Dalm, V. A. S. H. | bioRxiv Science

bioRxiv2022

Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?

Neanderthals were a species of archaic human that became extinct around 40,000 years ago. Modern humans have inherited 1-6% of Neanderthal DNA as a result of interbreeding with the Neanderthals. These inherited Neanderthal genes have paradoxical influences, while some can provide protection to viral infections, some others are associated with autoimmune/auto-inflammatory diseases. We hypothesized that genetic variants with strong detrimental effects on the function of the immune system could potentially contributed to the extinction of the Neanderthal population. In modern humans more than 450 genes are associated with inborn errors of immunity (IEI). We used the publically available genome information from a Neanderthal from the Altai mountains and filtered for potentially damaging variants that were present in genes associated with IEI, and checked whether these variants were present in the genomes of the Denisovan, Vindija and Chagyrskaya Neanderthals. We identified 24 homozygous variants and 15 heterozygous variants in IEI-related genes in the Altai Neanderthal. Interestingly, two homozygous variants in the UNC13D gene and one variant in the MOGS gene were present in all archaic genomes. Defects in the UNC13D gene are known to cause a severe and often fatal disease called hemophagocytic lymphohistiocystosis (HLH). One of these variants p.(Asn943Ser) has been reported in patients with HLH. Variants in MOGS are associated with glycosylation defects in the immune system affecting the susceptibility for infections. So, although we do not know exactly the functional impact yet, these three variants could have resulted in an increased susceptibility to severe diseases, and may have contributed to the extinction of Neanderthals after exposure to specific infections.

evolutionary biology↗

bioRxiv2021

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model.

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signalling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3K{delta} syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110{delta}E1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

neuroscience↗