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Penkert J et al., The American Journal of Human Genetics - Carriers of disease-causing TP53 variants range from mild to severe cancer phenotypes. Using relative fitness scores from a deep CRISPR mutagenesis screen of 9,225 TP53 mutations, this registry study of 437 individuals from 168 families shows that variants scoring 0.673 or higher go with earlier cancer and with full Li-Fraumeni syndrome. Key terms: Li-Fraumeni syndrome, TP53, deep CRISPR mutagenesis, relative fitness score, cancer surveillance.

Study Highlights:
A previous screen introduced 9,225 TP53 mutations into a colorectal cancer cell line and scored how well each mutant survived TP53 activators, giving a relative fitness score (RFS). The authors linked these scores to 437 individuals from 168 families in the German Cancer Predisposition Syndrome Registry. Carriers of variants with an RFS of 0.673 or higher developed cancer earlier; an RFS below 0.673 had a hazard ratio of 0.41 (95% CI 0.25 to 0.66, p 0.0002) for cancer. The association held among the 407 individuals whose variant is predicted to produce an altered protein, excluding NULL variants (hazard ratio 0.43). Families with a high score met the definition of Li-Fraumeni syndrome in 110 of 148 cases (74.3%), against 3 of 20 (15%) with a low score.

Conclusion:
Relative fitness scores from deep CRISPR mutagenesis separated TP53 variant carriers with earlier cancer and more severe Li-Fraumeni spectrum phenotypes, which suggests they could feed future variant classification and tailored surveillance. The finding was not validated in an independent cohort, the scores come from a single colorectal cell line, and they exist only for variants in the DNA binding domain.

Article title:
Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome

First author:
Penkert J

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.09.016

Reference:
Penkert J., Großhennig A., Dutzmann C.M., Ewert A., Zimmer R., Schoene-Bake J., et al. Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.016

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:
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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/crispr-fitness-score-cancer-risk-li-fraumeni

QC:
This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.

QC Summary:
- sentences checked: 88
- supported by the article: 87
- flagged and reviewed by a human: 1
- metadata checks passed: 4 of 4

QC result: Pass.

Tzoumkas K et al., The American Journal of Human Genetics - COL4A3 and COL4A4 are paralogous genes that build the same collagen IV network in the kidney filter, and variant guidelines have generally treated them as interchangeable. This episode follows a population-scale study in the UK Biobank, replicated in All of Us, showing that truncating and NC1 domain missense variants carry much stronger associations with hematuria and proteinuria in COL4A4 than in COL4A3, while glycine substitutions behave alike in both genes. Key terms: COL4A3, COL4A4, Alport syndrome, hematuria, UK Biobank.

Study Highlights:
Using whole-genome sequencing from the UK Biobank (n ≈ 500,000) with replication in All of Us (n ≈ 414,000), the authors ran per-variant association tests, gene-based collapsing analyses and phenome-wide association studies across hematuria, proteinuria and chronic kidney disease. They identified 64 COL4A3 and 92 COL4A4 rare variants significantly associated with hematuria or proteinuria. Glycine substitutions in the collagenous domain conferred similar risks in both genes, but truncating and NC1 missense variants were strongly associated with disease only in COL4A4, with proteinuria case rates of 52.7% and 37.2% in COL4A4 compared with 17.1% and 12.1% in COL4A3. The difference persisted after excluding the British founder variant p.Ser969Ter and was independently replicated in All of Us. A genome-wide analysis found the COL4A3 and COL4A4 locus to be the dominant genetic signal for hematuria, accounted for by rare coding variants, with no evidence of independent trans-acting modifiers.

Conclusion:
The authors conclude that gene identity, not variant class alone, should inform risk stratification, variant interpretation and genetic counseling in collagen IV heterozygotes. The analyses were restricted to individuals of European ancestry, phenotypes came from ICD-10 codes and laboratory data that likely underestimate prevalence, the difference was not extended to severe CKD, and the mechanism behind the gene-specific effect remains speculative.

Article title:
Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes

First author:
Tzoumkas K

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.10.002

Reference:
Tzoumkas K., Doctor G.T., Sadeghi-Alavijeh O., Gale D.P. Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.10.002

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
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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/col4a3-col4a4-divergent-pathogenicity

QC:
This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.

QC Summary:
- sentences checked: 175
- supported by the article: 174
- flagged and reviewed by a human: 1
- metadata checks passed: 4 of 4

QC result: Pass.

Klaver M et al., The EMBO Journal - In 1961, Hayflick and Moorhead showed that normal human fibroblasts divide only a finite number of times. This episode follows a review of the six decades since, as senescence moved from a cell-culture limit to a tumor-suppressive stress response, a tissue-remodeling program, a contributor to aging and disease, and a target for therapy. Key terms: cellular senescence, SASP, senolytics, senomorphics, aging.

Study Highlights:
This review traces cellular senescence from the Hayflick limit of 1961 through telomere shortening, biomarkers and oncogene-induced senescence. The senescence-associated secretory phenotype revealed that senescent cells actively communicate with their tissues, and later work showed there is no single universal SASP. Genetic ablation in mice showed that senescent cells can contribute causally to age-related decline, while other studies showed roles in wound healing, development and tissue repair, and one p16-lineage study reported detrimental effects on the liver. Senolytics such as dasatinib plus quercetin and senomorphics followed, but UBX0101 failed to show significant benefit in Phase 2 and UBX1325 missed its Phase 2b primary endpoint. The authors identify the lack of validated biomarkers of target engagement as the major bottleneck in clinical senotherapy.

Conclusion:
The authors conclude that senescence is neither inherently beneficial nor inherently detrimental, and that its consequences depend on context, which senescent cells are involved, and how long they persist. This is a narrative review, not a new experiment, and much of the causal evidence comes from mouse models, with human trials so far early, limited by size or design, or unsuccessful.

Article title:
Cellular senescence: six decades of discovery and reinvention

First author:
Klaver M

Journal:
The EMBO Journal

DOI:
10.1038/s44318-026-00922-w

Reference:
Klaver M., Steeneken L.S., Veeningen N., Altulea A., Demaria M. Cellular senescence: six decades of discovery and reinvention. The EMBO Journal, 45, 7307-7325. (2026). https://doi.org/10.1038/s44318-026-00922-w

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
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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/cellular-senescence-six-decades-review

QC:
This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.

QC Summary:
- sentences checked: 183
- supported by the article: 182
- flagged and reviewed by a human: 1
- metadata checks passed: 4 of 4

QC result: Pass.

Wienbrandt L et al., Nature Genetics - Most genetic studies read only a fraction of the genome and infer the rest from a reference panel. This episode covers a new panel built from whole-genome sequencing of 490,319 UK Biobank participants, benchmarked against the TOPMed r3 panel across 35 datasets and used to reanalyze COVID-19 association studies from four European countries. Key terms: genotype imputation, haplotype reference panel, UK Biobank, EagleImp, COVID-19 GWAS.

Study Highlights:
Researchers phased whole-genome data from 490,319 UK Biobank participants into reference panels of more than 361 million variants and extended EagleImp to run on a standalone server and inside the UK Biobank Research Analysis Platform. Compared with the TOPMed r3 panel of 133,597 individuals, the UK Biobank panel achieved lower phasing switch error rates for all superpopulations except AMR and for 25 of 26 1000 Genomes subpopulations. Mean absolute error improved for 4 of 5 superpopulations and 12 subpopulations, while TOPMed performed better across all frequency categories in AFR. Estimated R2 improved across all 5 superpopulations and 22 subpopulations for variants down to 0.01% frequency, with the largest gain, +24.39%, in East Asian samples. Reimputing an Italian severe COVID-19 study of 835 cases and 1,255 controls yielded a genome-wide significant association at 3p21.31 and a new lead SNP, rs73064425, that matched three independent studies.

Conclusion:
The authors conclude that the UK Biobank panel is the most suitable panel for imputing worldwide populations when no population-specific panel is available, and that common-variant imputation is not yet saturated in the European populations tested. The benchmark has limits: estimated imputation R2 stays low for most subpopulations below 0.01% frequency, truth-based measures may be inaccurate at low frequencies, and TOPMed r3 still performed better in AFR on mean absolute error and holds more panel-specific variants.

Article title:
A haplotype reference panel constructed from 490,319 UK Biobank genomes improves genotype imputation for global populations

First author:
Wienbrandt L

Journal:
Nature Genetics

DOI:
10.1038/s41588-026-02819-0

Reference:
Wienbrandt L., Prieß C., Schmöhl M., Neff V., Gretsova M., Torres G., et al. A haplotype reference panel constructed from 490,319 UK Biobank genomes improves genotype imputation for global populations. Nature Genetics. (2026). https://doi.org/10.1038/s41588-026-02819-0

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
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▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
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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/uk-biobank-haplotype-reference-panel-imputation

QC:
This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.

QC Summary:
- sentences checked: 176
- supported by the article: 143
- flagged and reviewed by a human: 33
- metadata checks passed: 4 of 4

QC result: Warn.

Fowler J et al., Nature Genetics - Normal esophageal lining is a patchwork of mutant clones that compete for space as we age. This study asked whether cancer treatment changes which of those clones win. Normal esophagus removed at surgery from 70 patients with esophageal cancer, who had received no treatment, combination chemotherapy (ECX, EOX or FLOT) or chemoradiation (CROSS), was analyzed with duplex (NanoSeq), whole-genome and targeted sequencing, alongside protein structure modeling and a CRISPR experiment in mouse esophageal cultures. Key terms: somatic mutation, clonal selection, esophagus, chemoradiation, TP53.

Study Highlights:
Targeted sequencing of 1,995 samples of 2 mm2 across 324 cancer-associated genes found 23,692 independent mutations, and no chemotherapy mutational signature was detected, suggesting most clones existed before treatment. In patients given CROSS, the proportion of epithelium mutant for TP53 and PPM1D was double that of the other groups, their mutational burden and deletion burden were higher, and over 5% of samples carried a copy number event covering the TP53 locus. HLA-B and SPOP mutants were selected only in CROSS patients, with 13 of 22 HLA-B nonsynonymous mutations predicted to abolish the protein. RAC1, NFE2L2 and MTOR mutants were under positive selection only in the FLOT group, the only regimen giving 5-fluorouracil together with leucovorin, and structural modeling suggested the MTOR mutants would likely remain sensitive to rapalogs. In mouse esophageal cultures, guide RNAs targeting exon 6 of Ppm1d were enriched after irradiation but not after 5-fluorouracil.

Conclusion:
Weeks of neoadjuvant treatment can reshape a mutational landscape built over decades, selectively expanding preexisting mutant clones in a treatment-specific way, which may point to genes involved in cellular resilience to therapy. The groups were small (FLOT had seven patients), exposure data were limited, the mouse experiment did not test the full CROSS combination, the selection of MTOR, RAC1 and NFE2L2 mutants by 5-fluorouracil is inferred rather than tested, and selection in normal tissue cannot be assumed to match selection in cancer cells.

Article title:
Cancer treatment alters mutant selection in normal esophagus

First author:
Fowler J

Journal:
Nature Genetics

DOI:
10.1038/s41588-026-02738-0

Reference:
Fowler J.C., Arbore G., Sood R.K., Abnizova I., Albarello L., Pickering O., et al. Cancer treatment alters mutant selection in normal esophagus. Nature Genetics, 58, 2566-2578. (2026). https://doi.org/10.1038/s41588-026-02738-0

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/cancer-treatment-mutant-selection-normal-esophagus

QC:
This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.

QC Summary:
- sentences checked: 171
- supported by the article: 167
- flagged and reviewed by a human: 4
- metadata checks passed: 4 of 4

QC result: Pass.

Chovanec P et al., eLife - When CRISPR/Cas9 cuts DNA, editing is usually judged by the small insertions and deletions left at the break. But a cut can also be repaired by swapping DNA between the two identical sister chromatids, an exchange that leaves no sequence change and is invisible to standard sequencing. Using sci-L3-Strand-seq, a single-cell method that reads which parental template strand each daughter cell inherited, this study mapped Cas9-induced sister chromatid exchange (SCE) in human cells, after cutting either one unique site or 237 repetitive Alu sites at once. Key terms: CRISPR/Cas9, sister chromatid exchange, Strand-seq, DNA double-strand break repair, structural variants.

Study Highlights:
Duplex Cas9 cleavage at a single site or at 237 repetitive targets caused a pronounced G1/S arrest within 24 hr, while the D10A and H840A nickases did not measurably perturb cell-cycle progression after washout. Cutting a unique locus strongly enriched SCE at the break site, reaching 41% in the same cell cycle and 17% in the subsequent division. Across all cells, cutting 237 Alu sites gave only mild on-target enrichment, 1.20-fold in the post-washout condition (n=2547 cells), but a high-SCE subset of 261 cells showed 1.39-fold enrichment with an average of 14.61 on-target SCEs per cell. Reciprocal daughter-cell pair analysis found that 14 of 50 Cas9-induced SCE events were coupled with structural variants, in contrast to 87 of 87 spontaneous SCEs in XRCC1-null cells that were reciprocal and copy-neutral in a companion study. Cutting inside LIG3, LIG4, XRCC1 and XRCC4 did not change genome-wide SCE counts, with a median of three SCEs per cell in all four conditions, consistent with delayed functional loss after editing.

Conclusion:
Cas9-induced double-strand breaks are potent local triggers of sister chromatid exchange, and a measurable fraction of these exchanges carries structural alterations that conventional sequencing cannot see, so they do not universally reflect error-free homologous recombination. All experiments were done in wild-type cells, Cas9 can cut the same site several times so individual outcomes cannot be tied to a single cleavage event, and the deletion signature pointing to a TRAIP/under-replicated-region pathway rests on a single daughter-cell pair.

Article title:
Genome-wide mapping of Cas9-induced sister chromatid exchange across single and over 200 genomic sites in human cells

First author:
Chovanec P

Journal:
eLife

DOI:
10.7554/eLife.112073

Reference:
Chovanec P., He S., Yin Y. Genome-wide mapping of Cas9-induced sister chromatid exchange across single and over 200 genomic sites in human cells. eLife, 15. (2026). https://doi.org/10.7554/eLife.112073

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/cas9-sister-chromatid-exchange-strand-seq

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-29.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: The scientific body from the cold open through the take-home was audited; the fixed intro, outro and the card-deck analogy were not treated as factual claims.
- transcript topics: sister chromatid exchange as a silent repair outcome; Cas9 double-strand breaks and isochromatid geometry; sci-L3-Strand-seq template-strand sequencing; cell-cycle arrest after Cas9 and nickase treatment; on-target SCE at single unique loci; SCE enrichment across 237 repetitive Alu targets

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:
- 41% on-target SCE in the first division and 17% after washout
- largest post-washout reduction of 74%
- ~90% bulk editing efficiency and why it is not the same as the SCE rate
- median of three SCEs per cell across the four repair-gene conditions
- 1.20-fold enrichment with 6.13 on-target SCEs per cell in 2547 cells
- 1.39-fold enrichment with 14.61 on-target SCEs per cell in 261 high-SCE cells

QC result: Pass.

Herrick N et al., Human Genetics and Genomics Advances - Orofacial clefts are among the most common birth defects, affecting about 1 in 700 births, yet known genetic signals explain only a fraction of their heritability, and cleft studies cannot reach the huge sample sizes used for traits like height. This study borrowed statistical power from a related trait: the genetics of normal human face shape. Using a pleiotropy-informed method called conditional false discovery rate, the team re-analyzed an existing GWAS of nonsyndromic cleft lip with or without cleft palate and found new candidate risk loci, three of which passed a 5% FDR threshold in an independent replication cohort. Key terms: orofacial cleft, facial shape, GWAS, conditional false discovery rate, pleiotropy.

Study Highlights:
The team conditioned summary statistics from a European nsCL/P GWAS of 3,969 individuals on two independent facial shape GWASs, from 4,680 US and 3,566 UK individuals. SNPs associated with nsCL/P were enriched among SNPs associated with facial shape but not among those for unrelated traits such as height, schizophrenia or LDL cholesterol. The cFDR approach identified 21 independent loci at a 5% threshold and 15 more at 10%, and the new loci had effect sizes comparable to known ones, with no significant difference in a Mann-Whitney U test (p = 0.26). Of 13 new lead SNPs tested in The Cleft Collective cohort of 1,084 affected individuals and 7,913 controls, five replicated at p < 0.05, and loci near MSX2, ASPSCR1 and FHOD3 passed a 5% FDR threshold. Spatial transcriptomics of a Carnegie stage 13 human embryo showed expression and gene specificity scores for these genes in the pharyngeal arches, among other regions.

Conclusion:
Leveraging the shared genetics of face shape and clefting can recover cleft risk loci that a standard GWAS of the same data misses, and it supports the long-standing idea that embryonic face shape is itself part of cleft risk. The analysis is limited to people of European ancestry, the authors expect about 10% of the 36 loci to be false positives, not every new locus replicated, and the expression data support but do not prove a role for the candidate genes.

Article title:
Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci

First author:
Herrick N

Journal:
Human Genetics and Genomics Advances

DOI:
10.1016/j.xhgg.2026.100655

Reference:
Herrick N., Goovaerts S., Manchel A., Lee M.K., Zhang X., Davies A., et al. Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci. Human Genetics and Genomics Advances, 7, 100655. (2026). https://doi.org/10.1016/j.xhgg.2026.100655

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/face-shape-genetics-orofacial-cleft-risk-loci

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: All scientific content: cleft burden and missing heritability, the face shape hypothesis, cFDR method and cohorts, enrichment vs control traits, 36 loci, cohort overlap, effect sizes, replication, regional plots, CS13 expression and gsMap, gene discussion, limitations.
- transcript topics: Orofacial cleft incidence and missing heritability; Embryonic face shape as a cleft risk factor; Conditional false discovery rate GWAS design; Enrichment of nsCL/P SNPs in facial shape vs unrelated traits; 21 loci at 5% cFDR and 15 at 10% cFDR; Effect sizes of known vs new loci

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:
- Incidence about 1/700 live births and over 50 known loci
- Facial GWAS of 4,680 US and 3,566 UK individuals; nsCL/P subset of 3,969
- Enrichment for facial shape but not seven unrelated traits
- 21 loci at 5% and 15 at 10% cFDR; original GWAS 10 plus 2 signals; 24 relied on face
- 55%, 86% and 13% cohort overlap
- Effect sizes above 0.2, means 0.31 and 0.35, p = 0.26

QC result: Pass.

Lisfeld J et al., The American Journal of Human Genetics - SRSF3 is an essential splicing factor, one of the serine/arginine-rich proteins that help cells cut and paste their RNA messages and send them out of the nucleus. Losing it completely is lethal in mouse embryos. This study describes nine individuals with new, non-inherited SRSF3 variants and variable developmental phenotypes, with developmental delay and/or mild to moderate intellectual disability as the most consistent feature. Functional experiments in patient fibroblasts and human cell lines showed that each variant damaged the protein in a different combination of ways, which may help explain why affected individuals differ so much. Key terms: SRSF3, splicing, de novo variants, neurodevelopmental disorder, spliceosomopathy.

Study Highlights:
Through GeneMatcher, the team recruited nine subjects with six heterozygous de novo SRSF3 variants: two missense variants in the RNA recognition motif, three frameshifts and a recurrent nonsense variant, p.Arg149*, found in four unrelated subjects. In fibroblasts from subject 3, transcripts carrying the c.330_331del frameshift were largely degraded by nonsense-mediated decay, with only about 12.5% of SRSF3 reads carrying the deletion, yet overall SRSF3 mRNA and protein levels were normal, suggesting compensation from the other allele. In HEK293T cells, all five variant proteins tested formed less complex with polyadenylated RNA than wild type, while the three C-terminally truncated proteins were poorly phosphorylated, less stable, at about 46% to 59% of wild-type levels, and showed reduced nucleocytoplasmic shuttling in HeLa cells. Complex formation with the export factors YTHDC1 and NXF1 was reduced for p.Arg137Ilefs*16 and p.Arg149* and increased for p.Ser81Trp.

Conclusion:
De novo SRSF3 variants define a new spliceosomopathy with a broad developmental spectrum, and the variants appear to act through distinct mechanisms rather than simple loss of half the protein. The cohort is small, most functional work used overexpressed proteins in cell lines rather than affected tissues, the evidence against haploinsufficiency comes from one subject and one cell type, and the c.330_331del variant remains of uncertain significance.

Article title:
De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes

First author:
Lisfeld J

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.09.018

Reference:
Lisfeld J., Chinn I.K., Yuan B., Casar C., Müller C., Elron E., et al. De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.018

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/srsf3-de-novo-variants-splicing-factor-development

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Splicing and SR proteins; SRSF3 structure and autoregulation; cohort, variants and clinical features; subject 3 fibroblasts; phosphorylation, stability, RNA binding, shuttling and export-factor binding of variants; implications, SRSF1 comparison and limits.
- transcript topics: Splicing and SR proteins; SRSF3 structure and phosphorylation cycle; Poison exon autoregulation; Six de novo SRSF3 variants in nine subjects; Clinical spectrum; NMD and compensation in subject 3 fibroblasts

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- 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:
- Nine subjects via GeneMatcher with six de novo heterozygous variants; p.Arg149* in four unrelated subjects
- SRSF3 is 164 amino acids; complete loss lethal in mouse embryos; 12 SR proteins in humans
- Developmental delay in seven; mild to moderate ID in four; autistic behavior in four; seizures in two; facial dysmorphism in seven
- About 12.5% of reads (259 of 2,080) carry c.330_331del; normal mRNA and protein vs 42 controls; about 35% remaining after 8 h ActD
- Truncated proteins at about 46%, 59% and 55%
- Polyadenylated RNA binding about 60% to 24% of wild type

QC result: Pass.

Jang Y et al., The American Journal of Human Genetics - Every cell in the body picks up its own small set of DNA changes over a lifetime, and many of these somatic mutations are carried by only a tiny fraction of cells. This study, part of the SMaHT Network, asks how reliably standard bulk whole-genome sequencing can find mutations present at a variant allele fraction below 1%. The team built a ground truth from one donor's skin: clonal stem cell lines grown from single fibroblasts defined real mutations, and lines from other skin biopsies of the same donor defined mutations that should be absent. With about 1,360× Illumina coverage confirmed by PacBio and AVITI, point mutations below 1% were detected accurately in the easily mapped parts of the genome. Key terms: somatic mosaicism, whole-genome sequencing, variant allele fraction, benchmarking, SMaHT.

Study Highlights:
Primary fibroblasts from a 29-year-old donor contained five subclones, captured as clonal iPSC lines, giving benchmark mutations from 0.1% to 25% variant allele fraction, while iPSC lines from other biopsies of the same donor supplied negative controls; both sets held about 11,000 SNVs and 2,800 indels. Using the negative controls, PacBio and AVITI had the lowest substitution error rates in easy regions, 0.003% and 0.005%, and mismatch rates rose by 1 to 2 orders of magnitude in harder regions. In fibroblasts, more than 99.5% of bulk-only calls above 1% were confirmed by PacBio or AVITI, the estimated false-positive rate was near zero above 0.8% and about 11% below 0.5%, and homopolymer indels could be detected reliably only above 3%. In postmortem lung and colon, combining about 200× from two tissues found 13 additional shared mutations, a 145% gain in sensitivity below 3%, all confirmed by PacBio or single-cell data.

Conclusion:
Ultra-deep bulk whole-genome sequencing can detect point mutations below 1% allele fraction with high accuracy, provided calling is restricted to easily mapped regions and sample quality is checked, and pooling coverage across tissues from one donor recovers shared developmental mutations. The benchmark comes from a single donor's fibroblasts, confirmation below 0.5% was limited by long-read and AVITI coverage, most indels sit in homopolymers or hard regions where detection remains unreliable, and postmortem samples needed extra filtering.

Article title:
Accurate detection of sub-1% frequency somatic mutations by whole-genome sequencing

First author:
Jang Y

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.09.010

Reference:
Jang Y., Gardiner S., Wang Y., Natu A., Dehankar M.K., Tomasini L., et al. Accurate detection of sub-1% frequency somatic mutations by whole-genome sequencing. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.010

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/detecting-sub-1-percent-somatic-mutations-wgs

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Context on somatic mutations, VAF and SMaHT; prior benchmark weaknesses; study design with iPSC lines; platform error rates; SNV and indel detection; phasing-based false-positive rates; caller complementarity; coverage effects; postmortem filters; joint tissue analysis; implications and limits.
- transcript topics: Somatic mutations and variant allele fraction; SMaHT Network goals; Benchmark built from one donor's fibroblasts and iPSC lines; Sequencing platform error rates; Sub-1% SNV detection and confirmation; Read-backed phasing false-positive estimates

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- 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:
- SMaHT: 10-15 tissues from 150 non-diseased donors at about 300x
- Donor LB, 29-year-old male, 25 clonal iPSC lines from six biopsies
- About 2,000 SNVs and 550 indels per line; 99.5% and 98.5% PacBio validation
- Benchmark and negative sets of about 11,000 SNVs and 2,800 indels; VAF 0.1%-25%
- About 1,360x Illumina, about 380x PacBio, about 220x AVITI
- Easy regions about 74% of GRCh38

QC result: Pass.

Meyer-Schuman R et al., The American Journal of Human Genetics - Autism is diagnosed about four times more often in male individuals than in female individuals, and one explanation is mild variants in dosage-sensitive genes on the X chromosome, which a female carrier can buffer with her second copy but a male cannot. This study tests that idea in MECP2, the Rett syndrome gene, by looking at the switches that control how much of it is made rather than the gene itself. Using a massively parallel reporter assay in human stem-cell-derived neurons, the team mapped the active transcription factor binding sites in five MECP2 regulatory elements and tested 22 ultra-rare variants passed from unaffected mothers to autistic sons. Two variants changed regulatory activity, and one in the promoter lowered MECP2 RNA and protein by about 30% when edited into the native gene. Key terms: MECP2, autism, massively parallel reporter assay, noncoding variants, X chromosome.

Study Highlights:
Whole-genome data from 30,916 individuals in 8,245 autism families yielded 22 ultra-rare noncoding variants in MECP2 regulatory elements, each private to one family, found only in male probands and inherited from an unaffected mother, tested alongside 19 gnomAD control variants. Shuffling predicted transcription factor motifs mapped activator or repressor hotspots in four of the five elements, and knocking down two predicted activators, TCF3 and ZNF281, lowered MECP2 RNA by about 55% and 47% after three weeks. A variant in the primate-specific repressor element CRE A, carried by two affected brothers, increased activity in both the reporter and luciferase assays. The promoter variant g.154097837A>G, found in a boy with autism and ADHD and a full-scale IQ of 97, weakened NFY-B binding at the MECP2 promoter from the 51st to the 9th percentile of bound promoters and reduced MECP2 RNA and protein by about 30% in edited neurons.

Conclusion:
The findings suggest that noncoding MECP2 variants that modestly lower or raise expression can contribute to idiopathic, male-biased autism, and they provide a framework for finding regulatory variants in other X chromosome neurodevelopmental genes. The evidence rests on two families and on reporter assays and edited neurons in a dish, which take short sequences out of their native chromatin context, so the link between these variants and autism still needs additional variant discoveries and molecular validation.

Article title:
A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism

First author:
Meyer-Schuman R

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.09.011

Reference:
Meyer-Schuman R., Cherry F., Sui Y., Papastathopoulos-Katsaros A., Zhong Y., Li Y., et al. A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.011

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at 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/mecp2-regulatory-variants-male-biased-autism

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Context on MECP2 dosage and sex bias, cohort and variant filtering, MPRA design in iNeurons, hotspot and transcription factor findings, CRE A and promoter variant validation, NFY-B CUT&Tag and expression results, implications and limitations.
- transcript topics: MECP2 dosage sensitivity and X-linked sex bias; Variant discovery in 8,245 autism families; Lentiviral MPRA with motif shuffling in iNeurons; CRE 2 activators TCF3 and ZNF281; Context-dependent ZNF362 site; CRE A repressor variant in two brothers

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- 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:
- 30,916 individuals in 8,245 families across 12 cohorts
- 22 private maternally inherited variants in male probands and 19 gnomAD controls
- 270 bp tiles offset by 70 bp, over 1,000 mutations per CRE, four replicates, ~135 barcodes per element
- Hotspots in four of five CREs; CRE B inactive in neurons
- TCF3 knockdown 20% then ~55%; ZNF281 47%
- CRE A variant g.154046133T>C increased activity and was inherited by two affected brothers

QC result: Pass.