The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior

Adenylosuccinate lyase (ADSL), an enzyme that is crucial for purine biosynthesis, carries an amino acid substitution that is present in almost all humans today but absent in Neandertals and Denisovans. This substitution reduces the stability of the enzyme, but what functional consequences it has are unknown. Here, we show that when introduced into mice, this substitution causes substrates of the enzyme to accumulate in amounts that correlate negatively with ADSL expression levels. In the brain, where the expression of the enzyme is low, the substitution results in particularly high substrate levels. When the behavior of the mice is analyzed, female mice expressing the modern human-like version of ADSL access water more efficiently for drinking than their wild-type littermates. In addition to the amino acid substitution, a haplotype in the ADSL gene occurs at a carrier frequency of >97% in present-day humans and exhibits evidence of positive selection. It is associated with less ADSL expression as well as with increased concentrations of succinyladenosine, one of the substrates of the enzyme, in cerebrospinal fluid. Thus, two genetic changes have reduced ADSL activity in human tissues since modern and archaic humans separated, affecting purine biosynthesis, particularly in the brain.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-08-04
DOI
https://doi.org/10.1073/pnas.2508540122
Citations
1
Primary Topic
Biochemical and Molecular Research
Type
article
Field-Weighted Citation Impact
0.81

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article

The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior

Michael C. Roy, Richard Ågren, Svante Pääbo, Xiang-Chun Ju et al.
1 citations
Proceedings of the National Academy of Sciences
Biochemical and Molecular Research
0.81
article

The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior

Michael C. Roy, Richard Ågren, Svante Pääbo, Xiang-Chun Ju, Wieland Β. Huttner, Laís Ceschini Machado, Chika Azama, Hugo Zeberg, Jiawei Xing, Adam Siepel, Shin‐Yu Lee, Izumi Fukunaga, Toshihiro Endo
article en
1 citations

Abstract

Adenylosuccinate lyase (ADSL), an enzyme that is crucial for purine biosynthesis, carries an amino acid substitution that is present in almost all humans today but absent in Neandertals and Denisovans. This substitution reduces the stability of the enzyme, but what functional consequences it has are unknown. Here, we show that when introduced into mice, this substitution causes substrates of the enzyme to accumulate in amounts that correlate negatively with ADSL expression levels. In the brain, where the expression of the enzyme is low, the substitution results in particularly high substrate levels. When the behavior of the mice is analyzed, female mice expressing the modern human-like version of ADSL access water more efficiently for drinking than their wild-type littermates. In addition to the amino acid substitution, a haplotype in the ADSL gene occurs at a carrier frequency of >97% in present-day humans and exhibits evidence of positive selection. It is associated with less ADSL expression as well as with increased concentrations of succinyladenosine, one of the substrates of the enzyme, in cerebrospinal fluid. Thus, two genetic changes have reduced ADSL activity in human tissues since modern and archaic humans separated, affecting purine biosynthesis, particularly in the brain.

Proceedings of the National Academy of SciencesVol. 122(32)
Okinawa Institute of Science and Technology Graduate University (JP), Cold Spring Harbor Laboratory (US), Karolinska Institutet (SE), Quantitative BioSciences (US), Max Planck Institute for Evolutionary Anthropology (DE), Institut de Recherche et d’Innovation (FR), Max Planck Institute of Molecular Cell Biology and Genetics (DE)
Knut och Alice Wallenbergs Stiftelse, Max-Planck-Gesellschaft, Okinawa Institute of Science and Technology Graduate University, Vetenskapsrådet, National Institutes of Health, Japan Society for the Promotion of Science
Clean water and sanitation
Openalex Percentile: Top 25%
Biochemical and Molecular Research
0.81
DOIOpen Access PDFOpenAlex
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