Long genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer's disease: Implications for disease etiology

Abstract

Aging, the greatest risk factor for Alzheimer's disease (AD), may lead to the accumulation of somatic mutations in neurons. We investigated whether somatic mutations, specifically in longer genes, are implicated in AD etiology. First, we modeled the theoretical likelihood of genes being affected by aging-induced somatic mutations, dependent on their length. We then tested this model and found that long genes are indeed more affected by somatic mutations and that their expression is more frequently reduced in AD brains. Furthermore, using gene-set enrichment analysis, we investigated the potential consequences of such long gene disruption. We found that long genes are involved in synaptic adhesion and other synaptic pathways that are predicted to be inhibited in the brains of AD patients. Taken together, our findings indicate that long gene-dependent synaptic impairment may contribute to AD pathogenesis.

Keywords: Alzheimer's disease; DNA damage; long genes; somatic mutations; synaptic adhesion.

FIGURE 1

Longer genes have an increased likelihood to be affected by sSNVs. (A) The length distribution of human genes has a long tail that extends toward a group of extremely long genes of 1‐2 mega base pairs (272 very long genes are indicated with open circles (see below) and gene length in base pairs (bp). Gene length information was retrieved from Ensembl Biomart (GENCODE v19, GRCh37p13). (B) Gene length follows a log‐normal distribution with parameters μ = 4.35 (22.5 kb) and σ = 0.68 (dashed line). The outlier bin near 1 kb represents the large family of olfactory receptors that have gone through extreme evolutionary expansion. The 272 genes that are indicated by the open circles in 1B and in the shaded gray area under the curve in 1C show the subgroup of very long genes (genes with gene length > μ+2σ) that were used for the enrichment analyses in this study. (C) Binomial probability model for gene conservation over time in which somatic mutations (sSNVs) take place at a fixed and uniform rate across the genome, age in years (y). An average‐sized gene mostly survives the mutational burden of aging, with only ≈1% of its copies being affected by somatic mutations in a 65‐year‐old subject. For longer genes, however, ≈60% of copies are expected to have been affected by at least one sSNV between the sixth and seventh decades of life. (D) sSNVs occur more often in longer genes (Kolmogorov‐Smirnov test: P < 1.0 × 10⁻⁴). Gene length distributions for genes having potential pathogenic sSNVs from the studies by Park et al. (Red, 208 genes), Ivashko‐Pachima et al. (Blue, 499 genes), Lodato et al. (Green, 175 genes), and all human protein‐coding genes (Black, 20535 genes) are shown. Circles following the same color code plotted below density graph represent individual gene lengths. Box plots visualize the median with flanking lower and upper hinges (corresponding to the 25th and 75th percentiles), and the whiskers represent the 95% confidence interval

FIGURE 2

Long genes are significantly downregulated in AD‐relevant brain regions. Plots show differentially expressed genes, that is, genes that show significantly increased or decreased expression when comparing AD patients to non‐demented controls, from previously published RNA sequencing studies (Table 4). Protein‐coding genes are binned in 50 consecutive groups (gray bars), based on transcribed gene length. We compared the number of genes showing either increased or decreased expression in each bin (height of gray bar) with that of the total gene pool using hypergeometric tests (red circles, Bonferroni threshold for significance is indicated with dashed blue line)

FIGURE 3

Long genes are significantly downregulated in inhibitory neurons of the entorhinal cortex. Plots show differentially expressed genes, that is, genes that show significantly increased or decreased expression when comparing AD patients to non‐demented controls, in single inhibitory or excitatory neurons from the entorhinal cortex (Table 4). Protein‐coding genes are binned in 50 consecutive groups (gray bars), based on transcribed gene length. We compared the number of genes showing either increased or decreased expression in each bin (height of gray bar) with that of the total gene pool using hypergeometric tests (red circles, Bonferroni threshold for significance is indicated with dashed blue line)