Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Ludovica Montanucci,Martin Sikora,Jaume Bertranpetit,Pierre Luisi,Giovanni Marco Dall’Olio,Hafid Laayouni

doi:10.1186/1471-2148-12-98

Abstract

BackgroundAsparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints.ResultsOur results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1.ConclusionsThese findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Highlights

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes
We describe how signatures of positive selection and population differentiation are distributed to node centrality values, and we discuss how these values can be interpreted in the light of what is known about the biology of the Asparagine N-Glycosylation pathway
Signatures of population differentiation and positive selection on the genes of the Asparagine N-Glycosylation pathway, and Genes included in the analysis are listed in Additional file 1: Table S1 and Figure 1 shows a representation of the Asparagine N-Glycosylation pathway

Summary

Introduction

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Asparagine N-Glycosylation is one of the most important forms of protein modification, and involves almost all the proteins in the secretory pathway, including proteins in the Endoplasmic Reticulum, in the Golgi and on the Cell Membrane. This pathway is responsible for most of the cell-specific inter-variability on the proteins of the cell membrane in eukaryotic organisms. This method is based on the fact that recent positive selection leaves a strong footprint on the pattern of haplotype variability, namely extended linkage disequilibrium

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