Newly Published Genetics/Brain Tissue Study Will Help Refine the Search for Specific Early Genetic Markers of Risk of Autism in Babies and Toddlers

Published March 22, 2012 in PLoS Genetics

By Dr. Eric Courchesne

A new study of autism published today in PLoS Genetics (Age Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages) has discovered abnormal gene activity and gene deletions in the same brain region that also has a 67% overabundance of brain cells. This region – the prefrontal cortex—is involved in social, emotional, communication and language skills. The finding brings new understanding of what early genetic abnormalities lead to excess brain cells and to the abnormal brain wiring that cause core symptoms in autism. Importantly, the study also shows that gene activity abnormalities in autism change across the lifespan.

The research is one of the first to focus on gene activity inside the young autistic brain, and is the first to examine how gene expression activity changes across the lifespan in autism. It is also one of the largest postmortem studies of autism to date. This close-up look inside the brain uncovered the presence of abnormal levels of activity in genes (“gene expression”) and gene defects (deletions of portions of DNA sequences) that control the number of brain cells and their growth and pattern of organization in the developing prefrontal cortex. The abnormal gene activity occurred in several networks that are important during prenatal brain development (cell cycle, neurogenesis, DNA damage detection and response, apoptosis and survival networks). This seems to rule out a number of current speculations about postnatal causes of autism and, combined with the new evidence of a 67% excess of prefrontal brain cells, points instead to prenatal causal events in a majority of cases.

The study’s direct examination of bothmRNA and DNA from the same frontal cortex region in each individual is also a unique approach to discovering the genetics of abnormal brain development in autism. The combined mRNA and DNA results indicate that a large and heterogeneous array of gene and gene expression defects disrupt prenatal processes that are critical to early prefrontal cortex formation. “Although DNA defects vary from autistic case to case, the diverse genetic deletions seem to underlie a relatively common biological theme, hitting a shared set of gene pathways that impact cell cycle, DNA damage detection and repair, migration, neural patterning and cell differentiation,” according to the study. Importantly, the set of functional gene pathways identified by the study’s direct analyses of autistic brain tissue are consistent with those identified by previous studies that analyzed copy number variations in living autistic patients.

A second major discovery in this study is that the pattern of abnormal gene activity changes across the lifespan in autism. Thus, in adults with autism, the study found abnormal activity in genes involved in remodeling, repair, immune response and signaling. This raises opportunities for new research directions that ask whether and how such later alterations in genetic activity impact brain structure and function. A hope is that perhaps this later, second stage of unusual genetic activity we detected in adults with autism has something to do with enhancing adaptive connections and pruning back earlier maladaptive connections. Further research needs to better understand the impact of those later changes in genetic activity.

Findings in the new study will help refine the search for specific early genetic markers of risk of autism in babies and toddlers. Next steps include identifying what causes the altered genetic activity at early stages of development, when nerve cells in prefrontal cortex arise and the first steps in creating brain circuitry are being taken. Knowledge of these specific patterns of abnormal gene activity may also give rise to future studies that search for medical interventions that target abnormal gene activity in an age-specific fashion.

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