GBA3: a polymorphic pseudogene in humans that experienced repeated gene loss during mammalian evolution

Area of Science:

• Evolutionary biology
• Genetics
• Biochemistry

Background:

• The cytosolic β-glucosidase GBA3 gene is crucial for metabolizing plant β-glycosides.
• Pseudogenization of GBA3, evidenced by a truncated allele (rs358231), is observed in humans and other mammals.
• Dietary adaptations are hypothesized to have influenced GBA3 gene loss during evolution.

Purpose of the Study:

• To investigate the evolutionary history and causes of GBA3 pseudogenization across mammals.
• To explore the relationship between GBA3 loss-of-function alleles, human population genetics, and dietary habits.
• To understand the potential physiological roles of GBA3 beyond β-glycoside metabolism.

Main Methods:

• Analysis of human GBA3 alleles and population distribution.
• Comparative genomics of GBA3 orthologs in various mammalian lineages.
• Investigation of GBA3's role in sialic acid biology, including interactions with NEU2 and CMAH.

Main Results:

• GBA3 exhibits extensive loss-of-function in humans due to inactivating and damaging mutations.
• Significant differences in loss-of-function allele frequencies exist among human populations, correlating with staple diets.
• At least nine independent GBA3 pseudogenization events occurred in mammals, predominantly in carnivorous species.
• GBA3 loss was also observed in omnivorous and herbivorous species, suggesting complex evolutionary drivers.
• GBA3's involvement in a cellular network with NEU2 and CMAH points to potential roles in sialic acid biology.

Conclusions:

• Recurrent GBA3 pseudogenization in mammals is strongly linked to diet-related evolutionary factors and relaxed selective constraints.
• Dietary shifts, particularly reduced intake of plant β-glycosides, likely drove GBA3 loss in various mammalian lineages.
• The precise physiological function of GBA3 remains incompletely understood, with potential roles in sialic acid metabolism requiring further investigation.