Reduced purine biosynthesis in humans after their divergence from Neandertals

  1. Vita Stepanova  Is a corresponding author
  2. Kaja Ewa Moczulska
  3. Guido Vacano
  4. Ilia Kurochkin
  5. Xiangchun Ju
  6. Stephan Riesenberg
  7. Dominik Macak
  8. Tomislav Maricic
  9. Linda Dombrowski
  10. Maria Schörnig
  11. Konstantinos Anastassiadis
  12. Oliver Baker
  13. Ronald Naumann
  14. Ekaterina Khrameeva
  15. Anna Vanushkina
  16. Elena Stekolshchikova
  17. Alina Egorova
  18. Anna Tkachev
  19. Randall Mazzarino
  20. Nathan Duval
  21. Dmitri Zubkov
  22. Patrick Giavalisco
  23. Terry G Wilkinson II
  24. David Patterson
  25. Philipp Khaitovich
  26. Svante Pääbo  Is a corresponding author
  1. Skolkovo Institute for Science and Technology, Russian Federation
  2. Max Planck Institute for Evolutionary Anthropology, Germany
  3. University of Denver, United States
  4. Skolkovo Institute of Science and Technology, Russian Federation
  5. Technische Universität Dresden, Germany
  6. TU Dresden, Germany
  7. Max Planck Institute for Cell Biology and Genetics, Germany
  8. 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

  1. Vita Stepanova

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    For correspondence
    vita.stepanova@skolkovotech.ru
    Competing interests
    The authors declare that no competing interests exist.
  2. Kaja Ewa Moczulska

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6051-1265
  3. Guido Vacano

    The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5979-9310
  4. Ilia Kurochkin

    Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3100-0903
  5. Xiangchun Ju

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephan Riesenberg

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Dominik Macak

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Tomislav Maricic

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Linda Dombrowski

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Maria Schörnig

    Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5334-5342
  11. Konstantinos Anastassiadis

    Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9814-0559
  12. Oliver Baker

    Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Ronald Naumann

    Max Planck Institute for Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Ekaterina Khrameeva

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  15. Anna Vanushkina

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  16. Elena Stekolshchikova

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  17. Alina Egorova

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  18. Anna Tkachev

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  19. Randall Mazzarino

    The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Nathan Duval

    The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Dmitri Zubkov

    Center for Neurobiology and Brain Restoration, Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  22. Patrick Giavalisco

    Department I, Max Planck Institute of Molecular Plant Physiology, Golm, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4636-1827
  23. Terry G Wilkinson II

    The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. David Patterson

    The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Philipp Khaitovich

    Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4305-0054
  26. Svante Pääbo

    Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
    For correspondence
    paabo@eva.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4670-6311

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.

Reviewing Editor

  1. Genevieve Konopka, University of Texas Southwestern Medical Center, United States

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.

Version history

  1. Received: May 9, 2020
  2. Accepted: May 2, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. Version of Record published: May 19, 2021 (version 2)

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.

Metrics

  • 3,666
    Page views
  • 484
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Vita Stepanova
  2. Kaja Ewa Moczulska
  3. Guido Vacano
  4. Ilia Kurochkin
  5. Xiangchun Ju
  6. Stephan Riesenberg
  7. Dominik Macak
  8. Tomislav Maricic
  9. Linda Dombrowski
  10. Maria Schörnig
  11. Konstantinos Anastassiadis
  12. Oliver Baker
  13. Ronald Naumann
  14. Ekaterina Khrameeva
  15. Anna Vanushkina
  16. Elena Stekolshchikova
  17. Alina Egorova
  18. Anna Tkachev
  19. Randall Mazzarino
  20. Nathan Duval
  21. Dmitri Zubkov
  22. Patrick Giavalisco
  23. Terry G Wilkinson II
  24. David Patterson
  25. Philipp Khaitovich
  26. Svante Pääbo
(2021)
Reduced purine biosynthesis in humans after their divergence from Neandertals
eLife 10:e58741.
https://doi.org/10.7554/eLife.58741

Share this article

https://doi.org/10.7554/eLife.58741

Further reading

    1. Evolutionary Biology
    Zhiliang Zhang, Zhifei Zhang ... Guoxiang Li
    Research Article

    Biologically-controlled mineralization producing organic-inorganic composites (hard skeletons) by metazoan biomineralizers has been an evolutionary innovation since the earliest Cambrian. Among them, linguliform brachiopods are one of the key invertebrates that secrete calcium phosphate minerals to build their shells. One of the most distinct shell structures is the organo-phosphatic cylindrical column exclusive to phosphatic-shelled brachiopods, including both crown and stem groups. However, the complexity, diversity, and biomineralization processes of these microscopic columns are far from clear in brachiopod ancestors. Here, exquisitely well-preserved columnar shell ultrastructures are reported for the first time in the earliest eoobolids Latusobolus xiaoyangbaensis gen. et sp. nov. and Eoobolus acutulus sp. nov. from the Cambrian Series 2 Shuijingtuo Formation of South China. The hierarchical shell architectures, epithelial cell moulds, and the shape and size of cylindrical columns are scrutinised in these new species. Their calcium phosphate-based biomineralized shells are mainly composed of stacked sandwich columnar units. The secretion and construction of the stacked sandwich model of columnar architecture, which played a significant role in the evolution of linguliforms, is highly biologically controlled and organic-matrix mediated. Furthermore, a continuous transformation of anatomic features resulting from the growth of diverse columnar shells is revealed between Eoobolidae, Lingulellotretidae, and Acrotretida, shedding new light on the evolutionary growth and adaptive innovation of biomineralized columnar architecture among early phosphatic-shelled brachiopods during the Cambrian explosion.

    1. Developmental Biology
    2. Evolutionary Biology
    Eman Hijaze, Tsvia Gildor ... Smadar Ben-Tabou de-Leon
    Research Article

    Biomineralization had apparently evolved independently in different phyla, using distinct minerals, organic scaffolds, and gene regulatory networks (GRNs). However, diverse eukaryotes from unicellular organisms, through echinoderms to vertebrates, use the actomyosin network during biomineralization. Specifically, the actomyosin remodeling protein, Rho-associated coiled-coil kinase (ROCK) regulates cell differentiation and gene expression in vertebrates’ biomineralizing cells, yet, little is known on ROCK’s role in invertebrates’ biomineralization. Here, we reveal that ROCK controls the formation, growth, and morphology of the calcite spicules in the sea urchin larva. ROCK expression is elevated in the sea urchin skeletogenic cells downstream of the Vascular Endothelial Growth Factor (VEGF) signaling. ROCK inhibition leads to skeletal loss and disrupts skeletogenic gene expression. ROCK inhibition after spicule formation reduces the spicule elongation rate and induces ectopic spicule branching. Similar skeletogenic phenotypes are observed when ROCK is inhibited in a skeletogenic cell culture, indicating that these phenotypes are due to ROCK activity specifically in the skeletogenic cells. Reduced skeletal growth and enhanced branching are also observed under direct perturbations of the actomyosin network. We propose that ROCK and the actomyosin machinery were employed independently, downstream of distinct GRNs, to regulate biomineral growth and morphology in Eukaryotes.