bims-humivi 2026-10-04 papers

Genetics. 2026 Sep 28. pii: iyag258. [Epub ahead of print]

Evolutionary regimes determine the accuracy of epistasis inference from temporal genetic data.

Epistasis, the non-additive effects of mutations, shapes fitness landscapes and evolutionary trajectories. Temporal genetic data reveal evolutionary dynamics and could be used to infer epistatic interactions, especially through linkage disequilibrium (LD) between interacting mutations. However, other evolutionary forces can also generate LD, challenging inference. Here, we systematically evaluated the accuracy of a variety of epistasis inference approaches across a range of selective pressures, recombination rates, and population sizes. In general, we found that inference accuracy depends on the evolutionary regime: methods based on marginal path likelihood (MPL) performed best under strong selection and low recombination, whereas quasi-linkage equilibrium (QLE) approaches were more accurate when recombination is frequent. We further showed that the strength of genetic drift can influence inference accuracy for approaches that learn from changes in allele frequencies over time. Collectively, our results show that the detectability of epistasis from temporal genetic data depends on the interplay between selection, recombination, and genetic drift, providing guidance for method selection across evolutionary contexts.

Keywords: epistasis; fitness; genetic linkage; inference; temporal genetic data

DOI: https://doi.org/10.1093/genetics/iyag258

bioRxiv. 2026 Sep 12. pii: 2026.09.11.751054. [Epub ahead of print]

Microevolutionary cophylogeny reflects host-symbiont population dynamics and human mitonuclear interactions.

Rowan Hart, Matthias Steinrücken.

Cophylogeny, the study of phylogenetic similarity between interacting organisms, provides insights into the specificity and shared evolutionary history of symbiosis. While the ecological drivers of cophylogeny have been investigated at the macroevolutionary scale, the influence of these processes on microevolution remains unclear. This is due, in part, to the fact that the ancestral relations between individuals within a sexually reproducing eukaryotic host species cannot be well represented with a single phylogenetic tree, since genetic distances between individuals change substantially across the genome due to meiotic recombination. This heterogeneity can be captured and utilized through the inference of an ancestral recombination graph (ARG) built from the genomic data of the host. Here, we propose to measure microevolutionary cophylogeny by comparing a symbiont evolutionary tree to a host ARG. This approach simultaneously measures genome-wide cophylogeny, as well as locus-specific signals. Through simulations, we investigate the effects of transmission mode, population structure, admixture, and allelic incompatibility on microevolutionary cophylogeny. In contrast to macroevolutionary patterns, we find a limited relationship between cophylogeny and vertical transmission, with vertically transmitted host-symbiont systems displaying no cophylogeny in large panmictic populations. We apply our approach to mitochondrial and nuclear genomes within the 1000 Genomes Project- a host-symbiont system with strict maternal transmission-and observe substantial variation in mitochondrial-nuclear (mitonuclear) cophylogeny across human populations. Finally, we investigate locus-specific signals of cophylogeny and observe limited evidence of mitonuclear incompatibility.

DOI: https://doi.org/10.64898/2026.09.11.751054

Nat Commun. 2026 Aug 29. pii: 10302. [Epub ahead of print]17(1):

Deviations from genetic additivity driven by rare variants at biobank scale.

Frederik H Lassen, Samvida S Venkatesh, Nikolas A Baya, Cecilia M Lindgren, Duncan S Palmer.

Additive genetic models are the default for genome-wide association studies, but deviations from additivity are crucial for understanding disease mechanisms and therapeutic responses. Yet existing methods for testing nonadditivity are computationally infeasible for large-scale analysis or rely on Hardy-Weinberg assumptions, making them unsuitable for rare variants in large biobanks. We use an orthogonal allelic recoding framework that enables scalable testing of nonadditive genetic effects without Hardy-Weinberg assumptions while integrating seamlessly with existing linear mixed models. Analyzing up to 399,943 UK Biobank individuals across 2906 plasma proteins and 55 quantitative traits, we demonstrate that approximately one-third of cognate gene-protein relationships exhibit nonlinear dose responses. We identify recessive effects, including FUT10 variants associated with reduced lung function, and validate these findings in the All of Us cohort. We show that many complex traits show partial recessivity, reconciling conflicting inheritance patterns in the literature, and that joint two-degree-of-freedom models substantially improve statistical power when the underlying trait is partially recessive. Our framework efficiently partitions additive and nonadditive heritability components at biobank scale, providing a quantitative map of gene dose-response relationships with direct implications for therapeutic target identification and precision medicine.

DOI: https://doi.org/10.1038/s41467-026-76151-w

J Assist Reprod Genet. 2026 Oct 01.

Successful live birth after preimplantation genetic testing for combined nuclear RNASEH2C and mitochondrial MT-TL1 variants.

Xiao Hu, Yi Zhang, Zhenxing Wan, Jing Dai, Yifan Gu, Lu Zhou, Fei Gong, Guangxiu Lu, Yue-Qiu Tan, Juan Du, Ge Lin.

INTRODUCTION: Preimplantation genetic testing (PGT) reduces reproductive risks for genetically high-risk families. To date, simultaneous PGT for nuclear and mitochondrial gene variants has rarely been reported. PGT targeting mitochondrial DNA (mtDNA) variants remains challenging and requires further clinical evidence.
CASE REPORT: We herein report a 3-year-old girl with severe global developmental delay. The proband harbored compound heterozygous RNASEH2C variants (maternal c.194G > A and paternal c.433C > T) and a maternally inherited m.3250 T > C variant in MT-TL1 with 72.9% heteroplasmy. PGT was performed for her parents, including RNASEH2C haplotype phasing, m.3250 T > C variant load quantification, and chromosomal copy number variation analysis. All eight embryos exhibited lower m.3250 T > C heteroplasmy (0-17.8%) than the mother (20.2%-27.9%). One aneuploid embryo with 17.8% heteroplasmy was aliquoted into 16 specimens for technical validation, and consistent variant loads (18.2% ± 1.7%) were observed across all aliquots. An euploid embryo carrying heterozygous RNASEH2C c.194G > A and low-level m.3250 T > C heteroplasmy (1.8%) was transferred, resulting in the birth of a healthy boy with uneventful birth and two-year postnatal follow-up.
CONCLUSIONS: This case represents a successful application of combined nuclear, mitochondrial, and chromosomal PGT in a family. Our findings provide valuable clinical evidence supporting blastocyst-stage PGT for mtDNA variants, indicating PGT to be a reliable reproductive option for females with low-level pathogenic mtDNA variants.

Keywords: MT-TL1 ; RNASEH2C ; Preimplantation genetic testing

DOI: https://doi.org/10.1007/s10815-026-04041-7