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.

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.

Metrics

  • 3,823
    views
  • 496
    downloads
  • 15
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Computational and Systems Biology
    2. Evolutionary Biology
    Kara Schmidlin, Sam Apodaca ... Kerry Geiler-Samerotte
    Research Article

    There is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common in evolution and occur when, for example, resistance to one drug results in sensitivity to another. Major questions remain about the extent to which tradeoffs are reliable, specifically, whether the mutants that provide resistance to a given drug all suffer similar tradeoffs. This question is difficult because the drug-resistant mutants observed in the clinic, and even those evolved in controlled laboratory settings, are often biased towards those that provide large fitness benefits. Thus, the mutations (and mechanisms) that provide drug resistance may be more diverse than current data suggests. Here, we perform evolution experiments utilizing lineage-tracking to capture a fuller spectrum of mutations that give yeast cells a fitness advantage in fluconazole, a common antifungal drug. We then quantify fitness tradeoffs for each of 774 evolved mutants across 12 environments, finding these mutants group into classes with characteristically different tradeoffs. Their unique tradeoffs may imply that each group of mutants affects fitness through different underlying mechanisms. Some of the groupings we find are surprising. For example, we find some mutants that resist single drugs do not resist their combination, while others do. And some mutants to the same gene have different tradeoffs than others. These findings, on one hand, demonstrate the difficulty in relying on consistent or intuitive tradeoffs when designing multidrug treatments. On the other hand, by demonstrating that hundreds of adaptive mutations can be reduced to a few groups with characteristic tradeoffs, our findings may yet empower multidrug strategies that leverage tradeoffs to combat resistance. More generally speaking, by grouping mutants that likely affect fitness through similar underlying mechanisms, our work guides efforts to map the phenotypic effects of mutation.

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease
    Zachary H Williams, Alvaro Dafonte Imedio ... Welkin E Johnson
    Research Article Updated

    HERV-K(HML-2), the youngest clade of human endogenous retroviruses (HERVs), includes many intact or nearly intact proviruses, but no replication competent HML-2 proviruses have been identified in humans. HML-2-related proviruses are present in other primates, including rhesus macaques, but the extent and timing of HML-2 activity in macaques remains unclear. We have identified 145 HML-2-like proviruses in rhesus macaques, including a clade of young, rhesus-specific insertions. Age estimates, intact open reading frames, and insertional polymorphism of these insertions are consistent with recent or ongoing infectious activity in macaques. 106 of the proviruses form a clade characterized by an ~750 bp sequence between env and the 3′ long terminal repeat (LTR), derived from an ancient recombination with a HERV-K(HML-8)-related virus. This clade is found in Old World monkeys (OWM), but not great apes, suggesting it originated after the ape/OWM split. We identified similar proviruses in white-cheeked gibbons; the gibbon insertions cluster within the OWM recombinant clade, suggesting interspecies transmission from OWM to gibbons. The LTRs of the youngest proviruses have deletions in U3, which disrupt the Rec Response Element (RcRE), required for nuclear export of unspliced viral RNA. We show that the HML-8-derived region functions as a Rec-independent constitutive transport element (CTE), indicating the ancestral Rec–RcRE export system was replaced by a CTE mechanism.