Genes dysregulated in the blood of people with Williams syndrome are enriched in protein-coding genes positively selected in humans

2020

Autism

Self Cite

Autism spectrum disorders and Williams syndrome exhibit quite opposite features in the social domain, but also share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this article, we adopted a comparative molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of subjects with these two conditions. We found a significant overlap between differentially expressed genes compared to neurotypical controls, with most of them exhibiting a similar trend in both conditions, but with genes being more dysregulated in Williams syndrome than in autism spectrum disorders. These genes are involved in aspects of brain development and function (particularly dendritogenesis) and are expressed in brain areas (particularly the cerebellum, the thalamus, and the striatum) of relevance for the autism spectrum disorder and the Williams syndrome etiopathogenesis. Lay abstract Autism spectrum disorders and Williams syndrome are complex cognitive conditions exhibiting quite opposite features in the social domain: whereas people with autism spectrum disorders are mostly hyposocial, subjects with Williams syndrome are usually reported as hypersocial. At the same time, autism spectrum disorders and Williams syndrome share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this article, we adopted a comparative molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these conditions. We found a significant overlap between genes dysregulated in the blood of patients compared to neurotypical controls, with most of them being upregulated or, in some cases, downregulated. Still, genes with similar expression trends can exhibit quantitative differences between conditions, with most of them being more dysregulated in Williams syndrome than in autism spectrum disorders. Differentially expressed genes are involved in aspects of brain development and function (particularly dendritogenesis) and are expressed in brain areas (particularly the cerebellum, the thalamus, and the striatum) of relevance for the autism spectrum disorder and the Williams syndrome etiopathogenesis. Overall, these genes emerge as promising candidates for the similarities and differences between the autism spectrum disorder and the Williams syndrome socio-cognitive profiles.

Section: Methodsmentioning

confidence: 99%

Autism and Williams syndrome: Dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood

Niego

2020

Autism

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“…Genes positively selected in our species are enriched in candidates for high‐prevalent, complex cognitive conditions, like SZ (Srinivasan et al, 2016) or autism spectrum disorders (ASD) (Polimanti & Gelernter, 2017). Even in conditions with a neat genetic origin, like Williams syndrome (WS), abnormally expressed genes outside the WS region are enriched in genes that have been positively selected in modern humans compared with extinct hominins (Benítez‐Burraco, 2020a). A possible explanation of this overlap between genes involved in the evolution of the human brain, cognition, and behaviour, and genes causing complex cognitive and behavioural human conditions is that recently evolved components of the human phenotype are less resistant to gene mutations (and more generally, to developmental perturbations) because they lack compensatory mechanisms to damage, as commonly found in biological functions shaped by prolonged selective pressures (see Toro et al, 2010, for a useful discussion on ASD).…”

Section: Introductionmentioning

confidence: 99%

Abnormal features of human self‐domestication in bipolar disorder

Hansen

2023

Eur J of Neuroscience

Bipolar disorder (BD) is a severe mental condition characterized by episodes of elevated mood and depression. Being a heritable condition, it features a complex genetic architecture, although it is not still clear how genes contribute to the onset and course of the disease. In this paper, we adopted an evolutionary‐genomic approach to this condition, focusing on changes occurred during human evolution as a source of our distinctive cognitive and behavioural phenotype. We show clinical evidence that the BD phenotype can be construed as an abnormal presentation of the human self‐domestication phenotype. We further demonstrate that candidate genes for BD significantly overlap with candidates for mammal domestication and that this common set of genes is enriched in functions that are important for the BD phenotype, especially neurotransmitter homeostasis. Finally, we show that candidates for domestication are differentially expressed in brain regions involved in BD pathology, particularly, the hippocampus and the prefrontal cortex, which have been subject to recent changes in our species. Overall, this link between human self‐domestication and BD should facilitate a better understanding of the BD etiopathology.

“…A robust link exists between evolution and abnormal development, with genes positively selected in our species being enriched in candidates for high-prevalence, complex cognitive conditions like SZ (Srinivasan et al, 2016) or autism spectrum disorders (ASD) (Polimanti and Gelernter, 2017). Even in conditions with a neat genetic origin, like Williams syndrome (WS), abnormally expressed genes outside the WS region are enriched in protein-coding genes that have been positively selected in modern humans compared to extinct hominins (Benítez-Burraco, 2020a). This overlap between genes selected in humans (and seemingly accounting for the evolution of the human brain, human cognition, and human behavior) and genes causing complex cognitive conditions seems to be explained by the fact that recently evolved components of the human phenotype are less resistant to gene mutations (and more generally, to developmental perturbations) because they lack the robust compensatory mechanisms to damage commonly found in biological functions shaped by selective pressures that have acted over longer periods of time (see Toro et al, 2010 for a useful discussion on ASD).…”

Section: Introductionmentioning

confidence: 99%

Abnormal features of human self-domestication in bipolar disorder

Hansen

2020

Preprint

Self Cite

Bipolar disorder (BD) is a severe mental condition characterized by episodes of elevated mood and depression. Being a heritable condition, it features a complex genetic architecture, and it is not still clear how genes contribute to the onset and course of the disease. In this paper we adopted an evolutionary-genomic approach to this condition, focusing on changes occurring during human evolution as a source of our distinctive cognitive and behavioral phenotype. We show clinical evidence that the BD phenotype can be construed as an abnormal presentation of the human self-domestication phenotype. We further demonstrate that candidate genes for BD significantly overlap with candidates for mammal domestication, and that this common set of genes is enriched in functions that are important for the BD phenotype, especially neurotransmitter homeostasis. Finally, we show that candidates for domestication are differentially expressed in brain regions involved in BD pathology, particularly, the hippocampus and the prefrontal cortex. Overall, this link between domestication and BD should facilitate a better understanding of the BD etiopathology.