We analyze the metabolomes of humans, chimpanzees and macaques in muscle, kidney and three different regions of the brain. Whereas several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.
All data generated are included in the paper as Supplementary files 1-10 and Source data files referred to in the figure legends.
- Svante Pääbo
- Svante Pääbo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Mouse breeding and experiments were done under the permission AZ: 24-9162.11/12/12 (T 10/14) from the Landesdirektion Sachsen.This study was reviewed and approved by the Institutional Animal Care and Use Ethics Committee at the Shanghai Institute for Biological Sciences, CAS. All non-human primates used in this study suffered sudden deaths for reasons other than their participation in this study and without any relation to the tissue used.
Human subjects: Human postmortem samples were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, USA, the Maryland Brain Collection Center, Maryland, USA, and the Harvard Brain Tissue Resource Center. Informed consent for the use of human tissues for research was obtained by these institutions in writing from all donors or their next of kin.
- Genevieve Konopka, University of Texas Southwestern Medical Center, United States
- Received: May 9, 2020
- Accepted: May 2, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
© 2021, Stepanova et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.