Dataset Information

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

ABSTRACT: The gene encoding the cytosolic ?-glucosidase GBA3 shows pseudogenization due to a truncated allele (rs358231) that is polymorphic in humans. Since this enzyme is involved in the transformation of many plant ?-glycosides, this particular case of gene loss may have been influenced by dietary adaptations during evolution. In humans, apart from the inactivating allele, we found that GBA3 accumulated additional damaging mutations, implying an extensive GBA3 loss. The allelic distribution of loss-of-function alleles revealed significant differences between human populations which can be partially related with their staple diet. The analysis of mammalian orthologs disclosed that GBA3 underwent at least nine pseudogenization events. Most events of pseudogenization occurred in carnivorous lineages, suggesting a possible link to a ?-glycoside poor diet. However, GBA3 was also lost in omnivorous and herbivorous species, hinting that the physiological role of GBA3 is not fully understood and other unknown causes may underlie GBA3 pseudogenization. Such possibility relies upon a putative role in sialic acid biology, where GBA3 participates in a cellular network involving NEU2 and CMAH. Overall, our data shows that the recurrent loss of GBA3 in mammals is likely to represent an evolutionary endpoint of the relaxation of selective constraints triggered by diet-related factors.

SUBMITTER: Lopes-Marques M

PROVIDER: S-EPMC7360587 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Lopes-Marques Monica M Serrano Catarina C Cardoso Ana R AR Salazar Renato R Seixas Susana S Amorim António A Azevedo Luisa L Prata Maria J MJ

Scientific reports 20200714 1

The gene encoding the cytosolic β-glucosidase GBA3 shows pseudogenization due to a truncated allele (rs358231) that is polymorphic in humans. Since this enzyme is involved in the transformation of many plant β-glycosides, this particular case of gene loss may have been influenced by dietary adaptations during evolution. In humans, apart from the inactivating allele, we found that GBA3 accumulated additional damaging mutations, implying an extensive GBA3 loss. The allelic distribution of loss-of- ...[more]

PMID: 32665690

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Project description:Pseudogenes are fossil relatives of genes. Pseudogenes have long been thought of as "junk DNAs", since they do not code proteins in normal tissues. Although most of the human pseudogenes do not have noticeable functions, ?20% of them exhibit transcriptional activity. There has been evidence showing that some pseudogenes adopted functions as lncRNAs and work as regulators of gene expression. Furthermore, pseudogenes can even be "reactivated" in some conditions, such as cancer initiation. Some pseudogenes are transcribed in specific cancer types, and some are even translated into proteins as observed in several cancer cell lines. All the above have shown that pseudogenes could have functional roles or potentials in the genome. Evaluating the relationships between pseudogenes and their gene counterparts could help us reveal the evolutionary path of pseudogenes and associate pseudogenes with functional potentials. It also provides an insight into the regulatory networks involving pseudogenes with transcriptional and even translational activities.In this study, we develop a novel approach integrating graph analysis, sequence alignment and functional analysis to evaluate pseudogene-gene relationships, and apply it to human gene homologs and pseudogenes. We generated a comprehensive set of 445 pseudogene-gene (PGG) families from the original 3,281 gene families (13.56%). Of these 438 (98.4% PGG, 13.3% total) were non-trivial (containing more than one pseudogene). Each PGG family contains multiple genes and pseudogenes with high sequence similarity. For each family, we generate a sequence alignment network and phylogenetic trees recapitulating the evolutionary paths. We find evidence supporting the evolution history of olfactory family (both genes and pseudogenes) in human, which also supports the validity of our analysis method. Next, we evaluate these networks in respect to the gene ontology from which we identify functions enriched in these pseudogene-gene families and infer functional impact of pseudogenes involved in the networks. This demonstrates the application of our PGG network database in the study of pseudogene function in disease context.

Dataset Information

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

Publications

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

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