A practical application of generative adversarial networks for RNA-seq analysis to predict the molecular progress of Alzheimer's disease

PLoS Comput Biol. 2020 Jul 24;16(7):e1008099. doi: 10.1371/journal.pcbi.1008099. eCollection 2020 Jul.

Abstract

Next-generation sequencing (NGS) technology has become a powerful tool for dissecting the molecular and pathological signatures of a variety of human diseases. However, the limited availability of biological samples from different disease stages is a major hurdle in studying disease progressions and identifying early pathological changes. Deep learning techniques have recently begun to be applied to analyze NGS data and thereby predict the progression of biological processes. In this study, we applied a deep learning technique called generative adversarial networks (GANs) to predict the molecular progress of Alzheimer's disease (AD). We successfully applied GANs to analyze RNA-seq data from a 5xFAD mouse model of AD, which recapitulates major AD features of massive amyloid-β (Aβ) accumulation in the brain. We examined how the generator is featured to have specific-sample generation and biological gene association. Based on the above observations, we suggested virtual disease progress by latent space interpolation to yield the transition curves of various genes with pathological changes from normal to AD state. By performing pathway analysis based on the transition curve patterns, we identified several pathological processes with progressive changes, such as inflammatory systems and synapse functions, which have previously been demonstrated to be involved in the pathogenesis of AD. Interestingly, our analysis indicates that alteration of cholesterol biosynthesis begins at a very early stage of AD, suggesting that it is the first effect to mediate the cholesterol metabolism of AD downstream of Aβ accumulation. Here, we suggest that GANs are a useful tool to study disease progression, leading to the identification of early pathological signatures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism
  • Cerebral Cortex / metabolism
  • Cholesterol / metabolism
  • Cluster Analysis
  • Deep Learning
  • Disease Models, Animal
  • Disease Progression
  • Exome Sequencing
  • Humans
  • Inflammation
  • Mice
  • Models, Genetic
  • RNA, Messenger / metabolism
  • RNA-Seq*
  • Synapses / metabolism
  • Temporal Lobe / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • RNA, Messenger
  • Cholesterol

Grants and funding

This research was supported by KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (20-BR-02-09 (JK) and 20-BR-02-10 (JP, HK, MC)) and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, South Korea (grant number: H I14C1135) (MC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.