Insights into the Evolutionary Features of Human Neurodegenerative Diseases

Bioinformatics Centre, Bose Institute, Kolkata, India.
PLoS ONE (Impact Factor: 3.23). 10/2012; 7(10):e48336. DOI: 10.1371/journal.pone.0048336
Source: PubMed


Comparative analyses between human disease and non-disease genes are of great interest in understanding human disease gene evolution. However, the progression of neurodegenerative diseases (NDD) involving amyloid formation in specific brain regions is still unknown. Therefore, in this study, we mainly focused our analysis on the evolutionary features of human NDD genes with respect to non-disease genes. Here, we observed that human NDD genes are evolutionarily conserved relative to non-disease genes. To elucidate the conserved nature of NDD genes, we incorporated the evolutionary attributes like gene expression level, number of regulatory miRNAs, protein connectivity, intrinsic disorder content and relative aggregation propensity in our analysis. Our studies demonstrate that NDD genes have higher gene expression levels in favor of their lower evolutionary rates. Additionally, we observed that NDD genes have higher number of different regulatory miRNAs target sites and also have higher interaction partners than the non-disease genes. Moreover, miRNA targeted genes are known to have higher disorder content. In contrast, our analysis exclusively established that NDD genes have lower disorder content. In favor of our analysis, we found that NDD gene encoded proteins are enriched with multi interface hubs (party hubs) with lower disorder contents. Since, proteins with higher disorder content need to adapt special structure to reduce their aggregation propensity, NDD proteins found to have elevated relative aggregation propensity (RAP) in support of their lower disorder content. Finally, our categorical regression analysis confirmed the underlined relative dominance of protein connectivity, 3'UTR length, RAP, nature of hubs (singlish/multi interface) and disorder content for such evolutionary rates variation between human NDD genes and non-disease genes.

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Available from: Tina Begum, Nov 22, 2014
    • "In contrast to these observations Huang et al., reported that human disease and non-disease genes evolve at a similar rate with marginal difference in their evolutionary rate [4]. Subsequently studies that attempted to resolve this controversy have also yielded dissimilar results [7] [8]. Thus, how human disease genes evolve with respect to human non-disease genes still remains an open question. "
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    ABSTRACT: Comparisons of evolutionary features between human disease and non-disease genes have a wide implication to understand the genetic basis of human disease genes. However, it has not yet been resolved whether disease genes evolve at slower or faster rate than the non-disease genes. To resolve this controversy, here we integrated human disease genes from several databases and compared their protein evolutionary rates with non-disease genes in both housekeeping and tissue-specific group. We noticed that in tissue specific group, disease genes evolve significantly at a slower rate than non-disease genes. However, we found no significant difference in evolutionary rates between disease and non-disease genes in housekeeping group. Tissue specific disease genes have a higher protein complex number, elevated gene expression level and are also associated with conserve biological processes. Finally, our regression analysis suggested that protein complex number followed by protein multifunctionality independently modulates the evolutionary rate of human disease genes.
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    • "Among all the identified factors, gene expression level is claimed to be the most important correlate of protein evolutionary rates to date (Bloom et al. 2006; Drummond et al. 2006; Panda et al. 2012). "
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    ABSTRACT: To date, numerous studies have been attempted to determine the extent of variation in evolutionary rates between human disease and non-disease (ND) genes. In our present study, we have considered human autosomal monogenic (Mendelian) disease genes which were classified into two groups according to the number of phenotypic defects i.e. specific disease gene [SPD, one gene: one defect] and shared disease gene [SHD, one gene: multiple defects]. Here, we have compared the evolutionary rates of these two groups of genes i.e. SPD genes and SHD genes with respect to ND genes. We observed that the average evolutionary rates are slow in SHD group, intermediate in SPD group and fast in ND group. Group-to-group evolutionary rate differences remain statistically significant regardless of their gene expression levels and number of defects. We demonstrated that disease genes are under strong selective constraint if they emerge through edgetic perturbation or drug-induced perturbation of the interactome network, show tissue restricted expression and are involved in transmembrane transport. Among all the factors, our regression analyses interestingly suggest the independent effects of (i) drug-induced perturbation and (ii) the interaction term of expression breadth and transmembrane transport on protein evolutionary rates. We reasoned that the drug-induced network disruption is a combination of several edgetic perturbations and thus, has more severe effect on gene phenotypes.
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