Show Notes
Arterbery et al., The American Journal of Human Genetics - Hundreds of genes have been reported as causes of cerebral palsy, yet there is no agreed model of what a pathogenic variant in a child with CP actually means. This study treats CP as a phenotypic feature that some genetic disorders make more likely, tests the reported genes against the population prevalence of CP across tens of thousands of published individuals, and finds statistical evidence of association for only 89 of 515, before applying that stratification to genome sequencing of 460 children with CP. Key terms: cerebral palsy, Mendelian disease, genome sequencing, Human Phenotype Ontology, gene-disease association. Study Highlights:Across 21 published genomic diagnostic cohorts, variants deemed causal of cerebral palsy had been reported in 515 genes, with no consensus on whether such variants cause CP, mimic it, or coexist with it. The authors modelled CP as a phenotypic feature with a known population prevalence and applied a Bonferroni-corrected binomial test to 280 genes drawn from 5,508 publications describing 43,897 individuals, rejecting the null hypothesis of no association for 86 genes, and for 89 when combined with the genes enriched across the CP sequencing cohorts. Genome sequencing of 460 children with CP from 453 families at Shriners Children's identified pathogenic or likely pathogenic variants in 60 genes in 15.8% of the children. Only 16 of those 60 genes had significant literature evidence for CP association, which still represented a 16.3-fold enrichment over the overlap expected by chance. The results support a stratified approach in which the strength of evidence for each gene shapes how a molecular finding in a child with CP is interpreted. Conclusion:A pathogenic variant found in a child with cerebral palsy does not carry the same weight for every gene: for most of the 515 genes reported so far, the literature does not yet provide statistical evidence that the associated disorder raises the likelihood of CP. Treating CP as a phenotype with graded genetic evidence offers a framework for attributing causality more carefully in precision genomic diagnosis, while leaving open that more genes may prove to be associated as data accumulate. Music:Enjoy the music based on this article at the end of the episode. Article title:A phenotypic paradigm for cerebral palsy genetics First author:Arterbery Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.08.007 Reference:Arterbery, A.S., Gargano, M.A., et al., and Robinson, P.N. (2026). A phenotypic paradigm for cerebral palsy genetics. The American Journal of Human Genetics 113, 1972-1986. https://doi.org/10.1016/j.ajhg.2026.08.007 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/cerebral-palsy-genetics-phenotypic-model QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-13. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music<...
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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...
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:<...
Lin et al., The American Journal of Human Genetics - Bi-allelic variants in IDUA classically cause mucopolysaccharidosis type I, a lysosomal storage disorder that affects many organs from childhood. This study describes 14 adults and young adults from 12 families who first came to eye clinics with retinitis pigmentosa and were later found to carry bi-allelic IDUA variants. Seven of them showed no systemic features of the disease even after detailed assessment, and enzyme activity in white blood cells was reduced but never absent. Cell-based enzyme assays and long-read RNA sequencing explain how mild, hypomorphic alleles can leave just enough enzyme to spare the body but not the retina. Key terms: IDUA, mucopolysaccharidosis type I, retinitis pigmentosa, hypomorphic variants, splicing. Study Highlights:Individuals aged 19 to 73 were recruited from inherited retinal disease cohorts in the UK, Ireland, Italy, the Netherlands and the United States, and none carried two null alleles; most had a loss-of-function allele paired with a missense variant. Leukocyte alpha-L-iduronidase activity was reduced but detectable in all nine individuals tested, and urine glycosaminoglycans were above normal in only half of those tested, with modest elevations. In an IDUA-knockout cell line, several missense variants, including p.His91Tyr and p.Arg383His, showed relative specific activity around 0.5% to 1.5% of wild type, with poor processing or stability. The recurrent c.298A>G variant left enzyme activity intact as a protein change, but nanopore long-read sequencing showed that it mostly causes exon 2 skipping, with only about 1.3% of reads from that allele spliced normally. Conclusion:Hypomorphic IDUA genotypes that leave low residual enzyme activity can cause late-onset retinitis pigmentosa with mild or apparently no systemic disease, extending the known spectrum of MPS I and arguing for including IDUA in inherited retinal disease gene panels. The cohort is small and mostly of European ancestry, systemic assessment varied in depth, and without longitudinal follow-up some individuals classed as having isolated retinal disease may still develop systemic features. Article title:Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I First author:Lin Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.09.008 Reference:Lin, S., Yu, S.-H., Browning, A. C., et al., Roosing, S., Steet, R., and Arno, G. (2026). Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I. The American Journal of Human Genetics 113, 1-12. https://doi.org/10.1016/j.ajhg.2026.09.008 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/idua-hypomorphic-retinitis-pigmentosa-mps-i QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-11. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/out...
Thorne et al., Proceedings of the National Academy of Sciences - GLP-1 receptor agonists such as semaglutide produce large weight loss, but part of what is lost is lean mass, energy expenditure falls, and weight tends to return when treatment stops. This study tests a complementary idea in mice: switching on heat-producing fat by silencing ZFP423, a repressor of brown and beige fat identity, with an adipose-targeted antisense oligonucleotide. The RNA drug raised energy expenditure and improved metabolism on its own, and combined with semaglutide it produced more weight and fat loss while roughly halving the loss of lean mass. Key terms: GLP-1 receptor agonist, ZFP423, antisense oligonucleotide, adipose thermogenesis, lean mass. Study Highlights:Antisense oligonucleotides against Zfp423 were linked to palmitic acid to reach fat tissue, and two of twelve candidates, ASO37 and ASO44, were selected for strong knockdown without signs of toxicity. In lean mice on chow, weekly treatment for 10 weeks beiged white fat, raised oxygen consumption and body surface temperature without changing activity, and improved glucose tolerance even though body weight stayed the same, while muscle and heart function were preserved. In obese mice, three doses lowered fasting triglycerides, glucose and body weight, and fat mitochondria from treated mice showed more than threefold higher oxygen consumption than controls, partly through UCP1 and partly through the futile creatine cycle. Combined with semaglutide, ASO37 produced 9.2 g of weight loss against 6.6 g for either drug alone, cut body fat to 4.2 g, and limited lean mass loss to 5.5% compared with about 10% with semaglutide alone. Conclusion:In mice, silencing ZFP423 in fat with an RNA drug turns on thermogenic beige fat and complements GLP-1 receptor agonist treatment by adding fat loss and sparing lean mass. The work was done only in mice, the antisense drugs target mouse Zfp423 rather than human ZNF423, combination studies lasted three weeks, and several authors are employees of Ionis Pharmaceuticals or inventors on a related patent application. Article title:An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss First author:Thorne Journal:Proceedings of the National Academy of Sciences DOI:10.1073/pnas.2618845123 Reference:Thorne, A. K., Waldeck, N. J., Rose, J. P., Stachowski, M. J., Guak, H., Keeble, A. R., et al., and Bass, J. (2026). An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss. Proceedings of the National Academy of Sciences 123(40), e2618845123. https://doi.org/10.1073/pnas.2618845123 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/zfp423-rna-therapy-beige-fat-glp1-lean-mass QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-06. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the ZFP423 rationale...
Zhu et al., Proceedings of the National Academy of Sciences - Genome-wide studies of schizophrenia and other psychiatric disorders find hundreds of hits, yet those hits barely clear the significance threshold and tend to be common variants, unlike traits such as LDL cholesterol. This study shows that other traits whose heritability is enriched in the central nervous system share the same pattern, that the pattern survives careful matching of statistical power between binary and quantitative traits, and that it is best explained by an evolutionary model in which brain-related traits have very large mutational targets and their variants face stronger selection. Key terms: genetic architecture, natural selection, GWAS, psychiatric genetics, mutational target size. Study Highlights:Using stratified LD score regression across 220 cell types, the authors classified 164 traits and found 50 brain-related quantitative traits and four brain-related disorders, all psychiatric, among 151 UK Biobank traits and 13 diseases. Schizophrenia hits had a narrower spread of z-scores and higher minor allele frequencies than LDL or coronary artery disease hits, and the difference remained after downsampling the other GWAS to the effective sample size of the schizophrenia study. Fitting a pleiotropic stabilizing selection model, they inferred a selection distribution shifted toward stronger selection for brain-related traits and a median mutational target of about 1.32% of the genome, against 0.27% for other traits. Simulations showed that stronger selection, once GWAS ascertainment is applied, enriches hits for common variants, and rare loss-of-function burden tests showed that highly constrained genes have larger effects on brain-related traits than on other traits. Conclusion:Traits mediated by the central nervous system share a distinct genetic architecture of many small, relatively common effects, which the authors attribute to large mutational target sizes and stronger selection on brain-relevant variants and genes. The brain-related traits studied act as proxies for the processes under selection, so the specific targets of selection cannot be identified, and confounding was not fully excluded because family-based GWAS remain underpowered. Article title:Genetic architectures of brain-related traits are shaped by strong selective constraints First author:Zhu Journal:Proceedings of the National Academy of Sciences DOI:10.1073/pnas.2609814123 Reference:Zhu, H., Simons, Y. B., Spence, J. P., Sella, G., and Pritchard, J. K. (2026). Genetic architectures of brain-related traits are shaped by strong selective constraints. Proceedings of the National Academy of Sciences 123(36), e2609814123. https://doi.org/10.1073/pnas.2609814123 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/brain-traits-strong-selection-genetic-architecture QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-04. QC Scope:- article metadata and core scientific claims from the narration- excludes analog...