Fourteen years ago, scientists published the groundbreaking discovery that the modern human genome contains evidence of past hybridizations with our extinct cousins, the Neanderthals. Since that time, numerous studies have explored the many ways in which these Neanderthal-derived variants influence modern human health. Scientists have reported a wealth of associations between Neanderthal DNA  and human phenotypes and conditions, including propensity for severe COVID, autoimmune diseases, prostate cancer, diabetes 2,  hypercoagulation, pain sensitivity, brain and skull shape, brain connectivity, depression, and even protection against the positive symptoms of schizophrenia.

In a new study published in Molecular Psychiatry,  Pauly et al. (2024) report an enrichment of certain types of Neanderthal DNA in people on the autism spectrum. Compared to ethnically-matched control groups, the team found that autistic people tend to have more Neanderthal variants that are otherwise rare in the general population, suggesting from a population perspective that many of these variants are slowly on their way out of the human genome. All three ethnic groups that were studied (black non-Hispanic, white Hispanic, and white non-Hispanic) displayed the same trend, although specific susceptibility variants differed greatly across each of the groups, suggesting that many factors are population-specific.

The team also identified specific variants or polymorphisms that were associated with autism.  Selecting only polymorphisms that influence gene expression in the brain (known as brain-associated quantitative trait loci or brain QTLs), they identified 25 QTLs enriched in autism. A notable example includes a common polymorphism in the SLC37A1 gene. Approximately 67% of white non-Hispanic autistic people with epilepsy who came from multiplex families carried this variant, compared to 22% of controls and 26% of autistic people without epilepsy. The functions of this gene are not well understood, but it is expressed in the brain in a cell organelle known as the endoplasmic reticulum, so it likely plays important roles in general cell metabolism. Interestingly, epilepsy often occurs in people with metabolic diseases.

Another common QTL in the USP47 gene was identified in white Hispanic people with autism, once again in association with epilepsy. Eighty percent of autistic males with epilepsy carried this polymorphism compared to 15% of controls. This gene has previously been implicated in epilepsy in general. Finally, a rare missense mutation in the COX10 gene was enriched in black non-Hispanic autistic people. Interestingly, loss-of-function of the COX10 gene in animal models specifically impairs inhibitory neurons in the brain, leading to an excitatory/inhibitory imbalance that has been associated with conditions like autism.

The authors emphasize that autistic people do not differ from non-autistic people in terms of how much Neanderthal DNA they carry. Instead, a subset of polymorphisms is enriched in people with autism as well as their families. As a nod to the complexity of the genetics that underlie autism, it is also important to note that not all people on the spectrum share these same susceptibility factors. Instead, these findings apply to a subset of people. However, Neanderthal variants account for susceptibility in a significant portion of this unique population and are a very promising avenue for further research. This work provides yet another important puzzle piece to our understanding of the complex genetics of autism.

Original Article: 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, in press.

Header Photo: Courtesy of hairymuseummatt (original photo), DrMikeBaxter (derivative work). Available on World History Encyclopedia: https://www.worldhistory.org/article/1092/the-neanderthal-sapiens-connection/