Zhou A et al., Human Genetics and Genomics Advances - Comparing LD‑pruning, COJO, SuSiE and PCA in haptoglobin (HP) cis‑region data, the study finds including non‑lead variants substantially increases variance explained (R2) and MR precision.

Study Highlights:
The study analyzed circulating haptoglobin (HP) using Fenland protein GWAS summary statistics with LD from UK Biobank, compared four variant selection methods (modified LD‑pruning, COJO, SuSiE, PCA), and extended results with simulations and 15 additional gene regions. In the HP region, incorporating non‑lead variants produced a median proportional gain in R2 of 145.1% and a median reduction in MR standard error of 36.3% relative to the lead variant alone. In simulations with one or two causal variants the methods recovered the expected genetic variance (≈40%) and, when causal variants were removed, non‑lead‑inclusive methods recovered more variance than lead‑only. The functional implication supported by the data is that including correlated non‑lead variants can materially increase instrument strength and precision in cis‑MR, but may raise risks of pleiotropy and numerical instability.

Conclusion:
Variant selection methods that incorporate correlated non‑lead variants reliably improve instrument strength (R2) and MR precision in cis‑MR compared with the lead‑variant‑only approach; comparisons with the lead variant are advised to detect instability.

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Reference:
Zhou A, Karhunen V, Tian H, Pott J, Patel A, Slob EAW, Burgess S. Variant selection to maximize variance explained in cis-Mendelian randomization. Human Genetics and Genomics Advances. 2026 Apr 9;7:100573. https://doi.org/10.1016/j.xhgg.2026.100573.

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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/hp-variant-selection-cis-mr

Lambton J et al., The American Journal of Human Genetics - Bi-allelic ATG12 variants disrupt ATG12‑ATG5 conjugation and LC3 lipidation, impairing autophagy in patient cells and model systems and causing cerebellar vermis hypoplasia.

Study Highlights:
The study characterized six affected individuals with bi-allelic ATG12 variants using patient fibroblasts, HeLa ATG12 knockout complementation, yeast complementation, and CRISPR zebrafish models. Methods included WES/WGS and Sanger sequencing, immunoblotting, LC3/p62 flux assays, HaloTag-LC3 processing, LDH sequestration, AlphaFold-Multimer structural modeling, yeast GFP-Atg8 assays, and zebrafish behavioral and imaging assays. Structural modeling and biochemical data indicate variants map to ATG12 interfaces with ATG5 and ATG3, destabilize ATG12 or its conjugate with ATG5, reduce LC3/Atg8 lipidation and autophagic flux in a variant-dependent manner. Functionally, ATG12 disruption associates with neurodevelopmental phenotypes including cerebellar vermis hypoplasia, ataxia and seizures in humans, and causes growth, brain-structure and locomotor defects with reduced survival in zebrafish.

Conclusion:
Bi-allelic ATG12 variants impair ATG12 function and autophagy, producing a recessive neurodevelopmental disorder marked by cerebellar vermis hypoplasia and neurological deficits.

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Reference:
Lambton J, Asano S, Huang Y, Suomi F, Eguchi T, Petree C, Huang K, Prigent M, Imam A, McCorvie TJ, Warren D, Hobson E, McCullagh H, Misceo D, Bjerre A, Smeland MF, Klingenberg C, Frengen E, Naik S, Ryan G, Sudarsanam A, Foster K, Vasudevan P, Samanta R, Rahman F, Maqbool S, Udani V, Efthymiou S, Houlden H, McFarland R, Collier JJ, Maroofian R, Yue WW, Varshney GK, Klionsky DJ, Legouis R, McWilliams TG, Mizushima N, Oláhová M, Alston CL, Taylor RW. Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder. The American Journal of Human Genetics. 2026 May 7;113:1–18. https://doi.org/10.1016/j.ajhg.2026.03.002

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Strand LG et al., PNAS - In C. elegans germline, the deubiquitinase DUO-1 is required for assembly and active maintenance of the synaptonemal complex and REC-8 cohesin, preventing RAD-51 accumulation and ensuring diakinesis compaction.

Study Highlights:
Using C. elegans germline as a developmental timecourse model, the authors combined cytological analyses (immunofluorescence, FISH, RAD-51/MSH-5/COSA-1 staining), temporally controlled auxin-inducible degron (AID) depletion, and TurboID proximity labeling with LC–MS to probe DUO-1 function. Loss or acute depletion of DUO-1 impairs SC assembly, leads to progressive axis/SC instability, depletion of REC-8 cohesin from chromosomes, hyperaccumulation of RAD-51-marked early DSB repair intermediates, and premature sister-chromatid separation. TurboID identifies PARG-1 and cohesin/HORMAD components as proximal partners and DUO-1::GFP localizes to nucleoplasm and a subset of chromosome axes, most prominently in late pachytene/early diplotene. Temporal AID experiments show DUO-1 is required continuously for early SC assembly, late-pachytene SC maintenance, and rapid preservation of diakinesis chromosome compaction, implying an active maintenance role for DUO-1 in preserving chromosome architecture during meiotic prophase.

Conclusion:
DUO-1 is continuously required throughout meiotic prophase in C. elegans to promote assembly and maintain stability of chromosome axes and synaptonemal complexes, protect REC-8 cohesin distribution, limit accumulation of early DSB repair intermediates, and ensure late-prophase chromosome compaction.

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Reference:
Strand LG, Choi CP, McCoy S, Nsamba ET, Silva N, Villeneuve AM. Active maintenance of meiosis-specific chromosome structures in Caenorhabditis elegans by the deubiquitinase DUO-1. Proc. Natl. Acad. Sci. U.S.A. 2026;123(12):e2532671123. https://doi.org/10.1073/pnas.2532671123

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• (00:00:00) - The architectural worksite of life
• (00:05:24) - The genetic disaster of Meotic mutants
• (00:10:49) - The Duplicity of Probes
• (00:16:29) - How does DNA repair become so fragile as we grow?