Molecular basis of human complex diseases

Abstract

Human complex diseases are elusive due to the complex genetic, physicochemical, environmental, and social factors that cause them. Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain. As the most common type of scoliosis, adolescent idiopathic scoliosis (AIS) has a strong genetic association. Non‐obstructive azoospermia (NOA), the most severe form of male infertility, is characterized by failure of spermatogenesis resulting in no sperm in the ejaculate. Although many hypotheses have been proposed in recent years to explain the pathogenesis, there a still a large gap in the understanding of the molecular basis of these complex diseases.

Here, we investigated the molecular mechanisms of the above three diseases with different strategies. Based on the "two-hit hypothesis" of AD, we explored the downstream regulatory mechanism of the core pathway CDK/pRB/E2F1. By re-mining of current AD and transcription factor datasets and functional similarity scoring, PAX6 was finally identified as a potential downstream regulator of E2F1 in AD progression. Using a series of filtering criteria based on the family whole genome sequencing (WGS) data in the AIS project, we identified a rare SLC6A9 functional variant in each of the two families. Following the long-term collection of the local cohort, it was discovered that one of these two variants, p.Y206F was enriched in the AIS population. External cohort screening for additional SLC6A9 variants also provided support for follow-up experiments. In addition, we discovered several additional SLC6A9 functional variants in two external AIS cohorts. In the third project, we first characterized specific mitochondrial events during spermatogenesis and identified differences in energy utilization before and after crossing the blood testicular barrier (BTB). Then, in comparison to NOA samples, we observed similar patterns of activation of Sertoli cell metabolic pathways in maturation arrest (MA) and Sertoli cell-only (SCO) types, as well as the intensity of glucose metabolism and ribosomal abnormalities in MA samples during spermatocyte stage.

In conclusion, we adopt different disease research strategies and analysis methods for different types of diseases, which provide a reference for future research on the pathogenesis and molecular basis of complex human diseases. (350 words)