Fish as Model Systems to Study Epigenetic Drivers in Human Self-Domestication and Neurodevelopmental Cognitive Disorders

Abstract

Modern humans exhibit phenotypic traits and molecular events shared with other domesticates that are thought to be by-products of selection for reduced aggression. This is the human self-domestication hypothesis. As one of the first types of responses to a novel environment, epigenetic changes may have also facilitated early self-domestication in humans. Here, we argue that fish species, which have been recently domesticated, can provide model systems to study epigenetic drivers in human self-domestication. To test this, we used in silico approaches to compare genes with epigenetic changes in early domesticates of European sea bass with genes exhibiting methylation changes in anatomically modern humans (comparison 1), and neurodevelopmental cognitive disorders considered to exhibit abnormal self-domestication traits, i.e., schizophrenia, Williams syndrome, and autism spectrum disorders (comparison 2). Overlapping genes in comparison 1 were involved in processes like limb morphogenesis and phenotypes like abnormal jaw morphology and hypopigmentation. Overlapping genes in comparison 2 affected paralogue genes involved in processes such as neural crest differentiation and ectoderm differentiation. These findings pave the way for future studies using fish species as models to investigate epigenetic changes as drivers of human self-domestication and as triggers of cognitive disorders.

Keywords: DNA methylation; cognitive disorders; domestication; domestication syndrome; epigenetics; fish; human evolution; neural crest; self-domestication; vertebrates.

Figure 1

Overlap of genes with epigenetic changes in fish early domesticates (FED) and anatomically modern humans (AMH). The overlap was tested using Fisher’s exact test for count data (a) and permutations (b). The results of permutations are represented as the distribution of the number of overlaps (shaded grey area) with the mean number of permuted overlaps (black vertical line) and significance threshold set to 0.05 (red line). The observed number of overlaps is shown by the green line and the distance of observed vs. expected (random) overlaps is shown with the black arrow. The z-score and the p-value indicate the significance of the overlap.

Figure 2

Enrichment analysis of overlapping genes with epigenetic changes in fish early domesticates and anatomically modern humans. (a) GO Biological Process terms enrichment where for each GO-term the color indicates the log10-transformed p-value of enrichment. The semantic space x (y-axis) and the semantic space y (x-axis) are the result of multidimensional scaling done by REViGO and represent semantic similarities between GO-terms. (b) Enrichment of mammalian phenotypes (MGI Mammalian Phenotype 2014). Each phenotype term (y-axis) is attributed significance values after enrichment tests (performed by Enrichr) which include the −log10-transformed p-value of enrichment (x-axis and length of grey lines) and the combined score estimated by Enrichr (color of the bubble and legend). To facilitate visualization according to the significance of enrichment based on p-values, terms are ranked in descending order from top to bottom.

Figure 3

Overlap of homologous genes with epigenetic changes in fish early domesticates (FED) and cognitive disorders. Pairwise comparisons are shown for FED vs. schizophrenia (SZ; (a,d)), Williams syndrome (WS; (b,e)) and autism spectrum disorders (ASD; (c,f)). Significance of overlaps were tested using Fisher’s exact test for count data (a–c) and permutations (d–f). The results of permutations are represented as the distribution of number of overlaps (shaded grey areas) with mean number of permuted overlaps (black vertical lines) and significance threshold set to 0.05 (red lines). Observed number of overlaps is indicated by the green lines and the distance of observed vs. expected (random) overlaps are shown with the black arrow. The z-scores and the p-values indicate the significance of the overlaps.

Figure 4

Pathway enrichment of genes with epigenetic changes in fish early domesticates (FED) and homologues of neurodevelopmental cognitive disorders. Pathways of the library Wikipathways enriched in schizophrenia (SZ; (a)), Williams syndrome (WS; (b)) and autism spectrum disorders (ASD; (c)). Each pathway (y-axis) is attributed significance values after enrichment tests (performed by Enrichr) which include the −log10-transformed p-value of enrichment (x-axis and length of grey lines) and the combined score estimated by Enrichr (color of the bubble and legend). To facilitate visualization according to significance of enrichment based on p-values, terms are ranked in descending order from top to bottom.

Figure 5

Enrichment of the Gene Ontology (GO) terms of genes with epigenetic changes in fish early domesticates (FED) and homologs of neurodevelopmental cognitive disorders. GO Biological Process terms enrichment in schizophrenia (SZ; (a)), Williams syndrome (WS; (b)) and autism spectrum disorders (ASD; (c)). For each GO-term the color indicates the log10-transformed p-value of enrichment which is also represented by the x-axis. The semantic space x (y-axis) is the result of multidimensional scaling done by REViGO and represent semantic similarities between GO-terms.