A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia.

Nathan G Skene,Marcia Roy,Seth Gn Grant

doi:10.7554/elife.17915

Abstract

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.

Highlights

Identifying the genetic mechanisms that underpin brain ageing across the lifespan may provide explanations for the maturation of behaviours and age of onset of diseases
The reason for using two scoring methods is that some age periods have many Trajectory Turning Points (TTTPs) and others have few: DeGeT controls for this by balancing the number of TTTPs within age groups, while ALiGeT scoring allows for the possibility that small time windows will have distinct molecular associations
We focussed on identifying age-dependent gene regulatory events that were detected when the trajectory in the level of gene expression changed

Summary

Introduction

Identifying the genetic mechanisms that underpin brain ageing across the lifespan may provide explanations for the maturation of behaviours and age of onset of diseases. Longitudinal studies show cognition, emotion and personality emerge progressively during childhood and adolescence, with executive functions peaking in early adulthood (Craik and Bialystok, 2006; De Luca et al, 2003). This coincides with the onset of some of the most devastating psychiatric disorders, most of which arise during later stages of brain development in the teenage years and early twenties (Kessler et al, 2007). There has been major progress in understanding the genetic basis of schizophrenia with the identification of many mutations and variants contributing to disease susceptibility.

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Conclusion