Genomic trade-offs: are autism and schizophrenia the steep price of the human brain?

Abstract

Evolution often deals in genomic trade-offs: changes in the genome that are beneficial overall persist even though they also produce disease in a subset of individuals. Here, we explore the possibility that such trade-offs have occurred as part of the evolution of the human brain. Specifically, we provide support for the possibility that the same key genes that have been major contributors to the rapid evolutionary expansion of the human brain and its exceptional cognitive capacity also, in different combinations, are significant contributors to autism and schizophrenia. Furthermore, the model proposes that one of the primary genes behind this trade-off may not technically be "a gene" or "genes" but rather are the highly duplicated sequences that encode the Olduvai protein domain family (formerly called DUF1220). This is not an entirely new idea. Others have proposed that the same genes involved in schizophrenia were also critical to the rapid expansion of the human brain, a view that has been expressed as "the same 'genes' that drive us mad have made us human". What is new is that a "gene", or more precisely a protein domain family, has been found that may satisfy these requirements.

Genome-wide association study of school grades identifies a genetic overlap between language ability, psychopathology and creativity

“…If so, this association might have an evolutionary basis as has been suggested previously particularly in the context of schizophrenia. 46,47 Alternatively, the association of psychiatric risk variants with increased language ability could be simply due to that the individuals with the risk variants compensate for their math deficits by being good in language.…”

Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution

“…In addition, variation in Olduvai copy number has been associated with cognitive disease: autism, schizophrenia, microcephaly and macrocephaly (Dumas et al 2012; Davis et al 2014b, 2015, 2019; Quick et al 2015). This ability to potentially confer both beneficial and detrimental effects has led to the proposal that the Olduvai family may constitute a cognitive genomic trade-off specific to the human lineage (Dumas and Sikela 2009; Sikela and Quick 2018).…”

“…1Genome organization, phylogeny, and recent evolution of human NBPF genes and Olduvai protein domains. a Shown to the right of chromosome 1 are the genome positions of NBPF genes and the number and arrangement of Olduvai domain subtypes based on the most recent human genome assembly (hg38) (Sikela and Quick 2018). Each block represents an Olduvai protein domain; each of the six primary Olduvai subtypes are depicted by a different color as denoted in the key.…”

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

“…We also noted a variant (rs534059912) in the GOLM1 gene (Golgi membrane protein 1), which was earlier reported in sporadic Alzheimer's dementia (AD) to influence the pre‐frontal cortical volume . A list of these 10 genes, evidence for disease association, and gene ontology descriptions are presented in Table (b) …”

“…43 A list of these 10 genes, evidence for disease association, and gene ontology descriptions are presented in Table 2(b). [44][45][46][47][48][49][50][51][52] Of the remaining genes, there were several with a plausible role in the biology of SMI, but not thus far implicated in any disease phenotype. These genes, with the ontology descriptions and plausible biological implications, are provided in Table 2(c).…”