Base by Base

Giorgio J et al., Nature Communications - A multi-cohort neuroimaging and genetics study (n=1,354) used PET and causal path modelling to test how sex, APOE-ε4 dosage and TREM2 rare variants influence stages of the canonical amyloid→tau cascade, focusing on entorhinal (EC) and neocortical (MetaTemp) tau. Key terms: APOE-ε4, TREM2, entorhinal tau, amyloid-beta, sex differences.

Study Highlights:
Using ADNI, A4 and HABS-HD cohorts, the authors show that females and APOE-ε4 homozygotes have greater entorhinal tau for a given level of amyloid-beta. APOE-ε4 homozygosity and TREM2 risk-variant carriership are linked to increased spread of tau from entorhinal cortex into neocortex. Interactions among APOE-ε4, TREM2 and sex modulate mediation along the Aβ→EC tau→MetaTemp tau pathway, with replication across cohorts.

Conclusion:
Genetic traits—female sex, APOE-ε4 homozygosity and TREM2 risk variants—produce heterogeneous effects at distinct stages of the amyloid-driven tau cascade: females and APOE-ε4 homozygotes are more susceptible to primary EC tau accumulation for a given Aβ burden, while APOE-ε4 homozygosity and TREM2 variants promote greater neocortical tau spread, with implications for individualized timing of anti-Aβ and anti-tau therapies.

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

Article title:
Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions

First author:
Giorgio J

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60370-8

Reference:
Giorgio J, Jonson C, Wang Y, Yokoyama JS, Wang J, Jagust WJ, et al. Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. Nature Communications. 2025;16:5812. doi:10.1038/s41467-025-60370-8

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/ep90-sex-apoe4-trem2-tau-deposition

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-29.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the canonical amyloid→tau cascade, genetic modifiers (sex, APOE-ε4, TREM2), their interactions with amyloid, and therapeutic implications; cross-checked against the canonical Nature Communications article.
- transcript topics: Sex differences in entorhinal cortex tau accumulation for a given amyloid level; APOE-ε4 dose effects on entorhinal and neocortical tau; TREM2 risk variants and microglial dysfunction in tau spread; Interactions: APOE-ε4 × Aβ and sex × Aβ on tau pathology; Clinical implications for anti-amyloid/anti-tau therapies and personalized medicine

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 4
- 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:
- Canonical AD cascade: amyloid-β initiates tau accumulation in the entorhinal cortex (EC) and tau spreads to the neocortex
- Females show greater EC tau for a given level of amyloid than males
- APOE-ε4 homozygosity increases primary EC tau and promotes neocortical (MetaTemp) tau spread
- TREM2 risk variants exacerbate tau spread and interact with APOE-ε4 on tau burden
- APOE-ε4 × Aβ and sex × Aβ interactions modulate EC tau levels
- Findings replicated across discovery and replication cohorts; cross-sectional design noted as a limitation

QC result: Pass.

Förster F et al., Nature Communications - This GWAMA of up to 21,495 European-ancestry participants used the Sniffin' Sticks odour identification test to map genetic variants influencing identification of twelve odours and an identification score. The study reports ten independent loci (seven novel), sex-stratified effects, and a Mendelian randomization finding that Alzheimer's genetic risk negatively affects smell identification. Key terms: olfaction, GWAS, sex-specific genetics, olfactory receptors, Mendelian randomization.

Study Highlights:
A meta-analysis across four cohorts (n≤21,495) tested identification of twelve Sniffin' Sticks odours and a total identification score. Ten independent loci reached genome-wide significance, seven of them novel, with most loci located in olfactory receptor clusters and other plausible candidates (e.g., ADCY2). Sex-stratified analyses identified female-specific loci and one sex-differential locus, with candidate genes showing predicted androgen response elements. Two-sample Mendelian randomization detected a negative causal effect of Alzheimer's disease genetic risk on the identification score while sex hormones showed no robust causal effect.

Conclusion:
The study adds seven novel loci for odour identification, reveals sex-specific genetic effects at multiple loci, and provides evidence that genetic risk for Alzheimer's disease contributes to poorer global olfactory identification; further molecular and larger cross-ancestry studies are needed to extend these findings.

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

Article title:
Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants

First author:
Förster F

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61330-y

Reference:
Förster F., Emmert D., Horn K., et al. Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants. Nature Communications (2025). DOI: https://doi.org/10.1038/s41467-025-61330-y

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-ep89-olfactory-gwas-sex-differences

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of the article's methods and results: GWAMA findings (ten loci, seven novel, two female-specific, one sex-differential), candidate genes (ADCY2, OR clusters, TAAR5, FBXL17, OR11H7), the pineapple odor driving the overall score, sex-differentiation mechanisms (AREs), Mendelian randomiza
- transcript topics: Sniffin' Sticks test and scoring; Genome-wide association meta-analysis (GWAMA) and loci; Loci near olfactory receptor (OR) clusters and candidate genes; Pineapple odor driving the global identification score; Sex-specific and sex-differential SNP effects and androgen/estrogen regulatory elements; Mendelian randomization: hormones and neurodegenerative diseases

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:
- Ten independent loci associated with odour identification; seven novel loci.
- Loci predominantly located near olfactory receptor (OR) gene clusters and GPCR/neural function genes.
- Two loci are female-specific and one locus is sex-differential (different by sex).
- ADCY2 highlighted as a female-specific candidate near locus 2 (orange odor).
- ADCY3 appears as a suggestive locus near 2p23.3 with potential relevance to cinnamon or general olfactory signaling.
- Pineapple odor drives the overall identification score; removing pineapple from the score eliminates the genome-wide association signal for the score.

QC result: Pass.

Wei Y et al., Nature Communications - A Swedish nationwide register study of 2.93 million children born 1982–2010 found that the heritability of childhood-onset type 1 diabetes remained high (~0.83) and stable over 30 years, while changes in measured environmental factors explained only a small fraction of the rise in incidence. Key terms: type 1 diabetes, heritability, Sweden, childhood-onset, environmental factors.

Study Highlights:
The study followed 2,928,704 children and recorded 20,086 childhood-onset T1D cases, showing incidence rose from birth year 1982 to 2000 then plateaued. Heritability estimated by AE liability models was 0.83 (95% CI 0.79–0.86) and remained stable across birth years and age-at-onset groups, with higher heritability at younger ages. Measured environmental and perinatal factors (including maternal smoking, maternal age, mode of delivery, gestational age and childhood adiposity) together explained only about 5–8% (under 10%) of the increasing incidence, implying additional or interacting drivers.

Conclusion:
Heritability of childhood-onset T1D in Sweden remained high and stable from 1982–2010, and available environmental factors account for only a small part of the observed increase in incidence, pointing to other environmental drivers or gene–environment interactions.

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

Article title:
Stable heritability of type 1 diabetes in a Swedish Nationwide Cohort Study

First author:
Wei Y

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60813-2

Reference:
Wei Y, Andersson T, Liu S, Feychting M, Kuja-Halkola R & Carlsson S. Stable heritability of type 1 diabetes in a Swedish Nationwide Cohort Study. Nature Communications (2025) 16:5327. doi:10.1038/s41467-025-60813-2

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/stable-heritability-t1d-sweden

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for alignment with the article's key findings: heritability and AE modeling, Swedish nationwide cohort design, incidence trends, environmental mediation, and the diabetogenic environment hypothesis; plus limitations and interpretation. Excluded non-scientific asides and promotional material.
- transcript topics: Heritability concept and AE liability threshold model; Swedish nationwide cohort and sibling design; Incidence trends 1982–2000 rise and 2000–2010 plateau; Environmental factors and causal mediation analysis; Diabetogenic environment theory and gene–environment interaction; Limitations and unmeasured factors in the study

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:
- Heritability estimate ~0.83 (83%) and stable across birth years
- Incidence almost doubled from 1982 to 2000, then plateaued 2001–2010
- Environmental factors (known/measured) explain ~5–8% of the rise in incidence
- Maternal smoking during pregnancy explains ~3.2% of the rise; maternal age at delivery ~0.8%
- Childhood overweight/obesity explained ~2–4% (boys) and ~1–2% (girls) of the rise
- Non-shared environmental contribution ~0.17 (17%), shared environment ~0

QC result: Pass.

Nature Communications - This study used fragment-level, sequence-based DNA methylation of circulating cell-free DNA to map cellular origins of tissue damage after liver transplant. An expanded methylation atlas of liver cell types and hybridization capture bisulfite sequencing of 130 serum samples from 44 patients showed that sustained hepatocyte and biliary epithelial cfDNA within the first month signals early allograft injury and that cfDNA composition distinguishes hepatocellular versus biliary etiologies. Key terms: cell-free DNA, DNA methylation, liver transplant, allograft injury, hepatocyte.

Study Highlights:
The authors generated an expanded liver cell-type methylation atlas from 476 methylomes and used hybridization capture bisulfite sequencing on 130 serum samples from 44 transplant patients. Post-reperfusion cfDNA concentrations rose ~5-fold driven mainly by hepatocyte, stellate and endothelial contributions, and hepatocyte cfDNA correlated with AST/ALT. Patients without allograft injury showed recovery of liver-derived cfDNA within the first week, whereas sustained hepatocyte and biliary epithelial cfDNA from POD7–POD30 indicated early allograft injury. CfDNA composition at biopsy timepoints discriminated hepatocellular, biliary, and mixed injury phenotypes.

Conclusion:
Cell-free methylated DNA in circulation can indicate allograft injury and discriminate amongst causes of allograft injury matching tissue-biopsy-proven diagnosis.

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

Article title:
Circulating cell-free DNA methylation patterns indicate cellular sources of allograftinjury after liver transplant

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60507-9

Reference:
https://doi.org/10.1038/s41467-025-60507-9

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/cfdna-methylation-liver-transplant

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main sections describing: the cfDNA methylation atlas expansion, the fragment-level deconvolution method, peri- and post-transplant cfDNA dynamics, differentiation of hepatocellular vs biliary injury, extra-hepatic cfDNA signals, and clinical translation/validation discussion.
- transcript topics: Expansion of liver cell-type DNA methylation atlas; Fragment-level deconvolution of cfDNA; Post-transplant cfDNA dynamics and tissue origins; Differentiation of hepatocellular vs biliary injury; Extrahepatic cfDNA signals (neuronal, cardiac, renal); Clinical implications, limitations, and validation needs

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:
- DOI matches the canonical DOI 10.1038/s41467-025-60507-9
- Article title matches canonical title (formatting variants allowed)
- Journal matches Nature Communications
- License matches CC BY 4.0 variant

QC result: Pass.

Nature Communications - A biobank-scale study using UK Biobank and Mount Sinai BioMe exomes examines three genetic contributors to incomplete penetrance and variable severity of monogenic cardiometabolic variants: heterogeneous missense variant effects, additive polygenic background, and marginal epistasis between carrier status and common variation. Key terms: variant pathogenicity, polygenic risk score, marginal epistasis, ESM1b, biobank exomes.

Study Highlights:
The authors applied the ESM1b protein language model to show that missense variant pathogenicity scores predict phenotype severity for carriers in multiple genes and distinguish gain- from loss-of-function variants. Polygenic risk scores independently modify phenotypes among pathogenic carriers, with noncarriers in PRS tails sometimes exceeding carriers in severity. Using the FAME method, they detected significant marginal epistasis modifying carrier effects for LDL, triglycerides, and MODY, with epistatic improvement percentages up to 170%. Findings were supported by replication in the BioMe cohort and expanded UKB exomes.

Conclusion:
Variant-level effect heterogeneity, polygenic background, and marginal epistasis each contribute to variable penetrance and severity of monogenic metabolic conditions; integrating ESM1b scores, PRS, and interaction effects could improve clinical prognosis for carriers.

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

Article title:
Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60339-7

Reference:
https://doi.org/10.1038/s41467-025-60339-7

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/variable-impact-pathogenic-variants-monogenic-metabolic

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited portions of the transcript that discuss ESM1b variant pathogenicity scores, PRS carrier modification of phenotypes, marginal epistasis with FAME, replication in biobanks, and translational implications, plus limitations. Excluded non-scientific intro language and sponsor-like lines.
- transcript topics: ESM1b variant pathogenicity scoring; Variant effect heterogeneity across monogenic genes; Polygenic risk scores and carrier phenotypes; Marginal epistasis and FAME method; Biobank-scale data sources and replication; Clinical implications and limitations

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:
- Three genetic contributors to penetrance and disease severity: heterogeneous variant effects, additive polygenic background, and marginal epistasis.
- ESM1b scores predict mean phenotype and distinguish GOF vs LOF variants in several monogenic genes.
- PRS modulates carrier phenotype; noncarriers in PRS tails can exhibit more extreme phenotypes than pathogenic carriers for some traits.
- Marginal epistasis between carrier status and polygenic background significantly modifies phenotype, with EIP values up to 170% (triglycerides) and substantial values for LDL/HDL/M
- Biobank-scale replication in Mt. Sinai BioMe and expanded UKB exomes supports findings.
- Potential translational implications include reclassification of variants of uncertain significance using ESM1b and integration into prognosis.

QC result: Pass.

️ Episode 85: Genomic landscape of virus-associated cancers

In this episode of PaperCast Base by Base, we explore the comparative genomic analysis of virus-positive and virus-negative tumors across nine cancer types linked to five oncogenic viruses uncovering epidemiological patterns, mutational signatures, and therapeutic implications.

Study Highlights:

The authors aggregated genomic data from 1,971 tumors spanning nine virus-associated cancers and performed comprehensive analyses of mutation burden and driver mutations across virus-positive and virus-negative cases. They identified that virus-positive tumors generally have a lower somatic mutation load but frequent mutations in RNA helicases DDX3X and EIF4A1 and distinct mutation signatures compared to virus-negative tumors. Epidemiological analysis revealed higher male incidence and geographic disparities for virus-positive cancers, while immunotherapy response data indicated improved outcomes for virus-positive gastric cancer and head and neck squamous cell carcinoma. Comparative copy number and structural variant analyses highlighted recurrent chromosomal losses and translocations associated with viral infection status.

Conclusion:

These findings provide a pan-cancer perspective on the distinct genomic and clinical landscapes of virus-associated malignancies and suggest RNA helicase mutations and viral status as potential biomarkers for targeted therapies.

Reference:

Nam Y, Gomez K, Reynier JB, Khamnei C, Aitken M, Zheng V, Lhakhang T, Casula M, Palmieri G, Cossu A, Levine A, Tiacci E, Rabadan R. Genomic landscape of virus-associated cancers. Nature Communications. 2025;16:5887. doi:10.1038/s41467-025-60836-9.

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/

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

Nature Communications - Genome sequencing identified rare NR6A1 variants in families with colobomatous microphthalmia, missing vertebrae and congenital kidney anomalies. In silico modeling, cell assays, and zebrafish knockdown/rescue experiments support pathogenicity and define NR6A1 as a pleiotropic developmental regulator. Key terms: NR6A1, coloboma, microphthalmia, vertebral anomalies, kidney anomalies.

Study Highlights:
Rare heterozygous NR6A1 variants were found in six independent families presenting coloboma/microphthalmia with missing vertebrae and some kidney anomalies, consistent with an autosomal dominant OVR syndrome with incomplete penetrance. Molecular modeling predicted disruption of DNA or intramolecular contacts, and two missense variants caused abnormal subcellular localization in HEK293 cells. Knockdown of zebrafish nr6a1a/nr6a1b produced eye, kidney, and somite defects that were rescued by wild‑type human NR6A1 mRNA but not by disease variants. NR6A1 is enriched in fetal ocular tissues and correlates with other coloboma genes, supporting a developmental role.

Conclusion:
NR6A1 variants cause a syndromic form of colobomatous microphthalmia with vertebral and renal anomalies (OVR syndrome); NR6A1 should be considered in genetic evaluation of MAC with associated skeletal or renal findings.

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

Article title:
Variants in NR6A1 cause a novel oculo vertebral renal syndrome

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60574-y

Reference:
https://doi.org/10.1038/s41467-025-60574-y

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/nr6a1-oculo-vertebral-renal

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections discuss NR6A1 variants, the two pathogenic missense variants (R92W, R436C), their distinct molecular mechanisms, in vivo zebrafish validation with rescue experiments, and the clinical implication of NR6A1 as an OVR syndrome gene; also covers the genome-first approach and phenotype spectrum.
- transcript topics: NR6A1 and oculo-vertebral-renal (OVR) syndrome; NR6A1 variants R92W and R436C functional consequences; DNA-binding disruption at R92W; Cytoplasmic mislocalization at R436C; Zebrafish nr6a1a/nr6a1b knockdown and mRNA rescue experiments; Genome-first approach (UK100K Genomes Project) and MAC/MA cohorts

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:
- Six rare NR6A1 variants identified across two cohorts (NEI coloboma/OVR and UK100KGP MAC) supporting autosomal dominant OVR syndrome.
- Missense variants R92W and R436C cause distinct functional defects (DNA-binding disruption for R92W; cytoplasmic retention for R436C).
- Zebrafish nr6a1a/nr6a1b knockdown recapitulates ocular, vertebral, and renal phenotypes; wild‑type NR6A1 mRNA rescues, but R92W/R436C variants do not.
- NR6A1 variants account for approximately 1.3%–1.4% of MAC/OVR cases across two cohorts.
- NR6A1 is implicated as a pleiotropic developmental regulator with potential links to retinoic acid signaling.

QC result: Pass.

Perez Y et al., Nature Communications - This episode reviews a single-cell and spatial transcriptomic study of dup15q syndrome using patient postmortem cortex and hiPSC-derived cortical organoids. The work maps developmental metabolic shifts, layer-identity changes, and postnatal synaptic transcriptional burdens linked to autism. Key terms: dup15q, single-cell RNA-seq, cortical organoids, glycolysis, autism.

Study Highlights:
The authors profiled 345,861 postmortem nuclei and 106,302 organoid cells to map cell-type specific transcriptional changes in dup15q. Early organoid progenitors and deep-layer neurons showed increased glycolysis, degraded layer identity, and reduced neurite arborization. In adolescent-adult postmortem cortex, upper-layer neurons carried elevated synaptic transcriptional burden that overlaps idiopathic autism. Conserved gene co-expression modules link metabolic reprogramming to synaptic and ion-channel networks across organoids and tissue.

Conclusion:
Dup15q drives dynamic, cell-type specific molecular shifts from prenatal metabolic reprogramming in progenitors and deep-layer neurons to postnatal synaptic transcriptional changes in upper-layer neurons, highlighting metabolic and synaptic networks as convergent features of syndromic and idiopathic autism.

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

Article title:
Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism

First author:
Perez Y

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61184-4

Reference:
Perez Y, Velmeshev D, Wang L, et al. Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism. Nature Communications. 2025;16:6177. doi:10.1038/s41467-025-61184-4

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/dup15q-single-cell-changes-autism-ep83

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main scientific narrative described in the transcript against the canonical article.

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:
- dup15q leads to increased glycolysis in deep-layer neurons during fetal-stage organoids
- DL neurons show degraded layer identity with co-expression of DL and UL markers
- Sholl analysis shows reduced arborization of dup15q deep-layer neurons in organoids and after xenotransplantation into mice
- adolescent/adult postmortem UL neurons exhibit increased synaptic transcriptional burden overlapping idiopathic autism
- MAPK signaling pathways are implicated and converge with idiopathic ASD
- Conserved co-expression modules between organoids and postmortem tissue (L5_6.2 glycolysis; L5_6.7 synaptic/ion-channel)

QC result: Pass.

Maslah N et al., Nature Communications - Translational study showing ruxolitinib and JAK2 suppression select for RAS pathway–mutant clones in myelofibrosis, enhancing their fitness via MAPK activation and linking this selection to worse clinical outcomes in treated patients. Key terms: ruxolitinib, JAK2, RAS mutations, myelofibrosis, clonal evolution.

Study Highlights:
Longitudinal NGS of 143 myelofibrosis patients and targeted analyses show ruxolitinib exposure is associated with accumulation and increased VAF of NRAS/KRAS/CBL mutations compared with non-exposed patients. Single-cell DNA sequencing and ex vivo CD34+ assays demonstrate ruxolitinib selects RAS-mutant clones both inside and outside JAK/STAT-activated driver clones. In vitro and in vivo competition models and Jak2 knockdown reveal JAK2 inhibition increases RAS-mutant cellular fitness via MAPK pathway activation and release from oncogene-induced senescence. Clinically, RAS pathway mutations predict worse transformation-free and overall survival only in ruxolitinib-treated patients.

Conclusion:
JAK2 inhibition can promote selection and expansion of RAS-mutant clones in MPNs through MAPK-driven fitness advantages, supporting RAS screening and consideration of combinatorial strategies when using JAK inhibitors.

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

Article title:
JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms

First author:
Maslah N

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60884-1

Reference:
Maslah N, Kaci N, Roux B, et al. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms. Nat Commun. 2025;16:6270. doi:10.1038/s41467-025-60884-1

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/ep82-jak2-inhibition-ras-selection-mpn

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering JAK2 inhibition, Ras/MAPK clonal selection, single-cell sequencing and ex vivo CD34+ cell data, in vivo murine competition models, clinical outcome associations, and therapeutic implications.
- transcript topics: JAK-STAT signaling and JAK inhibitors; RAS pathway mutations and clonal selection (NRAS/KRAS/CBL); Single-cell sequencing and ex vivo CD34+ cell experiments; In vivo murine bone marrow competition and transplantation models; MAPK activation and rescue from oncogene-induced senescence; Clinical outcomes: transformation-free survival and overall survival

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:
- Ruxolitinib exposure is associated with accumulation/selection of RAS pathway mutations (NRAS, KRAS, CBL) in myelofibrosis patients.
- RAS mutations predict worse transformation-free survival and overall survival primarily in the context of ruxolitinib treatment.
- MAPK pathway activation is linked to JAK2 downregulation, increasing oncogenic potential of RAS mutations under JAK2 inhibition.
- RAS-mutant clones can be selected under JAK2 inhibition in both JAK/STAT hyper-activated and WT contexts (driver vs non-driver clones).
- Ex vivo treatment of CD34+ cells and single-cell sequencing corroborate RAS clonal selection under ruxolitinib, with in vivo bone-marrow competition mirroring these effects.
- MEK inhibition (trametinib) alongside JAK inhibition can prevent expansion of RAS-mutant clones in model systems.

QC result: Pass.

Wei C-Y et al et al., Nature Communications - Retrospective analysis of 486,956 Han Chinese from the Taiwan Precision Medicine Initiative evaluated prevalence and clinical impact of actionable pharmacogenetic (PGx) variants across 19 genes and 58 drugs, with focused outcome analyses for four gene–drug pairs. Findings confirm widespread PGx variation and statistically increased risks for some adverse events, but absolute excess risks were small and most variant carriers tolerated therapy. Key terms: pharmacogenetics, Taiwan Precision Medicine Initiative, clopidogrel, azathioprine, statins.

Study Highlights:
In 486,956 TPMI participants, 99.9% carried at least one actionable PGx variant and the mean per person was 4.3 variants. Nearly half had been prescribed at least one drug with PGx recommendations and 17.8% received high-risk drugs without prior genotyping. Analyses of CYP2C19–clopidogrel, NUDT15/TPMT–azathioprine, ABCG2/CYP2C9/SLCO1B1–statins, and CYP2C9–NSAIDs validated genotype–ADE associations but showed small absolute excess risks and that most carriers did not experience adverse events. The results highlight implementation complexity and the need to integrate PGx with clinical factors.

Conclusion:
Actionable PGx variants are ubiquitous in this Han Chinese cohort and confer statistically significant risks for drug-related adverse events in several gene–drug pairs, but absolute risk increases are modest and most carriers tolerate treatment; clinical implementation should be cautious and combined with clinical, environmental and additional genetic data.

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

Article title:
Clinical impact of pharmacogenetic risk variants in a large chinese cohort

First author:
Wei C-Y et al

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61644-x

Reference:
Wei C-Y et al., Clinical impact of pharmacogenetic risk variants in a large Chinese cohort. Nature Communications (2025). doi:10.1038/s41467-025-61644-x

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/

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

Episode link: https://basebybase.com/episodes/pgx-tpmi-chinese-cohort-2025

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-20.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's discussion of the TPMI cohort (size, data sources), the four gene–drug pairs (AZA/NUDT15-TPMT, clopidogrel/CYP2C19, statins/ABCG2-CYP2C9/SLCO1B1, NSAIDs/CYP2C9), the core results (relative vs absolute risk), and the study limitations (CYP2D6 exclusion, phenoconversion, EMR data scope).
- transcript topics: TPMI cohort size and data sources (Han Chinese, EMR, SNP arrays); Four pharmacogenes–drug pairs: AZA (NUDT15/TPMT), clopidogrel (CYP2C19), statins (ABCG2/CYP2C9/SLCO1B1), NSAIDs (CYP2C9); Relative vs absolute risk interpretation and clinical utility of PGx; Limitations and future directions (phenoconversion, CYP2D6 exclusion, SNP-array limits, EMR data limits)

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:
- Cohort size: TPMI includes 486,956 Han Chinese participants
- Average number of actionable PGx variants per person: 4.3
- Proportion prescribed at least one PGx drug: 48.7%
- Proportion with actionable PGx variants who took high‑risk drugs: 17.8%
- Four gene–drug pairs analyzed: azathioprine (NUDT15/TPMT), clopidogrel (CYP2C19), statins (ABCG2/CYP2C9/SLCO1B1), NSAIDs (CYP2C9)
- CYP2C19 LOF carriers with clopidogrel had higher MACE risk (OR ~1.53); 85.9% tolerated clopidogrel

QC result: Pass.