Exploring the biological role of postzygotic and germinal de novo mutations in ASD

A Alonso-Gonzalez,M Calaza,A Carracedo,R Martínez-Regueiro,J Amigo,Cristina Rodriguez-Fontenla,C Arango,M Parellada,J González-Peñas,M Fernández-Prieto

doi:10.1038/s41598-020-79412-w

Abstract

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined ASD cohort (N = 2171 trios) was created using previously published data by the Autism Sequencing Consortium (ASC). New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.

Highlights

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by deficits in communication and social interaction together with restricted interests and repetitive behaviors[1]
Transmission and De novo Association test (TADA) assesses if a gene is affecting ASD risk based on several parameters: the gene mutation rate, the recurrence of de novo mutations (DNMs) in the gene and the severity of the mutations[22]
The main aim of TADA-Denovo is to identify those genes that could be differentially involved in ASD etiology depending on the type of DNMs harbored by them

Summary

Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by deficits in communication and social interaction together with restricted interests and repetitive behaviors[1]. Comorbidity is a characteristic of ASD that can appear at any time during child’s development. Since many ASD cases with comorbidity have a clear genetic background and early detection is key for intervention, the genetic diagnosis in this type of cases is a challenge[2]. Germinal de novo mutations (DNMs) occur within germ cells and they are transmitted to the offspring when the zygote is formed after fertilization. Every single cell line of the resulting embryo will carry an identical genetic load. Another type of DNMs, postzygotic mutations (PZMs), arise during zygote mitosis, leading to a mosaic of genetically different cell lines[8]. The frequency of mutagenesis and the generation of PZMs is increased prior to gastrulation and neurogenesis[9]

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