Why did autoimmunity evolve

Over the past decade, it has been postulated that alternative splicing AS is a critical post transcriptional event directing an enhancement of transcriptome and proteome diversity, particularly in higher organisms [ 29 ]. The frequent accumulation of non-synonymous mutations in alternatively spliced regions [ 30 ] initiates a faster rate of evolution in alternatively spliced exons than the constitutively spliced ones as evidenced from a comparison of orthologous human and mouse genes [ 31 ].

Investigation on the involvement of the three groups of genes in alternative splicing mechanism revealed that most of the IG genes favor alternative splicing to increase their proteomic diversity in contrast to AD and ID genes Table 1.

Such nature of IG is also biologically relevant since it was proposed that AS is crucial for a functional immune system as it offers the potency of high degree of diversity and the competence of individual cells to rapidly adapt and respond towards the changing environmental conditions [ 32 , 33 ]. Since, alternative splicing can bolster organism complexity by effectively increasing the proteome size, the m-RNA abundance would be higher for the immunological genes.

However, we already noticed IG genes are lowly expressed. Accounting EST data, the trend remain exactly same i. In the recent year it has been clarified that up to one-third of human AS events create a premature termination codon PTC that would cause the resulting mRNA to be degraded by nonsense-mediated mRNA decay NMD [ 34 , 35 ] and it was also stated that a higher rate of mRNA decay can be considered as an indicator of the lower gene expressivity [ 36 ].

Another implication of alternative splicing is to promote intrinsically disordered protein, thus enabling functional and regulatory diversity in human proteome [ 37 , 38 ]. Calculation of disorder residues in the three classes of proteins shows that the percentage of unstructured protein regions in IG, ID and AD genes are respectively The aberrant increase of disorderness in IG proteins again confirms the high flexibility of antigen binding sites in immunoglobulin.

Association with a large number of disorder residues of IG is also be an imperative reason for their faster evolutionary rate than AD and ID genes since in some protein families it has been demonstrated that the disordered regions evolve at a significantly faster rate than the ordered regions [ 40 ]. In recent years there has been growing evidence for extensive natural variations like SNPs to be the major contributor of alternative splicing variation in humans [ 41 ].

Numerous disease-causing mutations within the consensus 5' splice site create a cryptic splice site that leads to defective mRNA and protein products [ 42 , 43 ]. This phenomenon indicates that SNPs impede the disease genes AD, ID to take part in alternative splicing by altering the splicing signals and their lower involvement with alternative splicing than IG genes may imposes much more evolutionary pressure on disease genes.

However, in some cases, PMs may be detrimental to protein functionality and may compromise the cellular functions in which they reside [ 45 ]. Among many of the modifications, post-translational phosphorylation is one of the most common protein modifications that occur in animal cells. Calculation of PMs sites revealed that the fraction of potential phosphorylation residues i. This observation again emphasized the previous hypothesis that the abnormal frequency of PMs uncover cryptic epitopes or create some novel epitopes that may be not tolerated during T-cell selection and trigger the pathogenesis of autoimmune disorder [ 45 ].

Contextually, it has recently been discovered that an additional purifying selection are operated on the positions involved in phosphorylation as compared to their unmodified counterparts in the same protein [ 46 ]. Thus the higher enrichment of post-translational phosphorylation site in AD genes may be considered as a potential reason for their lower evolutionary rate. Furthermore, it is well established that buried residues in a protein are important determinants of protein stability while surface residues are involved in protein function [ 47 ].

Since buried residues evolve at a slower rate [ 48 ], the higher level of residue burial in AD genes can be accounted for their lower sequence divergence and as well as a possible means of achieving greater stability. Systematic approach to the analysis of SNPs indicated that SNPs resulting in deleterious amino acid changes predominantly affect the stability of the protein [ 49 ]. We then map the non-synonymous SNPs on protein buried region and quantify the hydrophobic, hydrophilic, amphipathic amino acid substitution frequency in each group of genes.

The average amino acid exchange frequencies among hydrophobic, hydrophilic and amphipathic amino acids among AD, ID, IG genes for buried regions of proteins are diagrammatically represented in Figure 2. We noticed transition from hydrophilic to hydrophobic or amphipathic to hydrophobic residue is more frequently substituted in the buried regions of AD proteins compared to ID and IG proteins. Moreover, the hydrophobicity of buried region in AD genes has found to increase significantly after substitution with SNPs than ID genes while no change of hydrophobicity has occurred in case of IG Figure 3.

Thus, influence of SNPs in increasing the hydrophobicity in buried region of AD proteins may be responsible for evolutionary constraint for maintaining protein stability. Differences in average hydrophobicity score between the three categories of genes before mutation wild type and after mutation mutant type with SNPs.

P-value shows the significant level. The dominant eigen vectors taken as equal to or greater than 1 that appear from this analysis can be interpreted as the most important contributors directing protein evolution [ 50 ]. PCA with gene level variables SNPs, CNVs, RR, duplicability ; m-RNA level variables isoform number, alternatively spliced exon, m-RNA abundance, disorderness ; protein level variables phosphorylation, protein residue burial , which are the dominant factors, are represented in table 2.

Multiple Regression Analysis was then performed to assess the contribution of each level variables determined in PCA in a single regression model from which we can identify the influence of all potential predictor variables and at the same time can eliminate step by step those predictors that contribute least to the regression model.

Recent years have witnessed rapid progress in elucidating the molecular causes of various diseases. Here we analyzed the evolutionary disparity between the functional and non-functional immune systems.

We noticed that autoimmune disease genes are more conserved than other immunological disease genes and both sets of genes evolved significantly at a slower rate than immunological genes. Though the evolutionary rates differences among the gene groups are statistically significant, the difference of mean values between autoimmune and immunological disease genes is small.

Significant differences in synonymous substitutions rates among the gene groups indicate the role of neutral substitutions in driving the evolutionary rate discrepancies among them.

Now, the slower evolving disease linked immune genes raise a fundamental question why non disease immune genes evolve at a higher rate compared to disease related immune genes since it was previously documented by several studies that non-disease genes evolve at a slower rate than disease genes [ 51 , 52 ], though some controversial reports [ 11 ] are also present.

To resolve this controversy, our previous study [ 12 ] exemplified that, monogenic diseases inherited by Mendelian fashion and polygenic disease genes inherited by non-Mendelian fashion are evolutionarily faster than housekeeping genes but monogenic disease genes show slower evolutionary rate than tissue specific genes.

Herein, the differences in single nucleotide polymorphisms, copy number variations, recombination rate, duplicability, alternative splicing, disorderness, post-translational modification, and protein residue burial can explain the evolutionary disparity among the three groups of genes.

The evolutionary conservation of disease related immunological genes in spite of their higher association with non-synonymous single nucleotide polymorphisms is an artifact of its beneficial impact on disease related genes Figure 4. Single nucleotide polymorphisms up-regulate recombination rates which in turns increase the gene expression as well as paralogs number in disease genes. Duplication driven disease gene formation has also supported by a series of evidence in an earlier literature [ 54 ].

Previously, it was underscored that duplication and alternative splicing could not be operated simultaneously rather they hold a negative correlation with each other [ 55 ]. Since the disease genes achieved their proteome size through gene duplication, we observed a lower involvement with alternative splicing.

Here also single nucleotide polymorphisms played a critical role in 5' splice site and create a cryptic splice site by altering the splicing signal. On the other hand the immunological genes follow the path of alternative splicing to enhance their diversity.

However, the frequent link with alternative splicing could not generate higher m-RNA abundance of immunological genes due to "Regulated Unproductive Splicing and Translation" RUST mechanism [ 56 ] in which premature termination codon containing isoforms are targeted to non-sense mediated decay to regulate the transcript level of functional protein.

Thus, we deciphered that the basic difference in the involvement of proteome expansion machinery put differential selective pressures on malfunctioning immune genes and the functional immune genes. Moreover, it is also observed in our search that autoimmune disease and other immunological disease genes are more prone to post-translational phosphorylation which may regarded as a possible reason for slower evolutionary rate.

In protein structure level, the higher residue burial is observed in two types of disease genes compared to non-disease genes and the propensity of single nucleotide polymorphisms to substitute hydrophilic, amphipathic amino acid by hydrophobic amino acid in disease groups could be prompted as a reason of lower sequence divergence in autoimmune disease and other immunological disease genes than immunological genes.

Conferring structural stability to the autoimmune disease genes also has a biological significance since incidence of autoimmunity sharply increases in the stable protein forms in the cell [ 57 ]. The schematic representation to illustrate synchronous effect of Single Nucleotide Polymorphisms on recombination rate, hydrophobicity, paralogs number, alternative splicing.

To the best of our knowledge, this is the first extensive comparison of disease and non-disease related immunological genes from evolutionary perspective. This finding also shades light into the mutational spectrum acting on DNA-mRNA-protein level of the three classes of genes.

Our study will surely enrich the knowledge of disease gene identification and may also help in medicinal improvement of autoimmune disease. Immune related disease genes mainly consist with Autoimmune disease, Immunoproliferative disease, Immunologic deficiency syndromes, hypersensitivity, Graft rejection, Purpura, thrombocytopenia, and Glomerulonephritis. Evolution could be to blame for our autoimmune diseases, such as lupus, multiple sclerosis and rheumatoid arthritis.

For the first time, we have evidence that people who are more susceptible to disorders of this kind are that way because their immune system is better equipped to combat dangerous infections, enabling them to live longer. So what could explain the existence of these conditions? Graham and her colleagues have found evidence for this idea using a long-running study of elderly people in Taiwan.

It has tracked more than people born between and for the past 27 years. They found that individuals with higher levels of these antibodies were likely to live longer.

Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Linking autoimmunity to the origin of the adaptive immune system. Robert Bayersdorf , Robert Bayersdorf. Oxford Academic. Google Scholar. Arrigo Fruscalzo. The example of malaria. New technology. Latest news Could 'cupping' technique boost vaccine delivery? Scientists identify new cause of vascular injury in type 2 diabetes. Adolescent depression: Could school screening help?

Related Coverage. How the immune system works. Medically reviewed by Daniel Murrell, MD. What is lupus? Medically reviewed by Vincent J. Jumping genes made us human, but can they cause disease?

What is DNA and how does it work?