Reduced purine biosynthesis in humans after their divergence from Neandertals

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.

Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals

“…Previous studies reported on the role of single modern human-specific amino acid substitutions in adenylosuccinate lyase, an enzyme involved in purine metabolism ( 35 ), and in NOVA1, a splicing regulator involved in neuronal maturation ( 36 ) [but see ( 37 )]. Our results identify the functional role of a single modern human-specific amino acid substitution in the control of the abundance of one type of neuroprogenitor during neocortex development.…”

Evolution is in the details: Regulatory differences in modern human and Neanderthal

“…A comparison of metabolite levels in pre-frontal cortex, visual cortex, cerebellum, kidney, and muscle between human and other primates (chimpanzee and macaque), showed ‘aminoacyl-tRNA biosynthesis’ as the most significant enriched pathway for metabolites having higher levels in human; for all three brain regions, but not muscle or kidney [100]. Likewise, the ‘Phenylalanine, tyrosine and tryptophan biosynthesis’ pathway was enriched for all three brain regions.…”

Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development

“…However, this effect may be influenced by unintended hemizygous deletions (49) [but see also (51)]. The second is an amino acid substitution in the enzyme adenylosuccinate lyase, which decreases the stability of the protein and reduces purine biosynthesis when edited to the modern human-like state in mice and increases purine biosynthesis when ancestralized in human cells (52).…”

“…It is unknown what further organismal effect this has, but when humans and great apes are compared, the reduction in purine synthesis is particularly pronounced in the brain (52).…”

“…However, this effect may be influenced by unintended hemizygous deletions ( 49 ) [but see also ( 51 )]. The second is an amino acid substitution in the enzyme adenylosuccinate lyase, which decreases the stability of the protein and reduces purine biosynthesis when edited to the modern human-like state in mice and increases purine biosynthesis when ancestralized in human cells ( 52 ). It is unknown what further organismal effect this has, but when humans and great apes are compared, the reduction in purine synthesis is particularly pronounced in the brain ( 52 ).…”