Show Notes
Ju X-C et al., PNAS - Human-specific ADSL A429V substitution and a common regulatory haplotype reduce ADSL activity and raise purine substrates in the brain, altering mouse behavior.
Study Highlights:
Model: mice humanized for ADSL carrying the modern-human A429V (with R428Q) were compared to wild-type littermates using ultraperformance LC–Orbitrap metabolomics and automated IntelliCage behavioral assays. Mechanistic/quantitative result: SAICAr and S-Ado concentrations increased up to ~2-fold in liver and 1.8–5.4-fold across cerebrum regions, and these increases correlated negatively with Adsl mRNA expression across tissues. Human genetics: a 7.8-kb haplotype (including rs8135371) at >97% carrier frequency is associated with lower ADSL expression, higher S-Ado in cerebrospinal fluid, and signals of positive selection. Functional implication: female humanized mice accessed water more efficiently under restricted conditions, linking reduced ADSL activity to altered behavior.
Conclusion:
Two genetic changes on the modern human lineage—a nearly fixed A429V amino acid substitution and a common regulatory haplotype—have reduced ADSL activity and expression, increasing purine substrates particularly in the brain and producing measurable behavioral effects in mice.
Music:
Enjoy the music based on this article at the end of the episode.
Reference:
Ju X-C, Huttner W, Ågren R, Machado LC, Xing J, Lee S-Y, Siepel A, Azama C, Roy MC, Pääbo S, Endo T, Fukunaga I, Zeberg H. The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior. Proc. Natl. Acad. Sci. U.S.A. 2025.122:e2508540122. https://doi.org/10.1073/pnas.2508540122
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 – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
Official website https://basebybase.com
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.castos.com/episodes/adsl-a429v-purine-brain
