FY2021 Annual Report

Human Evolutionary Genomics Unit
Prof. Svante Pääbo

Abstract

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

• Prof. Svante Pääbo, Group Leader
• Dr. Xiangchun Ju, Postdoctoral Researcher
• Dr. Shin-Yu Lee, Postdoctoral Researcher
• Chika Azama, Technical Staff
• Lena Hashimoto, Administrative Assistant (till Jan.2022)
• Chie Narai, Administrative Assistant (from Feb.2022)

2. Collaborations

2.1 Effects of Neandertal genetic variants in present-day populations

• Type of collaboration: Joint research
• Researchers:
  • Dr. Hugo Zeberg, Karolinska Institutet, Stockholm, Sweden

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

• Type of collaboration: Joint research
• Researchers:
  • Professor Bernd Kuhn, OIST

3. Activities and Findings

3.1 Genetic changes specific to modern humans

We have studied two genetic changes unique to modern humans. In addition we are initiating studies of a number of other such changes.

Adenylosuccinate lyase (ADSL). We published a broad comparison of the metabolomes of human, ape and macaques brains (Stepanova et al., 2021). One of the striking findings is that compounds in purine biosynthesis are present in lower amounts in humans than the other primates. Modern humans carry an amino acid substitution in the enzyme adenylosuccinate lyase (ASDSL) that catalyse two reaction in purine biosynthesis. To study if this change affects purine biosynthesis, we introduced it in mice. This change reduces purine biosynthesis. When we reverse the modern human substitution to the ancestral state in human cells, purine biosynthesis increase (Stepanova et al., 2021).

Mice with the modern human-specific change in the Adsl gene are now being analysed with respect to dominance and aggression as ADSL deficiency in humans have phenotypes related to such aspects of behavior.

Glutathione reductase (GR).  GR is an enzyme that prevents oxidative stress and maintaining a reduced intracellular environment. Almost all present-day humans carry an amino-acid substitution in this enzyme relative to apes and Neandertals. We expressed the modern human and the ancestral enzymes and show that the ancestral enzyme produces more reactive oxygen species and increases cellular levels of transcripts encoding cytokines. We also showed that the ancestral enzyme has been reintroduced into the modern human gene pool by gene flow from Neandertals and is associated with multiple traits in present-day people, including increased susceptibility for inflammatory-associated disorders and vascular disease (Coppo et al., 2022).

3.2: COVID-19

In addition to the major genetic risk factor for becoming critically ill upon infection with SARS-CoV-2 on chromosome 3 which we last year found to be derived from Neandertals, we have found that a haplotype on chromosome 12 that offers an ~25% protection against severe COVID-19 is derived from Neandertals (Zeberg and Pääbo, 2021).

We are following up our work on the risk haplotype on chromosome 3 using cell lines that are heterozygous for the haplotype. In such cell lines, we have used CRISPR-Cas9 to delete either the risk haplotype or the protective haplotype.

We developed and published a fast version of the LAMP-assay for SARS-CoV-2 detection (Boekelmann et al., 2021).

A phylogenetic tree illustrating the relationship of sequences in present-day populations at the OAS locus, indicating that the protective sequence variants are related to Neandertal variants.

4. Publications

4.1 Journals

1. Coppo, L., Mishra, P., Siefert, N., Holmgren, A., Pääbo, S., & Zeberg, H. (2022). A substitution in the glutathione reductase lowers electron leakage and inflammation in modern humans. Science Advances, 8(1): eabm1148.
2. Stepanova, V., Moczulska, K., Vacano, G. N., Kurochkin, I., Ju, X.-C., Riesenberg, S., Macak, D.,
   Maricic, T., Dombrowski, L., Schörnig, M., Anastassiadis, K., Baker, O., Naumann, R., Khrameeva,
   E., Vanushkina, A., Stekolschikova, E., Egorova, A., Nkatchev, A., Mazzarino, R., Duval, N., Zubkov,
   D., Giavalisco, P., Wilkinson, T. G., Patterson, D., Khaitovich, P., & Pääbo, S. (2021). Reduced
   purine biosynthesis in humans after their divergence from Neandertals. eLife, 10: e58741.
3. Zeberg, H., & Pääbo, S. (2021). A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proceedings of the National Academy of Sciences, 118(9): e2026309118.
4. Bokelmann, L., Nickel, O., Maricic, T., Pääbo, S., Meyer, M., Borte, S., & Riesenberg, S. (2021). Point-of-care bulk testing for SARS-CoV-2 by combining hybridization capture with improved colorimetric LAMP. Nature Communications, 12(1): 1467.

5. Intellectual Property Rights and Other Specific Achievements

Nothing to report

6. Meetings and Events

Nothing to report

7. Other

7-1. Honors

Foreign Member, Accademia Nazionale dei Lincei, Rome, Italy.
(https://www.lincei.it/it/content/p%C3%A4%C3%A4bo-svante)

The Massry Prize, Beverly Hills, CA, USA.
(https://keck.usc.edu/massry-prize/current-laureates)