Cromer SJ et al., The American Journal of Human Genetics - This paper reviews polygenic risk scores (PRS) and social determinants of health (SDoH) and outlines best practices for integrating PRS and SDoH across diverse populations to improve prediction and equity.

Study Highlights:
This review focuses on human populations and uses conceptual frameworks, hypothetical population examples, and synthesis of methodological studies to evaluate PRS and SDoH integration. It summarizes methods for PRS construction and transferability, SDoH measurement at individual and area levels, and analytic approaches including interaction, mediation, and calibration. Quantitatively, the authors note substantial declines in PRS predictive accuracy when applied to genetically distinct populations (for example, African-ancestry performance often ~20–40% of European-derived PRS). The review highlights harmonization, population-specific calibration, and interdisciplinary teams as functional steps to improve predictive validity and reduce inequitable impacts.

Conclusion:
Integrating PRSs with carefully measured and harmonized SDoH across diverse populations requires population-aware conceptual frameworks, calibrated analytic methods, diverse datasets, and ethical safeguards to improve predictive validity and equity.

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Reference:
Cromer SJ, Cobran EK, Iyer HS, Hysong MR, Vargas LB, Smith JL, Konigsberg IR, Bogumil D, Glover L, King G, PRIMED Consortium SDoH Working Group, Lange LA, Patel A, Wojcik G, Raffield L, Conti DV, et al. Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research. The American Journal of Human Genetics. 2026;113:1–25. https://doi.org/10.1016/j.ajhg.2026.02.007

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Wong BHH et al., PNAS - Mouse and human studies show the LPC transporter Mfsd2a enables plasma-derived LPC uptake into keratinocytes, preserving linoleate-rich phosphatidylcholine pools and promoting epidermal differentiation.

Study Highlights:
Using epidermis-specific (2aEpKO) and conventional (2aKO) Mfsd2a-deficient mice, lineage tracing, untargeted shotgun lipidomics, LightOx-LPC uptake assays, and primary human keratinocyte cultures, the authors mapped Mfsd2a expression to suprabasal/granular keratinocytes and demonstrated Mfsd2a-dependent uptake of plasma-derived LPC in vivo. Lipidomic quantification showed reductions in linoleate-containing phospholipids (PL-18:2 decreased ~15% in 2aEpKO and ~13% in 2aKO) and a marked loss of TAG-18:2 (−79% in 2aEpKO). Inducible epidermal Mfsd2a loss produced transient dermatitis, defective desquamation, retained lamellar bodies, and keratinocyte activation, while MFSD2A knockdown in human keratinocytes reduced LPC-driven differentiation. Functional rescue experiments in vitro revealed that LPC-18:1 and LPC-18:2 promote keratinocyte differentiation in an MFSD2A-dependent manner, linking plasma LPC uptake to epidermal lipid homeostasis and differentiation.

Conclusion:
Mfsd2a mediates uptake of plasma-derived LPC (notably LPC-18:2) into suprabasal keratinocytes to maintain linoleate-containing phospholipid pools and support keratinocyte differentiation and normal desquamation.

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Reference:
Wong BHH, Behmoaras J, Chua AWC, Galam DLA, Tan BC, Torta F, Chin CF, Mishra K, Ding M, Silver DL. Mfsd2a is important for maintaining epidermal homeostasis. Proc. Natl. Acad. Sci. U.S.A. 2026 Feb 19;123(8):e2531159123. https://doi.org/10.1073/pnas.2531159123

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Herpe L et al., PNAS - CRISPR knockout of Drosophila mtG3PDH (GPO1) reduces ATP production by ~60% and O2 consumption by ~33%, lowering mitochondrial efficiency and ROS emission.

Study Highlights:
Using CRISPR/Cas9-generated GPO1 mutant Drosophila and isolated thoracic mitochondria, the authors combined enzymatic assays, ATP production and oxygen consumption measurements, and H2O2 emission assays to probe mtG3PDH function. Loss of mtG3PDH markedly reduced mtG3PDH enzymatic activity and drove a ~60% decrease in ATP production and ~33% decrease in O2 consumption, producing a pronounced drop in mitochondrial efficiency (ATP/O). mtG3PDH-linked ROS emission was also strongly reduced (~70%), reflecting diminished direct and reverse electron-transfer ROS generation. Functionally, GPO1 flies showed sharply reduced survival and severe climbing impairment, linking the bioenergetic defects to organismal outcomes.

Conclusion:
mtG3PDH is essential for mitochondrial bioenergetics and redox homeostasis in Drosophila, with GPO1 loss causing major decreases in ATP production, O2 consumption, mitochondrial efficiency, and mtG3PDH-linked ROS that correlate with reduced survival and locomotion.

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Reference:
Herpe L, Aminot M, Pichaud N. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 2026;123(9):e2535701123. https://doi.org/10.1073/pnas.2535701123

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Korpela K et al., Gut Microbes - Review finds maternal fecal microbiota transplantation and targeted probiotics can restore Bifidobacterium and Bacteroides after C‑section or intrapartum antibiotics, with breastfeeding aiding recovery.

Study Highlights:
This review focuses on term infants, particularly C‑section and intrapartum antibiotic–exposed neonates, synthesizing cohort and intervention data using 16S rRNA gene amplicon sequencing and metagenomic approaches. Maternal fecal microbiota transplantation (maternal FMT) shifted C‑section infants’ gut communities to resemble vaginally born infants and uniquely restored Bacteroidaceae, while a Bifidobacterium–Lactobacillus–FOS supplement increased bifidobacteria; vaginal seeding did not normalize overall gut composition. The authors link restoration of key taxa to potential reductions in risks such as allergy and overweight and emphasize breastfeeding as an essential adjunct to restoration strategies.

Conclusion:
Evidence supports action to address early-life gut microbiota disruption: probiotics and maternal FMT show promising restorative effects, but optimal, scalable solutions and long-term immune outcomes remain to be established.

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Reference:
Korpela K, de Vos WM. Infant gut microbiota restoration: state of the art. Gut Microbes. 2022;14(1):e2118811. https://doi.org/10.1080/19490976.2022.2118811

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Li Z et al., Human Genetics and Genomics Advances. 7 ( - LASI-DAD 30× whole-genome sequencing of 2,680 Indian participants produced a 69.5M-variant LD panel that improves genotype imputation accuracy and PRS performance for Indian populations.

Study Highlights:
Using 30× WGS of 2,680 LASI-DAD participants, the authors constructed an LD lookup panel (69.5 million variants), phased with Eagle2.4, and identified LD structure with LDetect and Big-LD. They compared regional varLD to 1000G super-populations and evaluated imputation with Minimac4 and meta-imputation against TOPMed and GAsP. LASI-DAD increased imputation accuracy (aggregated r2) by a mean 38% versus TOPMed and 27% versus GAsP across allele frequencies and improved PRS predictive performance by 2.1%–35.1% across traits and studies. Finer-scale stronger LD and regional LD differences in LASI-DAD translate into more accurate LD estimates and better imputation and PRS transferability for Indian sub-populations.

Conclusion:
LASI-DAD is the largest nationally representative Indian WGS reference panel to date and it improves LD estimation, genotype imputation accuracy, and PRS construction for Indian and South Asian populations.

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Reference:
Li Z, Zhao W, Zhou X, Leung YY, Schellenberg GD, Wang L-S, Schönherr S, Forer L, Fuchsberger C, Dey S, Lee J, Smith JA, Dey AB, Kardia SLR. A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India. Human Genetics and Genomics Advances. 7 (2026) 100579. https://doi.org/10.1016/j.xhgg.2026.100579.

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Shi J et al., The EMBO Journal - PANDORA-seq profiling of mouse and human sperm heads identifies a conserved rsRNA length shift with age and a tsRNA/rsRNA 'aging cliff' that reprograms embryonic transcripts.

Study Highlights:
Using PANDORA-seq on C57BL/6J mouse sperm (intact and de-membranated heads) across five age groups and two independent human sperm cohorts, the authors identify a sharp tsRNA/rsRNA "aging cliff" in mice between 50–70 weeks and a head-specific rsRNA length shift. PANDORA-seq overcomes modification-induced detection bias to reveal increases in longer rsRNAs and decreases in shorter rsRNAs, particularly from 28S- and 18S-rRNAs, with parallel trends in human cohorts. Mitochondrial tsRNAs/rsRNAs in sperm heads, although low abundance, covary with genomic sncRNAs and help distinguish age groups. Transfection of age-mimicking tsRNA/rsRNA cocktails into mouse embryonic stem cells reprograms gene expression, upregulating metabolic and neurodegeneration-related pathways, providing a functional link to offspring phenotypes.

Conclusion:
PANDORA-seq uncovers a conserved, sperm head–specific rsRNA length shift and a tsRNA/rsRNA aging cliff in mice and humans, and age-mimicking sncRNA combinations can alter embryonic transcriptomes linked to metabolic and neurodegenerative pathways.

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Reference:
Shi J, Zhang X, Cai C, Liu S, Yu J, James ER, et al. Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging. The EMBO Journal. 2026;45(4):1362–1380. https://doi.org/10.1038/s44318-025-00687-8

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Saxton DS et al., Nature - In E. coli, the membrane-bound nuclease SNIPE directly cleaves incoming phage λ DNA during genome injection, blocking infection via ManYZ and tape-measure protein interactions.

Study Highlights:
In Escherichia coli, the membrane-anchored protein SNIPE was shown to block phage λ by directly cleaving DNA during genome injection. The authors combined radiolabelled 32P phage DNA assays, time-lapse CFP-ParB/ParS microscopy, TurboID proximity labelling and pBPA crosslinking to map SNIPE localization and interactions. They report that membrane-localized SNIPE requires a DUF4041 domain and a GIY-YIG nuclease domain to generate DNA fragments during injection, reducing CFP-ParB puncta ~30-fold and producing a smear of 32P-labelled fragments; an E414A nuclease mutant abolished activity. Functionally, SNIPE prevents λ replication and cell lysis and provides broad defence against many siphoviruses via interactions with ManYZ and phage tape-measure proteins.

Conclusion:
SNIPE is a membrane-localized bacterial defence protein that associates with ManYZ and phage tape-measure proteins to directly cleave incoming phage DNA during genome injection, thereby blocking infection.

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Reference:
Saxton DS, DeWeirdt PC, Doering CR, Roney IJ & Laub MT. A membrane-bound nuclease directly cleaves phage DNA during genome injection. Nature. 2026. https://doi.org/10.1038/s41586-026-10207-1

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Moye AR et al., The American Journal of Human Genetics - Biallelic loss-of-function variants in SAXO6, a microtubule inner protein of photoreceptor cilia, cause late-onset retinal dystrophy by destabilizing axonemal microtubules.

Study Highlights:
The study analyzed human patients with late-onset recessive retinal dystrophy and combined genetic sequencing (WES/WGS and long-read RNA) with high-resolution imaging and proteomics. Iterative ultrastructure expansion microscopy and immuno-gold TEM localized SAXO6 to specific microtubule doublets in photoreceptor connecting cilia and outer segments and to motile cilia in airway models. Cross-linking mass spectrometry on isolated bovine tracheal cilia detected an interaction between SAXO6 Mn-motif regions and α-tubulin (Lys370), supporting SAXO6 as a microtubule inner protein. Functionally, predicted null SAXO6 genotypes segregate with late-onset RP or cone-rod dystrophy, implicating MIP dysfunction in long-term photoreceptor stability.

Conclusion:
Biallelic loss-of-function variants in SAXO6 cause late-onset retinal dystrophy, likely by disrupting a microtubule inner protein that stabilizes photoreceptor axonemes.

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Reference:
Moye AR, McCafferty CL, Lin S, Han JH, Dudakova L, Rodenburg K, Szabó V, Nagy ZZ, Zur D, Vajter M, Kousal B, Moulin AP, Graff-Meyer A, Roosing S, Mahroo OA, Arno G, Webster AR, Ben-Yosef T, Liskova P, Engel BD, Zobor D, Quinodoz M, Rivolta C. Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause a late-onset retinal dystrophy. The American Journal of Human Genetics. 2026 Mar 5;113:1–18. https://doi.org/10.1016/j.ajhg.2026.02.001

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Siraj L et al., Nature - Using MPRA in five human cell types, the authors assayed 221,412 fine-mapped variants and identified 13,121 trait-associated regulatory variants (TARVs), mapping mechanisms at single-nucleotide resolution.

Study Highlights:
The study assayed 221,412 fine-mapped human GWAS and eQTL variants using a massively parallel reporter assay (MPRA) across five cell lines and performed saturation mutagenesis on 136 TARVs. MPRA identified 13,121 trait-associated regulatory variants (TARVs) and showed that emVar status within endogenous CREs improves precision for causal-variant prioritization. Saturation mutagenesis defined activity blocks, assigned transcription factors for 91% of previously non-canonical TARVs, and revealed that only 69% of TARVs disrupt known TF motifs. The authors also detected regulatory epistasis in ~11% of nearby variant pairs, demonstrating non-additive effects between cis variants.

Conclusion:
Large-scale MPRA combined with saturation mutagenesis systematically identifies and mechanistically annotates thousands of human trait-associated regulatory variants at single-nucleotide resolution, revealing motif-disrupting and non-canonical TF mechanisms and local epistasis.

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Reference:
Siraj L., Castro R.I., Dewey H.B., Kales S., Butts J.C., Nguyen T.T.L., Kanai M., et al. Functional dissection of complex trait variants at single-nucleotide resolution. Nature. https://doi.org/10.1038/s41586-026-10121-6

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Baldwin-Brown JG et al., Annual Review of Ecology and Systematics - Bayesian analysis of 76,445 Utah Population Database pedigrees identifies a patrilineal Y‑chromosome lineage producing a 2:1 male bias, consistent with segregation distortion.

Study Highlights:
We analyzed 76,445 anonymized human pedigrees from the Utah Population Database using a Bayesian pedigree-propagation algorithm (Warp), complemented by transmission disequilibrium testing, permutation and Monte Carlo simulations. These methods identified a single patrilineal Y-chromosome lineage with 89 informative transmissions that produced 60 male and 29 female offspring, a 67.4% male proportion. Warp and the TDT independently flagged the same family and permutation/Monte Carlo tests indicated the observed male bias was unlikely to arise by chance (p≈0.001–0.05). The pattern is consistent with a Y-linked segregation distorter and is discussed as a possible contributor to unexplained male infertility and human sex-ratio dynamics.

Conclusion:
A multi-method analysis of deep Utah pedigrees identifies a statistically significant male-biased patrilineal lineage consistent with a Y-linked segregation distorter in humans.

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Reference:
Baldwin-Brown JG, Wesolowski S, Zimmerman RM, Peterson B, Tristani-Firouzi M, Hernandez EH, Aston KI, Yandell M, Phadnis N. Signatures of sex ratio distortion in humans. Annual Review of Ecology and Systematics. 2026. https://doi.org/10.64898/2026.02.04.702084

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