FY2022 Annual Report

Human Evolutionary Genomics Unit
Professor Svante Pääbo

(From left to right) Chika, Dmitrii, Shin-Yu, Svante, Hugo, and Chie.


Our Unit started in May 2020. We build on previous work where we sequenced the genomes of Denisovans and Neandertals, hominin groups that diverged from modern humans about half a million years ago. Our goal is to identify genetic changes that resulted in phenotypes that differed between modern and extinct hominins.

1. Staff

  • Xiangchun Ju, Postdoc
  • Shin-Yu Lee, Postdoc (from April 2022)
  • Chika Azama, Technician
  • Tomoe Shimazaki, Technician(from June 2022-November 2022)
  • Limin Chen, Technician (from March 2023)
  • Chie Narai, Research Unit Administrator
  • Dmitrii Iliushchenko, Research Intern(from March 2023)

2. Collaborations

2.1. Dr. Hugo Zeberg(Karolinska Institutet, Stockholm, Sweden)

  • Effects of archaic genetic variants in present-day populations.

2.2. Prof. Bernd Kuhn, OIST

  • Effects of human-specific changes in the gene FOXP2.

2.3. Prof.Izumi Fukunaga(OIST)

  • Effects of human-specific changes in the gene ADSL.

2.4. Prof.Kazumasa Tanaka(OIST)

  • Effects of human-specific changes in the gene ADSL.

2.5. Dr. Wieland Huttner(Max Planck Institute for Cell Biology and Genetics, Dresden, Germany)

  • Effects of human-specific changes in genes involved in chromosomal segregation.

3. Activities and Findings

3.1: Genetic changes specific to modern humans

We study genetic changes unique to humans.

Adenylosuccinate lyase (ADSL). Last year, we showed that an amino acid change unique to modern humans in the enzyme adenylosuccinate lyase (ASDSL) reduces de novo purine biosynthesis (Stepanova et al., 2021). We have introduced this change into mice and are now performing more detailed analyses of the metabolic effects as well as effects on the behavior of the mice. We focus on dominance and aggression as ADSL deficiency in humans have phenotypes related to such aspects of behavior.
We also analyze the effects on muscle development and muscle performance. In parallel, we study an amino acid change unique to Neandertals in the enzyme adenosine monophosphate deaminase (AMPD1), involved in purine recycling and is present in skeletal muscle.

FOXP2. The transcription factor forkhead box P2 (FOXP2) is involved in the development of language and speech in humans. We have previously shown that when two amino acid substitutions (T303N, N325S) are introduced into mice they increase long-term depression in medium spiny neurons in the striatum of the brain. We now introduced each of these amino acid substitutions individually into mice and found that long-term depression is increased only in mice carrying the T303N substitution but not in mice carrying the N325S substitution (Bornschein et al., 2023).
Mitosis during brain development.  We examine six such amino acid substitutions in three proteins (KNL1, KIF18A, SPAG5) which have roles in kinetochore function and chromosome segregation. We introduce these modern human-specific substitutions in mice and find that three substitutions KIF18a and KNL1 result in a  prolongation of metaphase and fewer errors in chromosome segregation in neuronal progenitors during neocortex development. The ancestral substitutions shorte metaphase when introduced into human brain organoids. This suggests that the accuracy of chromosome segregation during brain development improved in modern humans after their divergence from Neanderthals (Mora-Bermudez et al., 2022).

P450 enzymes. The cytochrome genes variants CYP2C8*3 and CYP2C9*2 are inherited together, forming a haplotype. They are associated with altered metabolism of several drugs, for example reduced metabolism of warfarin and phenytoin, leading to the necessity to reduce the doses administered to patients. We showed that this clinically important haplotype is inherited from Neandertals (Häggström et al., 2022).

4. Publications

4.1 Journals

  1. Mora-Bermúdez, F., Kanis, P., Macak, D., Peters, J., Naumann, R., Xing, L., Sarov, M., Winkler, S., Oegema, C. E., Haffner, C., Wimberger, P., Riesenberg, S., Maricic, T., Huttner, W. B., & Pääbo, S. (2022). Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development. Science Advances, 8: eabn7702.

  2. Häggström, S., Ingelman-Sundberg, M., Pääbo, S., & Zeberg, H. (2022). The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neandertals. The Pharmacogenomics Journal, 22, 247-249.

  3. Bornschein, U., Zeberg, H., Enard, W., Hevers, W., & Pääbo, S. (2023). Functional dissection of two amino acid substitutions unique to the human FOXP2 protein. Scientific Reports, 13(1): 3747.

5. Intellectual Property Rights and Other Specific Achievements

Nothing to report

6. Meetings and Events

6.1 Public lecture in Tokyo: Neandelthal Genome and Modern Human Evolution

  • Date: 30 January, 2023
  • Venue: Yasuda Auditorium, University of Tokyo
  • Speaker: Dr. Svante Pääbo

6.2 Talk at OIST-IHJ Distinguished Global Thinkers Series

  • Date: 31 January, 2023
  • Venue: i-House/OIST Tokyo
  • Co-organizers: International House of Japan
  • Speaker: Dr. Svante Pääbo
  • Video

6.3 Meetings/Visitors

  • Prof. Go Yasuhiro, Cognitive Genomics Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Japan

7.1 Honors