How Ancient Neanderthal Genes May Influence Autism

A New Study Links Neanderthal DNA to Increased Autism Susceptibility in Modern Humans

Modern humans carry a surprising legacy from our ancient cousins, the extinct Neanderthals. A new study¹ suggests that archaic genes, inherited through interbreeding tens of thousands of years ago, may influence our susceptibility to autism.

The Genetic Legacy of Interbreeding

Neanderthals, a distinct species from modern humans, interbred with early Homo sapiens after they left Africa and before spreading across Europe and Asia. This interbreeding resulted in non-African populations today carrying between 1.5% and 4% Neanderthal DNA. Additionally, Homo sapiens also interbred with another extinct relative, the Denisovans. Some of the inherited Denisovan genes protect us from viral infections but may also increase the risk of mental illnesses.

A Rare and common SNP frequencies by ethnic control group. B Barplot with comparative Total NeanderScores between controls and autism broken down by ethnicity. No significant differences between autism and controls except in the white Hispanic (WHS) group. C Common NeanderScores across experimental and control groups by ethnicity. In general, autism groups—with the exception of white, non-Hispanics (WNH)—have lower common NeanderScores. D Rare NeanderScores of autism and controls by ethnicity. Note that all autism groups have significantly higher Rare NeanderScores compared to controls. (Due to small participant numbers, the control WHS group likely shows far lower Rare NeanderScores than they would with a larger N, resulting in an unusually dramatic deviation between controls and autism. Therefore, this particular result should be interpreted with caution.) E Cytoscape network illustrating clinical associations in autism (white nodes) with various brain-associated QTLs (colored nodes) that were either rare in autism or significantly enriched. SNPs are color-coded according to ethnic group. (Salmon = BNH, green = WHS, blue = WNH.).

A Small but Significant Legacy

Although the Neanderthal genetic legacy is small, it has significant implications for our physical and mental health. Previous research has connected this genetic legacy to various conditions, including neurological, psychiatric, and immune system disorders. Conversely, inherited Neanderthal gene variants also boost the immune system and modify sensitivity to ultraviolet radiation.

Now, findings made by researchers from Clemson University and Loyola University suggest you can add autism to this growing list of heritable traits. Researchers found that people with autism have an over-representation of specific Neanderthal-derived variations in their DNA compared to control groups. While these variations don’t guarantee autism, they may act as a hidden risk factor, adding another layer of complexity to understanding this neurological disorder. First author Alex Feltus, a professor at the Clemson Department of Genetics and Biochemistry said,

"This is the first evidence that I am aware of actually showing that Neanderthal DNA is associated with autism.”

Ancient DNA’s Role in Modern Autism

The researchers utilized data from public databases to compare genetic traits in autistic individuals, their unaffected siblings, and ethnically matched controls. They focused on single nucleotide polymorphisms (SNPs), the most common type of genetic variation among people. SNPs represent differences in a single DNA building block and can influence gene function, potentially affecting disease susceptibility.

The analysis identified 25 SNPs linked to brain development that were significantly over-represented in people with autism. However, these Neanderthal-derived variations do not directly cause autism but rather contribute to a higher susceptibility to the condition. Autism spectrum disorder is likely caused by an umbrella of different genetic factors that we’re only beginning to untangle. Another 2022 Nature Genetics study² by Mount Sinai researchers identified more than 250 genes with strong links to autism.

"The hypothesis is not, 'Did Neanderthals give us autism?' It’s that Neanderthals gave us some of the gene tweaks that give a higher susceptibility for autism,” he said.

Implications and Future Research

This study underscores the intricate nature of genetic inheritance and its impact on modern health. The researchers hope their findings will inspire further investigation into how ancient genes continue to shape brain development, intelligence, and overall human health, particularly concerning autism.

"Autism is a complex trait. It is controlled by many, many genes. A big part of what we do in my lab is try to understand the level of complexity. Of the 60,000 genes in the human genome, how many genes are at play when you’re developing autism or cancer or any other complex trait? We embrace complexity. We don’t try to erase complexity.”

Understanding the genetic factors influencing autism can provide critical insights into its development and potential interventions. As researchers continue to explore the links between ancient DNA and modern conditions, the complexity and inter-connectivity of our genetic heritage become increasingly evident, revealing how our ancient past continues to shape our present and future.

1. Pauly, R., Johnson, L., Feltus, F. A., & Casanova, E. L. (2024). Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings. Molecular Psychiatry, 1–10. https://doi.org/10.1038/s41380-024-02593-7

2. Fu, J. M., Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., Stevens, C. R., Cusick, C., Babadi, M., Banks, E., Collins, B., Dodge, S., Gabriel, S. B., Gauthier, L., Lee, S. K., … iPSYCH-BROAD Consortium. (2022). Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nature Genetics, 54(9), 1320–1331. https://doi.org/10.1038/s41588-022-01104-0