Brain changes before birth may influence autism risk

New research maps how the human brain changes before birth and across life, tracking tiny chemical tags on DNA as the cortex takes shape. The study suggests that some risks for autism and schizophrenia may emerge while the brain is still building its basic circuits in the womb, not years later.

The team examined nearly 1,000 donated brains, from 6 weeks after conception to 108 years old, and focused on the cortex, the outer layer that supports thinking, memory, perception, and behavior.

The experts found that the most dramatic shifts in DNA chemistry occur before birth, while postnatal changes are far smaller and steadier.

Why early brain changes matter

A research team led by Alice Franklin from the University of Exeter (UE) charted how epigenetics shapes the developing cortex across time. Epigenetics refers to chemical marks on DNA that influence gene activity without changing the DNA sequence.

One common mark is DNA methylation, a small chemical tag that can quiet genes, fine-tune them, or help coordinate when genes turn on. The prenatal period is a critical window of epigenomic plasticity in the brain. 

“Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain,” wrote Franklin.

Mapping DNA changes in the brain

The researchers tracked methylation at hundreds of thousands of sites across the genome and compared them week by week during fetal life.

The team detected large clusters of change in regions that control key developmental programs responsible for building the cortex.

Patterns were often nonlinear, with bursts of rapid change followed by plateaus. That fits what we know about waves of neurogenesis and circuit formation in the second trimester – when cells are multiplying, moving to their positions, and wiring connections.

How the cortex builds itself

Before birth, neurons and supporting cells follow a tight schedule, and methylation acts like a timing system for gene activity. The study finds many sites that become more methylated in prenatal life and then stay relatively stable after birth.

Some shifts concentrate near CpG islands, short DNA stretches that often sit near gene promoters. Those islands tend to be protected early on, then certain islands show targeted changes, which aligns with tissue-specific gene control reported in developmental biology.

The study also separated signals from different cell types in the developing cortex. Neurons began to show unique methylation patterns very early, distinct from glia and other cells.

The team tagged nuclei with SATB2, a protein linked to the identity of callosal projection neurons in the cortex. This allowed them to follow neuron-enriched and neuron-depleted fractions across fetal ages and see how neuron-specific programs come online.

Linking brain changes to autism

Many of the methylation sites changing in fetal life sit near genes associated with autism and schizophrenia. That does not prove causation, but it places disease-relevant genes into an early developmental timeline.

Independent genetics backs up the importance of early neurodevelopment. An exome analysis of 24,248 schizophrenia cases identified rare coding variants of large effect in several genes, underscoring neurodevelopmental risk.

Another exome study in autism pinpointed 102 risk genes, many tied to synapse formation and brain development.

Why gene regulation is central

Gene regulation during development is a layered process involving DNA sequence, chromatin structure, and epigenetic marks. Changes to methylation can alter gene expression directly, or work with other mechanisms to set cell identity.

Classic work on MECP2 shows how sensitive the brain is to methylation-linked control. Mutations in MECP2 cause Rett syndrome, a severe neurodevelopmental disorder, highlighting how disrupted methyl reading can derail neuronal function.

The strong prenatal shifts and the relative postnatal stability suggest that many methylation programs lock in before birth. That timing may help explain why some conditions show early, hard-to-reverse trajectories.

The evidence also suggests that understanding risk means studying fetal windows when cell fate and circuit templates are forming. The cortex appears to set long-lasting patterns during this stage, which then guide later refinement.

Limitations of the study

Epigenetic marks reflect both genetic instruction and environment, but methylation is not destiny. Many prenatal changes likely represent normal developmental milestones that must proceed for healthy outcomes.

The data come from donated human tissue, so the work is descriptive rather than interventional. Still, the scale of samples and the cell type resolution add weight to the conclusions.

Broader implications of the research

Mapping when and where methylation shifts happen now provides a reference for future studies. Researchers can test whether genetic risk converges on specific fetal weeks, cell types, or pathways.

That map could also guide lab models that recreate the right developmental windows. Better models would help parse which changes are harmless milestones and which signal risk.

Conditions like autism and schizophrenia are diverse and influenced by many genes and experiences. Knowing that risk-related biology is active before birth shifts attention to early stages of brain development.

This focus may help refine early detection research and sharpen questions about prenatal environments. The research also reinforces the value of maternal health and broadly supportive prenatal care, while avoiding simplistic cause claims.

The study is published in the journal Cell Genomics.

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