression via upper-triangular storage; CSR storage and Zarr cloud-native format; Quantization to int8/int16 and scale quantization; Dequantize-on-the-Fly (DQF) memory management; Coordinate ascent updates and OpenMP parallelism

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- LD matrix compression reduces storage by >50-fold; 1.4M HapMap3 variants stored in ~300 MB
- LD matrices stored in CSR format with quantization to int8/int16 (scale quantization)
- Dequantize-on-the-Fly (DQF) streams data and avoids full in-memory decompression, reducing memory usage
- Triangular LD mode reduces memory usage by about 40% compared with symmetric LD mode
- Two layers of parallelism: across chromosomes and within coordinate-ascent; ~30% total runtime reduction with 4 threads
- VIPRS v0.1 can infer 1.1M HapMap3 variants in under a minute; converges on up to 18M variants in tens of minutes using <15 GB RAM

QC result: Pass.

Pekar JE et al., Cell - Recombination-aware, whole-genome analyses of sarbecoviruses show that genomic fragments very closely related to SARS-CoV and SARS-CoV-2 circulated in horseshoe bats only years before human emergence. Phylogeography places recent ancestors in western China and northern Laos and indicates movement patterns inconsistent with bat-only dispersal, implicating intermediate hosts or wildlife trade. Key terms: sarbecovirus, recombination, phylogeography, horseshoe bats, zoonotic spillover.

Study Highlights:
The authors mapped recombination breakpoints and analyzed non-recombinant regions (NRRs) across sarbecovirus genomes to infer separate evolutionary histories for SARS-CoV-1-like and SARS-CoV-2-like viruses. Closest-inferred bat virus ancestors for both human SARS-CoVs often date just 1–6 years before human emergence in specific NRRs. Phylogeographic reconstructions place those recent ancestors in western China and northern Laos/Yunnan, and show viral diffusion rates approximating horseshoe bat movement. The geographic distances and required dispersal velocities make bat-only spread to emergence sites unlikely, supporting a role for intermediate hosts or wildlife trade.

Conclusion:
Non-recombinant genome segments reveal very recent bat ancestors of SARS-CoV and SARS-CoV-2 that likely could not have reached human emergence sites by bat movement alone, highlighting the importance of whole-genome surveillance in bats, targeted sampling in Southwest China and Northern Laos, and monitoring of wildlife trade pathways.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2

First author:
Pekar JE

Journal:
Cell

DOI:
10.1016/j.cell.2025.03.035

Reference:
Pekar JE, Lytras S, Ghafari M, et al. The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2. Cell. 2025;188:1–17. doi:10.1016/j.cell.2025.03.035

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/recency-geographical-origins-bat-viruses-sars-cov-sars-cov-2

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing non-recombinant regions (NRRs), recombination-aware dating, the Prisoner of War (PoW) molecular clock, phylogeography, dispersal velocities, geographic origins of closest bat ancestors, and implications about wildlife trade as a bridge to emergence.
- transcript topics: Recombination and non-recombinant regions (NRRs); NRR-based dating and closest-inferred bat ancestors; Prisoner of War (PoW) molecular clock and substitution saturation; Phylogeography and isolation by distance; Dispersal velocities and bat-host diffusion; Geographic origins of closest bat ancestors (SARS-CoV-1 in Western China; SARS-CoV-2 in Yunnan/Northern Laos)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Closest bat-virus ancestors for SARS-CoV-1 circulated in bats in 2001 (1 year before SARS-CoV-1 emergence in 2002; NRR14).
- Closest bat-virus ancestors for SARS-CoV-2 circulated in bats in 2014 (two NRRs with closest ancestors in 2014; HPD intervals given).
- SARS-CoV-1-like ancestors inferred in Western China (Yunnan, Sichuan, Guizhou) and SARS-CoV-2-like ancestors in Yunnan or Northern Laos.
- Outbreaks in Guangzhou (SARS-CoV-1) and Wuhan (SARS-CoV-2) are ~1000 km from bat-ancestor circulation sites.
- Weighted diffusion coefficients: SARS-CoV-1-like ~1666 km^2/year; SARS-CoV-2-like ~740 km^2/year.
- Isolation by distance indicates viruses spread at rates matching bat host movement; bat dispersal is relatively local.

QC result: Pass.

Palafox MF et al., The American Journal of Human Genetics - This episode explores a multi-omic study showing that mass spectrometry–based chemoproteomic detection of cysteine, lysine, and tyrosine (CpDAAs) highlights protein sites and regions enriched for pathogenic missense variants and variant uncertainty. Key terms: chemoproteomics, missense_variants, CpDAA, fumarate_hydratase, variant_interpretation.

Study Highlights:
The authors assembled curated chemoproteomic datasets profiling cysteine, lysine, and tyrosine reactivity across the human proteome and mapped CpDAAs to monogenic-disease genes, ClinVar variants, and protein structures. CpD proteins are enriched for OMIM disease genes, missense constraint, and protein-protein interactions, and CpDAAs are significantly closer to pathogenic missense variants in both 1D sequence windows and 3D structure. Lysine- and tyrosine-detected residues show the strongest enrichment for proximal pathogenic variants, while cysteine environments harbor many VUSs and pathogenic alleles. A case study of fumarate hydratase (FH) demonstrates that CpDAA-proximal variants cluster in 3D and that mutations at detected cysteines alter FH oligomerization.

Conclusion:
Integrating chemoproteomic amino-acid reactivity with genetic and structural data can help prioritize likely functional and druggable missense variants, complementing existing variant-effect predictors.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids

First author:
Palafox MF

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.04.017

Reference:
Palafox MF, Boatner L, Wilde BR, Christofk H, Backus KM, Arboleda VA. Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids. The American Journal of Human Genetics. 2025;112:1–15. doi:10.1016/j.ajhg.2025.04.017

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/chemoproteomics-missense-variants-cpdaas

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the scientific content presented in the transcript: CpDAA concept, 1D and 3D proximity analyses, FH case study with tetramerization, implications for variant interpretation and covalent drug targeting, and acknowledged limitations.
- transcript topics: Introduction to CpDAA concept and chemoproteomics; CpDAA mapping to disease-relevant genes (OMIM, ClinVar, FDA targets); 1D proximity analysis (6-amino-acid windows around CpDAAs); 3D proximity analysis (8-Å radius around CpDAAs in protein structures); Fumarate hydratase (FH) case study and Cys333/Cys434 CpDAA neighborhood; VUS, CADD scoring, and enrichment patterns by amino-acid type

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CpDAAs defined as reactive cysteine, lysine, and tyrosine residues identified by chemoproteomics
- CpD proteins are enriched for OMIM monogenic-disease genes and FDA drug targets
- Pathogenic missense variants are proximal to CpDAAs in 1D space (near CpDAAs, e.g., within ~6 amino acids)
- Pathogenic missense variants are proximal to CpDAAs in 3D space (within ~8 Å)
- Lysine and tyrosine CpDAAs show stronger enrichment for proximal pathogenic variants than cysteine CpDAAs
- FH (fumarate hydratase) as a case study shows CpDAA environments near pathogenic/VUS variants and disruption of tetramerization

QC result: Pass.

Nicastro M et al., The American Journal of Human Genetics - This episode covers Nicastro et al. (2025), who identify bi-allelic POPDC2 variants in four families causing a recessive cardiac syndrome marked by sinus-node dysfunction, atrioventricular conduction defects and, in some cases, hypertrophic cardiomyopathy. The study combines genetic sequencing, structural modeling, electrophysiology, tissue analyses and population biobank data to link impaired cAMP binding and loss of POPDC2 modulation of TREK-1 to the phenotype and to show heterozygous carriers are unlikely to be clinically affected. Key terms: POPDC2, cardiac conduction defects, hypertrophic cardiomyopathy, TREK-1, cAMP binding.

Study Highlights:
Researchers found homozygous or compound heterozygous POPDC2 variants in multiple families with early-onset sinus-node disease, AV block and occasional HCM. Homology models and AlphaMissense predict the variants impair cAMP binding and dimerization of POPDC2. In vitro, mutant POPDC2 failed to increase TREK-1 current density and muscle biopsy showed reduced POPDC1/POPDC2 abundance. Population analysis across >1 million individuals found no disease association for heterozygous carriers, supporting a recessive mode of inheritance.

Conclusion:
Bi-allelic loss-of-function POPDC2 variants cause a Mendelian autosomal recessive cardiac syndrome involving conduction disease and sometimes HCM; functional data implicate impaired cAMP binding and reduced TREK-1 regulation, and heterozygous carriers are unlikely to develop clinical disease based on population analyses.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

First author:
Nicastro M

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.04.016

Reference:
Nicastro M, Vermeer AMC, Postema PG, et al. Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy. The American Journal of Human Genetics. 2025;112:1–18. doi:10.1016/j.ajhg.2025.04.016

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/popdc2-recessive-cardiac-syndrome

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the scientific content segments: genetic etiology (POPDC2 LOF and autosomal recessive syndrome), structural modeling and cAMP binding, in vitro TREK-1 electrophysiology, simulation data linking TREK-1 changes to pacemaking, single-cell/transcriptomic localization in AV/sinus nodes, population-biob
- transcript topics: POPDC2 bi-allelic LOF variants and autosomal recessive cardiac syndrome; Structural modeling and predicted disruption of cAMP binding; TREK-1 electrophysiology and POPDC2 interaction in cells; In silico cardiac simulations linking TREK-1 reduction to bradycardia; Population genetics: heterozygous carrier analyses in biobanks; Single-cell and spatial transcriptomics of POPDC1/POPDC2 in AV node and sinus node

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Bi-allelic loss-of-function variants in POPDC2 cause an autosomal recessive cardiac syndrome with sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy (HC
- Variants predicted to diminish POPDC2’s cAMP binding and disrupt the dimer interface.
- Mutant POPDC2 proteins fail to increase TREK-1 current density in co-expression assays with TREK-1 compared to wild-type POPDC2.
- Heterozygous POPDC2 variants are not associated with the clinical syndrome in large population biobanks.
- POPDC2 is highly expressed in the sinus node and co-expressed with POPDC1 in AV node/pacemaker cells; POPDC1/POPDC2 co-expression supports trafficking to the membrane.
- Population analyses across >1 million individuals show no disease associations for heterozygous carriers of the identified POPDC2 variants.

QC result: Pass.

This episode summarizes a study that genotyped the CCR5Δ32 deletion in ancient and modern human genomes, compared genotyping methods for low‑coverage ancient DNA, reconstructed CCR5 haplotypes, and modeled the deletion's spatiotemporal frequency and selection history. The work benchmarks HAPI (with informed priors) against GATK and VG, maps haplotype distributions (A,B,C), and infers allele frequency trajectories and selection signals across ancestries and time periods. Key terms: CCR5-delta32, ancient DNA, haplotype, selection, genotyping.

Study Highlights:
The authors developed and benchmarked an HAPI genotyping pipeline tailored for low‑coverage ancient DNA and showed it outperformed GATK and VG when using informed priors, recovering CCR5Δ32 genotypes at very low coverage. They assembled haplotype backgrounds (named A, B, C) with tag SNPs linked to CCR5Δ32 and traced their geographic distributions in ancient samples. Spatiotemporal allele frequency maps and modeling indicate increases in CCR5Δ32 frequency in parts of Europe within the last several thousand years and detect ancestry‑specific signals compatible with recent positive selection. The study also highlights sensitivity to coverage, reference choice, and permissive vs strict filtering when inferring trajectories and selection coefficients.

Conclusion:
Ancient DNA genotyping using haplotype‑aware approaches can reliably recover CCR5Δ32 and its haplotype backgrounds at low coverage, enabling reconstruction of the deletion's geographic spread and suggesting recent, ancestry‑specific increases in frequency consistent with positive selection, while results remain sensitive to coverage and filtering choices.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Tracing the evolutionary history of the CCR5delta32 deletion via ancient and modern genomes

Journal:
Cell

DOI:
10.1016/j.cell.2025.04.015

Reference:
Ravn K, Cobuccio L, Muktupavela RA, et al. Tracing the evolutionary history of the CCR5delta32 deletion via ancient and modern genomes. Cell. 2025;188:3679-3695.e16. doi:10.1016/j.cell.2025.04.015

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ccr5-delta32-ancient-genomes

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and methods described in the transcript against the article’s findings and metadata, focusing on CCR5Δ32 biology, haplotype architecture, ancient DNA methodology, origin and selection, geographic distribution, and implications for modern genome editing.
- transcript topics: CCR5Δ32 function and HIV resistance; Haplotype architecture A, B, C and 84 tag SNPs; Ancient DNA genotyping with HAPI priors and low coverage; Origin on the Western Eurasian steppe (~6700 years ago); Karagash evidence; Bronze Age selection window (8000–2000 years BP); European allele-frequency trajectories and Northern Europe ~16% frequency

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CCR5Δ32 is a 32-base-pair deletion
- CCR5Δ32 resides on multiple haplotypes (A, B, C) defined by surrounding tag SNPs
- Origin traceable to about 6,700 years ago on the Western Eurasian steppe; Karagash skeleton provides preserved haplotype context
- CCR5Δ32 haplotype A is surrounded by a large set of tag SNPs (84 SNPs)
- Allele frequency maps show increased CCR5Δ32 frequency in parts of Europe in recent millennia; Northern Europe frequency up to ~16%
- HAPI genotyping with informed priors recovers CCR5Δ32 genotypes from genomes as low as 0.3X coverage

QC result: Pass.

Ficicioglu C et al., Genetics in Medicine (2025) 27, 101456 - Phase 1/2 COMPOSE trial tested subcutaneous pegtibatinase in 24 participants with classical homocystinuria; treatment was generally well tolerated and produced rapid, dose-dependent reductions in total plasma homocysteine (tHcy). Key terms: classical homocystinuria, pegtibatinase, enzyme replacement therapy, total plasma homocysteine, clinical trial.

Study Highlights:
COMPOSE randomized 24 participants across six ascending dose cohorts of pegtibatinase versus placebo to evaluate safety and effects on tHcy. Pegtibatinase was generally well tolerated with mostly mild injection-site reactions and no anaphylaxis or severe immune reactions. At 1.5 mg/kg BIW and 2.5 mg/kg BIW, geometric mean tHcy fell by 57% and 67% respectively, with all participants at these doses achieving tHcy <100 μM and one achieving normal tHcy. Anti-drug and anti-PEG antibodies were frequently detected but were typically low or transient and did not affect tHcy pharmacokinetics.

Conclusion:
Pegtibatinase was generally well tolerated and produced substantial, sustained reductions in tHcy at the two highest doses, supporting further evaluation as a potential enzyme replacement therapy for classical homocystinuria.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial

First author:
Ficicioglu C

Journal:
Genetics in Medicine (2025) 27, 101456

DOI:
10.1016/j.gim.2025.101456

Reference:
Ficicioglu C, Thomas JA, Ganesh J, Kudrow D, Lah M, Smith WE, Guner J, McDermott S, Vaidya SA, Wilkening L, Levy HL. Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial. Genetics in Medicine. 2025;27:101456. doi:10.1016/j.gim.2025.101456

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ep34-pegtibatinase-compose-hcu

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the scientific content in the transcript, including mechanism (metabolic sink), study design, efficacy (tHcy and methionine), safety/immunogenicity, and limitations as reported in the original article.
- transcript topics: Mechanism of action: metabolic sink in plasma to reduce tissue tHcy; COMPOSE study design: phase 1/2, 6 dose cohorts, 3:1 randomization; Efficacy outcomes: tHcy reductions at high doses, threshold of 100 μM; Individual patient outcomes: one case with <15 μM tHcy and low methionine enabling dietary protein increase; Methionine-cycle metabolite changes indicating pathway restoration; Safety and immunogenicity: TEAEs, injection-site reactions, urticaria, antibody data

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Pegtibatinase evaluated in the COMPOSE phase 1/2 randomized trial
- Six increasing dose cohorts ranging from 0.33 mg/kg QW to 2.5 mg/kg BIW
- Sample size of 24 randomized participants aged 12–65 years
- High-dose tHcy reductions: 57% (1.5 mg/kg BIW) and 67% (2.5 mg/kg BIW)
- All high-dose participants maintained tHcy <100 μM; one reached <15 μM
- Methionine and other methionine-cycle metabolites shifted toward normal levels

QC result: Pass.

Kim WJ et al., Cell - This episode examines a study that identifies recurrent neoantigens produced by SRSF2 and ZRSR2 splicing factor mutations in myeloid leukemias, isolates cognate TCRs, and demonstrates antigen-specific TCR-T cell activity in vitro and in vivo. Key terms: neoantigens, SRSF2, ZRSR2, TCR-T therapy, myeloid leukemia.

Study Highlights:
The authors used large-scale RNA-seq to identify recurrent mis-spliced isoforms from SRSF2- and ZRSR2-mutant myeloid malignancies and predicted HLA-I-binding peptides. They validated peptide presentation by HLA-IP LC-MS/MS and demonstrated immunogenicity with peptide priming and dextramer isolation of reactive CD8+ T cells. Panels of neoantigen-specific TCRs were cloned from donors and patients and TCR-engineered T cells specifically recognized and killed SRSF2-mutant leukemia cells in vitro and reduced tumor burden in NSG xenografts. Single-cell profiling of patient blood showed circulating neoantigen-reactive CD8+ T cells that are clonally expanded but exhibit impaired NF-kB/TNF signaling.

Conclusion:
Recurrent mis-splicing events from splicing factor mutations generate shared, actionable neoantigens in myeloid leukemias and can be targeted by isolated TCRs, supporting TCR-based immunotherapy strategies while noting patient T cell dysfunction and HLA allele scope as limitations.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias

First author:
Kim WJ

Journal:
Cell

DOI:
10.1016/j.cell.2025.03.047

Reference:
Kim WJ, Crosse EI, De Neef E, et al. Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias. Cell. 2025;188:1–19. doi:10.1016/j.cell.2025.03.047

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/mis-splicing-neoantigens-tcrs-ep33

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript's representation of the article's central scientific narrative: generation of recurrent mis-splicing-derived neoantigens by SRSF2/ZRSR2 mutations, prediction and validation of HLA-I neoepitopes, isolation and characterization of neoantigen-reactive TCRs (CLK3, RHOT2, c16orf70), funct
- transcript topics: AML immunotherapy challenges and targeting; Splicing-factor mutations (SRSF2, ZRSR2) and stereotyped mis-splicing; Neoantigen discovery pipeline (RNA-seq, NetMHCpan, MHCFlurry, HLA-A*02:01); HLA-I binding validation (T2 shift assay) and immunogenicity testing; Dextramer-based isolation of neoantigen-reactive CD8+ T cells; CLK3 neoantigen and exon 4 skipping; NMD involvement

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Splicing-factor mutations SRSF2 and ZRSR2 generate recurrent mis-splicing-derived neoantigens expressed on HLA-I
- neoantigen discovery used large RNA-seq cohorts and in silico predictions (NetMHCpan/MHCFlurry) for HLA-A*02:01 binding
- CLK3-derived neoantigen results from exon 4 skipping; linked to NMD processing and surface presentation
- RHOT2 and c16orf70 mis-spliced transcripts yield neoantigens validated by HLA-IP LC-MS/MS and dextramer staining
- TCRs recognizing CLK3 neoantigen show high affinity (picomolar EC50 range) and redirect CD8+ T cells to kill SRSF2-mutant leukemia cells
- In vivo NSG xenograft data show CLK3 TCR-T cells reducing tumor burden with specificity and minimal off-target effects

QC result: Pass.

Idursulfase Beta — A New Therapeutic Option for MPS II with Strong Clinical Evidence

Article title:
Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: a phase 3, two-part study compared to a historical placebo cohort

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101460

Reference:
Sohn YB, Yang A, Kim MS, Kim J, Kim JS, Oh Y, Jin DK. Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: a phase 3, two-part study compared to a historical placebo cohort. Genetics in Medicine. 2025:101460. doi:10.1016/j.gim.2025.101460

Music:
Enjoy the music based on this article at the end of the episode.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/idursulfase-beta-a-new-therapeutic-option-for-mps-ii-with-strong-clinical-evidence

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the phase 3 two-part trial design, primary/secondary endpoints (6-MWT, GAGs/HS/DS, liver/spleen volumes, FVC), safety/ADAs/NAbs, PK, and manufacturing differences as depicted in the transcript.
- transcript topics: Phase 3 two-part trial design with historical placebo; 6-minute walk test efficacy; Urine GAG/HS/DS reductions; Liver and spleen volume changes; Pulmonary function (absolute FVC); Immunogenicity: anti-drug antibodies and neutralizing antibodies

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- 6-MWT improvement of 62.2 meters with idursulfase beta vs 7.3 meters with historical placebo
- Urine total GAG reduction of -71.13% with idursulfase beta vs +21.39% with historical placebo
- Liver volume reduction of -26.67% with idursulfase beta vs -0.80% with historical placebo
- Spleen volume reduction of -26.46% with idursulfase beta vs +7.2% with historical placebo
- Absolute FVC change showed no significant difference (p = 0.79)
- Anti-drug antibodies detected in most participants; persistent NAb ~17% vs ~62.5% in comparator

QC result: Pass.