Reduced purine biosynthesis in humans after their divergence from Neandertals
- Skolkovo Institute for Science and Technology, Russian Federation
- Max Planck Institute for Evolutionary Anthropology, Germany
- University of Denver, United States
- Skolkovo Institute of Science and Technology, Russian Federation
- Technische Universität Dresden, Germany
- TU Dresden, Germany
- Max Planck Institute for Cell Biology and Genetics, Germany
- Max Planck Institute of Molecular Plant Physiology, Germany
Abstract
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.
Data availability
All data generated are included in the paper as Supplementary files 1-10 and Source data files referred to in the figure legends.
Article and author information
Author details
Kaja Ewa Moczulska
Konstantinos Anastassiadis
Patrick Giavalisco
Philipp Khaitovich
Funding
NOMIS Stiftung
- Svante Pääbo
Max Plank Society
- Svante Pääbo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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.
Copyright
© 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.
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Reduced purine biosynthesis in humans after their divergence from Neandertals
eLife 10:e58741.
https://doi.org/10.7554/eLife.58741
Further reading
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- Evolutionary Biology
Gene duplication drives evolution by providing raw material for proteins with novel functions. An influential hypothesis by Ohno (1970) posits that gene duplication helps genes tolerate new mutations and thus facilitates the evolution of new phenotypes. Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohno’s hypothesis to work. We experimentally tested Ohno’s hypothesis by evolving one or exactly two copies of a gene encoding a fluorescent protein in Escherichia coli through several rounds of mutation and selection. We analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohno’s hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. Consequently, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohno’s hypothesis that point to the importance of gene dosage.
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- Cell Biology
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Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of mreB from Pseudomonas fluorescens SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory pbp1A mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of mreB causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.
