Ancient Neanderthal DNA found to influence autism susceptibility

A recent study published in Molecular Psychiatry reveals that certain genetic traits inherited from Neanderthals may significantly contribute to the development of autism. This groundbreaking research shows that specific Neanderthal genetic variants can influence autism susceptibility, suggesting a link between our ancient relatives and modern neurodevelopmental conditions.

The study was motivated by the longstanding curiosity about how archaic human DNA, particularly from Neanderthals, influences modern human health. Homo neanderthalensis, commonly known as Neanderthals, are our closest known cousins on the hominin tree of life. It is estimated that populations of European and Asian descent have about 2% Neanderthal DNA, a remnant from interbreeding events that occurred when anatomically modern humans migrated out of Africa around 47,000 to 65,000 years ago.

While previous studies have identified Neanderthal genetic contributions to traits like immune function, skin pigmentation, and metabolism, the role of these ancient genes in brain development and neurodevelopmental conditions like autism has remained largely unexplored. In their new study, the researchers aimed to fill that gap by investigating whether Neanderthal DNA is more prevalent in autistic individuals compared to non-autistic controls.

Autism is a neurodevelopmental condition characterized by challenges in social interaction, communication, and repetitive behaviors or restricted interests. The severity and specific manifestations of these traits can vary widely among individuals. Given that autism is characterized by distinct patterns in brain connectivity, the researchers sought to better understand whether these patterns could be linked to Neanderthal DNA.

“I should state that I am on the autism spectrum myself. I’ve been involved with the online autistic and neurodiversity communities since circa 2003. I was a moderator on the well known forum, Wrong Planet, under the handle, ‘Sophist,’ and later developed my own autism website called Gestalt,” explained study author Emily Casanova, an assistant professor of neuroscience at Loyola University New Orleans and creator of the website Science Over a Cuppa.

“So, I’ve been interested in autism and figuring out what makes it tick for a long time. In the last decade, I’ve focused more on the genetics side, but I’ve also had an ongoing interest in evolutionary biology. For many years, that latter interest was just a hobby, but in recent years I’ve begun working more on things like studying the evolution of autism genes and just trying to understand how a lot of these developmentally-related genes evolve over time.”

“You may be wondering what that has to do with Neanderthals! Well, one of the topics I’ve been studying is how hybridization (the coming-together of two species) influences the offspring over subsequent generations,” Casanova continued. “Hybridization has a tendency to “shake things up” genetically — not just because you’re splicing two species together in an additive process — but because some genetic variants don’t always work so well when they’re suddenly thrown together in a single genome.”

“Variations tend to have partners they like to ‘travel with’ over generations and when sexual recombination splits them apart, sometimes that can create some new problems in the offspring. Interestingly, this process may also be a stimulus for more rapid evolution following hybridization.

“So, I’m very interested in these Neanderthal variants– not just in understanding how they may influence autism susceptibility but even how they might have guided our own subsequent brain evolution over the last 50,000 years,” she explained. “I don’t think it’s a coincidence that many of the variants implicated in autism are also implicated in human intelligence, so I find that possibility fascinating.”

The research team utilized whole exome sequencing (WES) data from the Simons Foundation Powering Autism Research (SPARK) Database, focusing on autistic individuals and their unaffected siblings. They compared these groups against individuals from the Genotype-Tissue Expression (GTEx) and 1000 Genomes (1000G) databases. Specifically, the researchers examined single nucleotide polymorphisms (SNPs) derived from Neanderthals, which are variations in a single DNA building block.

The researchers found that autistic individuals had a higher prevalence of rare Neanderthal-derived genetic variants compared to non-autistic controls. These rare variants, which occur in less than 1% of the population, were significantly enriched in the genomes of autistic individuals across three major ethnic groups: black non-Hispanic, white Hispanic, and white non-Hispanic.

“I know a lot of people are going to read the headline and immediately assume that autistic people have more Neanderthal DNA than non-autistic people– that they’re somehow ‘more Neanderthal,'” Casanova told PsyPost. “I wouldn’t say I blame them for the assumption, especially when the ‘Neanderthal Theory of Autism‘ had already been proposed and popularized by Leif Ekblad, an autistic independent researcher, as far back as 2001. This idea made its way around the online autistic community in the early 2000s and served partly as inspiration for Ekblad’s “Aspie Quiz,” which has continued to be one of the most popular online autism-related quizzes.”

“Our results are a little more nuanced than ‘autistic people are just more Neanderthal.’ For background, the human genome is made up of over 3 billion nucleotide pairs. The vast majority of our genomes is pretty identical to one another. But there’s a few places in the human genome that are sites of variation.”

“Neanderthal DNA provides some of that variation and some of those variants are common (1% or more of the population has that particular variant) or they can be rare (less than 1% has that variant),” Casanova explained. “In our study, we’ve found that autistic people, on average, have more rare Neanderthal variants, not that they have more Neanderthal DNA in general. That means that while not all Neanderthal DNA is necessarily influencing autism susceptibility, a subset is.”

In contrast to the rare variants, the study found that common Neanderthal-derived variants were less prevalent in black non-Hispanic and white Hispanic autistic individuals compared to controls. Common variants are those present in 1% or more of the population. This finding was not observed in white non-Hispanic autistic individuals, who did not show significant differences in common Neanderthal DNA compared to controls or unaffected siblings.

The researchers also identified specific clinical associations between Neanderthal-derived variants and autism-related traits. For example, a particular SNP (rs112406029) in the SLC37A1 gene was significantly associated with epilepsy in white non-Hispanic autistic individuals. This variant was more common in autistic individuals with epilepsy than in those without, and was even more prevalent in those with a family history of the condition.

Similar associations were found in other ethnic groups, linking certain Neanderthal variants to traits such as intellectual disability, language delay, and language regression. These findings suggest that Neanderthal-derived genetic variants may not only contribute to autism susceptibility but also influence specific comorbid conditions and traits.

“I was rather surprised that many of the Neanderthal-derived variants we found that were associated with autism dramatically varied by ethnic group,” Casanova said. “In hindsight, I suppose that shouldn’t be so surprising, but it does mean that a lot of these weak variants that are playing roles in autism are influenced by the background genome, which varies by ethnicity.”

“So, one variant may be strongly linked with autism in black Americans, while that same variant doesn’t appear to be playing a measurable role in white Hispanics and non-Hispanics. To me it suggests that our tendency to “white wash” genetics and ignore variants that aren’t implicated across all genetic backgrounds means that we’re missing out on a lot of important genetic factors.”

The findings have significant implications for our understanding of autism and its genetic underpinnings. By highlighting the role of ancient Neanderthal DNA, the research opens new avenues for exploring how hybridization events between archaic and modern humans have shaped neurodevelopmental conditions.

“In this current study, we only investigated the parts of the genome that contain protein-coding genes (known as the exome),” Casanova noted. “In the next phase, we plan on looking at the entire genome, since there’s a lot of interesting regulatory material that’s contained in those regions that’s undoubtedly influencing when and how genes are expressed. We also plan on including the Denisovan genome in our next phase of study to see if that DNA may be playing roles in autism in people with Asian/Native American backgrounds.”

“Some people in the autistic community get uncomfortable with genetics studies,” the researcher added. “In part, this is rooted in fears related to eugenics. The autistic community is well aware of how prenatal genotyping of Down Syndrome has led to abortion in about 30% of those cases. But I would just like to assure people that these Neanderthal-derived variants are also occurring in people, especially family members, without autism. So, while identifying these susceptibility factors may help us build a fuller picture of autism and its very complex roots, this knowledge cannot be used to aid in eugenics or similar agendas.”

The study, “Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings,” Rini Pauly, Layla Johnson, F. Alex Feltus, and Emily L. Casanova.