Abstract:In addition to high intelligence, humans evolved specialized social-cognitive skills, which are specifically affected in children with autism spectrum disorder (ASD). Genes affected in ASD represent suitable candidates to study the evolution of human social cognition. We performed an evolutionary analysis on 68 genes associated to neurodevelopmental disorders; our data indicate that genetic diversity was shaped by distinct selective forces, including natural selection and introgression from archaic hominins. W… Show more
“…We speculate that many of the missense alleles in the human population that do not result in overt developmental disorder may compromise the function of DYRK1A enough to reduce evolutionary fitness and preclude the evolutionary persistence of such variants. Intriguingly, DYRK1A is one of the genes that was subject to the strongest selective pressure after introgression of Neanderthal alleles in the gene pools of modern humans ( Green et al, 2010 ; Mozzi et al, 2017 ). Fig.…”
Haploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A. Four of the substitutions eliminated tyrosine autophosphorylation (L245R, F308V, S311F, S346P), indicating that these variants lacked kinase activity. Tyrosine phosphorylation of DYRK1A-L295F in mammalian cells was comparable to wild type, although the mutant showed lower catalytic activity and reduced thermodynamic stability in cellular thermal shift assays. In addition, we observed that one variant (DYRK1A-T588N) with a mutation outside the catalytic domain did not differ from wild-type DYRK1A in tyrosine autophosphorylation, catalytic activity or subcellular localization. These results suggest that the pathogenic missense variants in the catalytic domain of DYRK1A impair enzymatic function by affecting catalytic residues or by compromising the structural integrity of the kinase domain.
“…We speculate that many of the missense alleles in the human population that do not result in overt developmental disorder may compromise the function of DYRK1A enough to reduce evolutionary fitness and preclude the evolutionary persistence of such variants. Intriguingly, DYRK1A is one of the genes that was subject to the strongest selective pressure after introgression of Neanderthal alleles in the gene pools of modern humans ( Green et al, 2010 ; Mozzi et al, 2017 ). Fig.…”
Haploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A. Four of the substitutions eliminated tyrosine autophosphorylation (L245R, F308V, S311F, S346P), indicating that these variants lacked kinase activity. Tyrosine phosphorylation of DYRK1A-L295F in mammalian cells was comparable to wild type, although the mutant showed lower catalytic activity and reduced thermodynamic stability in cellular thermal shift assays. In addition, we observed that one variant (DYRK1A-T588N) with a mutation outside the catalytic domain did not differ from wild-type DYRK1A in tyrosine autophosphorylation, catalytic activity or subcellular localization. These results suggest that the pathogenic missense variants in the catalytic domain of DYRK1A impair enzymatic function by affecting catalytic residues or by compromising the structural integrity of the kinase domain.
“…Candidate genes for ASD are overrepresented among the genes that have changed in the human lineage [7, 8]. Additionally, introgression events from archaic hominins have been claimed to account for aspects of the diversity of genes related to neurodevelopmental disorders, including ASD [9]. Finally, experimental and biochemical data suggest that BRCA2 interacts with several proteins involved in brain function and associated to cognitive disease, specifically, TP53 [10], PARP1 [11], and FLNA [12].…”
The unique divergence of the BRCA2 gene in Neanderthals compared to modern humans has been hypothesized to account for a differential susceptibility to cancer. However, the role of the gene in brain development and its connection with autism suggest that these differences might be (also) related to the more encapsulated nature of the Neanderthal cognition and their (inferred) autistic-like features.
“…However, whatever the potential benefits of archaic introgression in the past, alleles of Neanderthal origin have been also associated with several neurological, dermatological, and immunological phenotypes, indicating an influence of ancient admixture on current disease risk in humans [ 91 , 92 , 93 ]. For example, introgressed alleles associated with the immune system response can increase the risk of inflammation or autoimmunity under environmental factors changing overtime [ 94 , 95 , 96 , 97 , 98 ].…”
Section: Genomic Signatures Of Adaptive Introgression From Archaicmentioning
The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Modern non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease.
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