️ Episode 150: Patrilineal segmentary systems and the post‑Neolithic Y‑chromosome bottleneck

In this episode of PaperCast Base by Base, we explore a Nature Communications study that proposes a peaceful, socio‑cultural explanation for the sharp decline in male effective population size observed 3,000–5,000 years ago. Instead of widespread violence, the authors show that the dynamics of patrilineal segmentary systems—where lineages split and reproductive success varies between descent groups—can alone generate the Y‑chromosome bottleneck while female lineages continue to expand.

Study Highlights:
The team builds forward‑time simulations of villages structured by patrilocal residence and patrilineal descent, calibrating Y‑chromosome and mtDNA mutation rates and tracking effective population sizes over 100+ generations. They compare scenarios with random versus lineal fission of descent groups and incorporate empirically grounded variance in reproductive success between groups, with and without modeled violence. Lineal fission combined with inter‑group variance in reproductive success consistently produces a strong reduction in male effective population size, whereas violence alone or random fission has a much weaker effect. Bayesian skyline plots from simulated data reproduce a male‑specific bottleneck alongside continued growth of female effective size, and the timing aligns with post‑Neolithic shifts as agro‑pastoralism and patrilineal inheritance spread. Sensitivity analyses show the bottleneck strengthens as variance in reproductive success increases, while female‑to‑male Ne ratios can reach values comparable to those inferred from real data.

Conclusion:
A shift toward patrilineal, segmentary social organization with lineal fission and unequal reproductive success between descent groups may be sufficient to explain the post‑Neolithic Y‑chromosome bottleneck without invoking pervasive warfare.

Reference:
Guyon L, Guez J, Toupance B, Heyer E, Chaix R. Patrilineal segmentary systems provide a peaceful explanation for the post‑Neolithic Y‑chromosome bottleneck. Nature Communications. 2024;15:3243. https://doi.org/10.1038/s41467-024-47618-5

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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️ Episode 149: Cultural Hitchhiking and the Post‑Neolithic Y‑Chromosome Bottleneck

In this episode of PaperCast Base by Base, we explore how patrilineal social structures and intergroup competition can reshape genetic diversity, offering a cultural explanation for the striking male‑specific bottleneck observed 5,000–7,000 years ago across the Old World.

Study Highlights:
The authors synthesize anthropological theory, population genomics, and mathematical modeling to test whether competition among patrilineal kin groups could drive a sharp reduction in Y‑chromosome diversity while leaving mitochondrial lineages relatively stable. They introduce an analytical Lotka–Volterra framework and a computational grid simulation to show that when descent groups are patrilineal and compete, entire Y‑chromosome clades can be lost at accelerated rates through cultural hitchhiking and drift. Simulations reproduce two key empirical signals seen in modern datasets: a bottleneck‑like collapse in male line diversity without requiring a demographic crash, and rapid, star‑like expansions of a few dominant Y lineages. Archaeogenetic patterns from post‑Neolithic farmer and pastoralist cultures further align with the model’s expectations, showing shallow coalescence and high Y‑line homogeneity within cultural groups across large geographies.

Conclusion:
By linking social organization to genetic patterns, this work reframes the post‑Neolithic Y‑chromosome bottleneck as a cultural phenomenon, sharpening how archaeogenetic signals can be interpreted to infer past social structure and conflict dynamics.

Reference:
Zeng, T. C., Aw, A. J., & Feldman, M. W. Cultural hitchhiking and competition between patrilineal kin groups explain the post‑Neolithic Y‑chromosome bottleneck. Nature Communications, 2018; 9:2077. https://doi.org/10.1038/s41467-018-04375-6

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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If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

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

️ Episode 148: Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants

In this episode of PaperCast Base by Base, we explore a comprehensive functional assessment of splice-site variants in CHEK2 using reporter minigenes, revealing how disrupted pre-mRNA splicing contributes to hereditary breast cancer risk and how these readouts can support clinical variant classification.

Study Highlights:
The authors screened 128 intron–exon boundary variants from large breast cancer cohorts with in silico tools and selected 52 candidates for minigene assays that collectively span all 15 CHEK2 exons.
In transfected MCF-7 cells, 46 of the 52 variants impaired splicing, frequently abolishing the full-length transcript and generating a remarkably complex set of 89 annotated RNA isoforms through exon skipping, intron retention, and alternative splice-site usage.

Several transcripts introduced premature termination codons consistent with predicted nonsense-mediated decay, while a minority preserved the open reading frame or altered the 5′UTR, illustrating diverse molecular consequences.

A notable mechanistic finding was activation of a rare noncanonical TG acceptor site by variant c.684-2A>G, with exon 6 enhancer motifs mapped as critical for this atypical splice-site recognition.
Incorporating minigene readouts into an ACMG/AMP-inspired Bayesian framework enabled tentative reclassification of 32 variants, including 27 as pathogenic or likely pathogenic and 5 as likely benign, while 20 remained VUS due to complex splicing profiles.

Conclusion: Minigene-based splicing assays provide scalable, allele-specific functional evidence that can sharpen clinical interpretation of CHEK2 variants and should be integrated alongside population and case–control data in variant curation workflows.

Reference: Sanoguera-Miralles L, Valenzuela-Palomo A, Bueno-Martínez E, Esteban-Sánchez A, Lorca V, Llinares-Burguet I, García-Álvarez A, Pérez-Segura P, Infante M, Easton DF, Devilee P, Vreeswijk MPG, de la Hoya M, Velasco-Sampedro EA. Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants. Clinical Chemistry. 2024;70(1):319–338. https://doi.org/10.1093/clinchem/hvad125

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: If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

Episode Slug: systematic-minigene-based-splicing-analysis-and-tentative-clinical-classification-of-52-chek2-splice-site-variants

Keywords: CHEK2; splicing; minigene; variant classification; hereditary breast cancer

️ Episode 147: Comprehensive Annotation of Complete ABO Alleles and Resolution of ABO Variants

In this episode of PaperCast Base by Base, we explore a groundbreaking study that introduces an improved long-read sequencing method to fully resolve ABO haplotypes, spanning from the 5′ to the 3′ untranslated regions. This work addresses a major gap in blood group genomics by delivering the most comprehensive annotation of complete ABO alleles to date.

Study Highlights:
Researchers analyzed specimens from 79 blood donors and 47 ABO variants using an optimized ultra-long-range PCR method combined with PacBio SMRT sequencing. They successfully amplified and sequenced the full 26.1 kb ABO gene without splicing, achieving complete coverage including the regulatory 5′ and 3′ UTRs. The study provided detailed haplotype sequences of predominant alleles in a Chinese population, revealing structural variations, recombination events, and previously unknown subtypes. Importantly, this method also resolved complex variants, including large deletions, chimeras, and intronic regulatory motifs, offering new insights into ABO allele diversity and molecular mechanisms.

Conclusion:
This comprehensive full-length ABO haplotype sequencing approach advances transfusion medicine by improving variant resolution, refining allele classification, and enabling more accurate genomic analysis for clinical and evolutionary applications.

Reference:
Ying Y, Zhang J, Hong X, Yuan W, Ma K, Huang X, Xu X, Zhu F. Comprehensive Annotation of Complete ABO Alleles and Resolution of ABO Variants by an Improved Full-Length ABO Haplotype Sequencing. *Clinical Chemistry*. 2025;71(4):510–519. https://doi.org/10.1093/clinchem/hvaf015

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 146: Automated and Decentralized Genomic Profiling of Plasma Cell-Free DNA in Solid Tumors

In this episode of PaperCast Base by Base, we explore the clinical feasibility of an automated and decentralized cfDNA sequencing system designed to identify actionable and resistance alterations in advanced solid tumors.

Study Highlights:
Researchers evaluated plasma cfDNA from 298 patients with advanced cancers using the Oncomine Precision Assay GX and Genexus integrated sequencer. Sequencing success rates were higher for cfDNA compared to tumor tissue, and 50% of patients had detectable ctDNA mutations. Concordance between plasma and tumor results reached 72%, with detection influenced by tumor type, burden, and metastatic site. Plasma-only alterations were observed in 18% of patients, particularly in those previously treated with targeted therapies, underscoring cfDNA’s role in capturing tumor evolution.

Conclusion:
This decentralized approach demonstrates strong potential for expanding timely genomic profiling and improving access to precision oncology.

Reference:
Chan HT, Otaki M, Hayashi N, Fukada I, Chin YM, Fukuda N, Hosonaga M, Wang X, Yunokawa M, Shinozaki E, Yamaguchi K, Wakatsuki T, Kasuga A, Nakamura Y, Takahashi S, Low SK. Automated and Decentralized Genomic Profiling of Plasma Cell-Free DNA for Identification of Targetable and Resistance Alterations in Advanced Solid Tumors. Clinical Chemistry. 2025;71(6):700-712. https://doi.org/10.1093/clinchem/hvaf045

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 145: A Validated Highly Sensitive Microsatellite Instability Assay Identifies PMS2 Variants in CMMRD

In this episode of PaperCast Base by Base, we explore a study that validates a next-generation sequencing-based highly sensitive microsatellite instability (hs-MSI) assay for the diagnosis of constitutional mismatch repair deficiency (CMMRD), a rare childhood-onset cancer predisposition syndrome. The work focuses on improving detection of PMS2 pathogenic variants, the most frequent but technically challenging cause of CMMRD.

Study Highlights:
The researchers applied the hs-MSI assay to a blinded cohort of 66 blood and 24 tumor samples from individuals with CMMRD and controls, demonstrating a sensitivity of 98.5% and specificity of 100% in detecting the syndrome. The hs-MSI results showed strong correlation with whole-genome low-pass instability scores (LOGIC/MMRDness) and identified distinct microsatellite indel patterns that differentiated PMS2 variant carriers with an accuracy of 0.997. Higher hs-MSI scores were also associated with earlier age of tumor onset, highlighting its potential role as a biomarker for cancer risk stratification.

Conclusion:
This validated hs-MSI assay provides a robust and clinically feasible tool to support CMMRD diagnosis, distinguish PMS2 involvement, and personalize surveillance strategies.

Reference:
Marín F, Canet-Hermida J, Bianchi V, Chung J, Wimmer K, Foulkes W, et al. A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency. *Clinical Chemistry*. 2024;70(5):737–746. https://doi.org/10.1093/clinchem/hvae027

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 144: Revised time estimation of the ancestral human chromosome 2 fusion

In this episode of PaperCast Base by Base, we explore a study that revisits one of the most defining events in human evolution: the fusion that gave rise to chromosome 2. This work refines previous estimates and provides a clearer timeline for when this pivotal genomic change occurred.

Study Highlights:
The authors developed an improved algorithm to analyze biased clustered substitutions, allowing more precise dating of genomic events. By comparing the genomes of humans with those of chimpanzees and bonobos, they estimated that the chromosome 2 fusion took place around 0.9 million years ago, with a confidence interval of 0.4 to 1.5 million years. Their findings suggest that this chromosomal event happened more recently than earlier studies had proposed, and the results also provide insights into evolutionary distances among great apes. The approach highlights how computational methods can refine our understanding of human speciation and the genetic divergence from our closest relatives.

Conclusion:
This study provides a sharper view of when the human chromosome 2 fusion occurred, offering new insights into the timing of our evolutionary history.

Reference:
Poszewiecka B, Gogolewski K, Stankiewicz P, Gambin A. Revised time estimation of the ancestral human chromosome 2 fusion. BMC Genomics. 2022;23:616. https://doi.org/10.1186/s12864-022-08828-7

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 143: The genetic history of the Southern Caucasus: 5,000 years of continuity despite high mobility

In this episode of PaperCast Base by Base, we explore a comprehensive archaeogenomic study tracing 230 ancient individuals from Georgia and Armenia over 5,000 years, from the Bronze Age to the Early Middle Ages. The research investigates how extensive mobility and cultural interactions shaped the genetic landscape of the Southern Caucasus.

Study Highlights:
The analysis of genome-wide data revealed a remarkably persistent local gene pool across millennia, even as populations absorbed ancestry from Anatolia, Iran, and the Eurasian Steppe during the Middle to Late Bronze Age. Evidence of population growth and increased diversity emerged in urban centers of eastern Georgia, where individual ancestry outliers were most frequent. The study also examined 21 individuals with artificially deformed skulls, showing that while the practice arrived with nomadic Steppe groups, it was quickly adopted as a local cultural tradition. By integrating haplotype sharing and runs of homozygosity, the researchers uncovered contrasting social structures between urban hubs with high diversity and rural communities with stronger endogamy.

Conclusion:
This study demonstrates that despite high levels of mobility and external influences, the Southern Caucasus maintained a core genetic continuity that highlights the resilience of local populations while providing new insights into cultural and demographic shifts.

Reference:
Skourtanioti E, Jia X, Tavartkiladze N, Bitadze L, Shengelia R, Tushabramishvili N, Aslanishvili V, Gasparyan B, Kandel AW, Naumann D, et al. The genetic history of the Southern Caucasus from the Bronze Age to the Early Middle Ages: 5,000 years of genetic continuity despite high mobility. Cell. 2025 Sep 18;188(19):5278–5294. doi:10.1016/j.cell.2025.07.013

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 142: Specifications of the ACMG/AMP Guidelines for PALB2 Variant Interpretation

In this episode of PaperCast Base by Base, we explore how the Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) developed gene-specific ACMG/AMP guidelines for the interpretation of PALB2 germline sequence variants, a key gene in hereditary cancer syndromes.

Study Highlights:
The HBOP VCEP assembled an international team of experts to refine the 2015 ACMG/AMP framework specifically for PALB2, a tumor suppressor gene involved in homologous recombination repair. They systematically reviewed 28 evidence codes, advising against the use of 13, limiting six, and tailoring nine to account for PALB2-specific biology. These specifications were validated through the curation of 39 pilot variants, achieving 84% concordance with ClinVar entries and leading to the reclassification of several variants of uncertain significance. The work emphasized the rarity of pathogenic missense variation in PALB2, focusing instead on loss-of-function mechanisms and evidence-based population frequency cutoffs.

Conclusion:
These conservative, PALB2-specific guidelines enhance the accuracy and consistency of variant classification, improving genetic counseling and risk management for individuals with PALB2-related cancer predisposition.

Reference:
Richardson, M.E., Bishop, M.F.H., Holdren, M.A., de la Hoya, M., Spurdle, A.B., Tavtigian, S.V., Brannan, T., Young, C.C., Zec, L., Hiraki, S., Turnbull, C., Tischkowitz, M., Bernstein, K.A., Masson, J.-Y., McNulty, S.M., Pesaran, T., Monteiro, A.N., Walker, L.C., Foulkes, W.D., & Couch, F.J. (2025). Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants. *The American Journal of Human Genetics*, 112(10), 1–15. https://doi.org/10.1016/j.ajhg.2025.08.020

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:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 141: RetiGene, a comprehensive gene atlas for inherited retinal diseases

In this episode of PaperCast Base by Base, we explore RetiGene, an expert-curated resource that consolidates genetic, transcriptomic, and functional information on inherited retinal diseases (IRDs). The study highlights the urgent need for a unified gene catalog to guide diagnosis and research in one of the most genetically heterogeneous groups of human disorders.

Study Highlights:
The authors identified and curated 470 genes strongly associated with IRDs, supported by extensive literature review, variant databases, and gene expression data. Another 196 genes were classified as candidate genes, while 17 were excluded due to insufficient or conflicting evidence. Phenotypic classification revealed associations across both syndromic and non-syndromic forms, with most genes showing autosomal recessive inheritance. Integration of bulk and single-cell RNA sequencing data revealed cell-type specificity of many genes, particularly in photoreceptors and retinal pigment epithelium, clarifying genotype-phenotype relationships. The database also distinguishes genes with solid evidence from those previously misattributed, providing a refined tool for diagnostics and research.

Conclusion:
RetiGene offers an updated, freely accessible gene atlas that improves genetic testing, supports functional studies, and enables future therapeutic development for inherited retinal diseases.

Reference:
Rivolta, C., Celik, E., Kamdar, D., Cancellieri, F., Kaminska, K., Ullah, M., Barberán-Martínez, P., Bouckaert, M., Cortón, M., Delanote, E., et al. (2025). RetiGene, a comprehensive gene atlas for inherited retinal diseases. *The American Journal of Human Genetics*, 112(10), 1–13. https://doi.org/10.1016/j.ajhg.2025.08.017

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

Support:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/