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Differential action of purifying selection explains the evolution of the major chaperone sub‐network in humans
Author(s) -
Hess Kyle,
Ellis Jacqueline,
Nguyen Peter,
Nikolaidis Nikolas
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.811.3
Subject(s) - biology , single nucleotide polymorphism , gene , genetics , negative selection , snp , chaperone (clinical) , in silico , computational biology , evolutionary biology , genotype , genome , medicine , pathology
The cellular stress response (CSR) is one of the most conserved mechanisms present in all species as it allows organisms to adapt to their ever‐changing environments and survive. The most important orchestrator of the CSR is a group of proteins called molecular chaperones, which regulate protein homeostasis and cell survival. Although the molecular chaperone networks are critical for cell health and disease in humans, the impact of the evolutionary process on their function remains largely unknown. In this study, we explored the microevolution process of an important component of the human chaperone network, composed by Hsp70s, Hsp40s, and BAGs, by analyzing single nucleotide polymorphisms (SNPs). The results can be summarized as follows: (1) in 92% of the genes the number of non‐synonymous SNPs (nsSNPs) is higher than the number of synonymous SNPs (sSNPs). (2) Sixty five percent of the genes had a significantly higher SNP density than the surrounding genes. (3) More than 80% of the genes had significantly higher SNP density within their exonic regions as compared to both intronic and un‐translated regions. (4) The majority of genes contained more sSNPs than nsSNPs within known functional regions (domains), while the number of sSNPs is similar between domains and non‐domain protein regions. (5) On average 50% of the genes contained a nsSNP on an amino acid position of known function. (6) Calculations of synonymous and non‐synonymous distances revealed the action of purifying selection, the intensity of which varied dramatically both between and within the gene families. To test some of these predictions we generated recombinant protein variants corresponding to the wild‐type and mutated HSPA1A , the major human heat‐inducible gene. We then used Isothermal titration calorimetry (ITC) and determined that most mutations only marginally altered the binding affinity to both nucleotide (ATP and ADP) and protein substrates. However, one mutation revealed alterations in the way the molecules interact and the reaction products are formed. Collectively, these results suggest that strong purifying selection due to functional constraints shaped the evolution of the major chaperone sub‐network in humans. The nsSNPs, which are either predicted or showed to alter the function of a particular protein, may either represent adaptations to particular environmental pressures, disease states, or are mutations that have not been eliminated yet from the population.