Abstract Hominin evolution is characterized by adaptive solutions often rooted in behavioral and cognitive changes. If balancing selection had an important and long-lasting impact on the evolution of these traits, it can be hypothesized that genes associated with them should carry an excess of shared polymorphisms (trans- SNPs) across recent Homo species. In this study, we investigate the role of balancing selection in human evolution using available exomes from modern (Homo sapiens) and archaic humans (H. neanderthalensis and Denisovan) for an excess of trans-SNP in two gene sets: one associated with the immune system (IMMS) and another one with behavioral system (BEHS). We identified a significant excess of trans-SNPs in IMMS (N=547), of which six of these located within genes previously associated with schizophrenia. No excess of trans-SNPs was found in BEHS, but five genes in this system harbor potential signals for balancing selection and are associated with psychiatric or neurodevelopmental disorders. Our approach evidenced recent Homo trans-SNPs that have been previously implicated in psychiatric diseases such as schizophrenia, suggesting that a genetic repertoire common to the immune and behavioral systems could have been maintained by balancing selection starting before the split between archaic and modern humans.

Abstract The FOXP subfamily is probably the most extensively characterized subfamily of the forkhead superfamily, playing important roles in development and homeostasis in vertebrates. Intrinsically disorder protein regions (IDRs) are protein segments that exhibit multiple physical interactions and play critical roles in various biological processes, including regulation and signaling. IDRs in proteins may play an important role in the evolvability of genetic systems. In this study, we analyzed 77 orthologous FOXP genes/proteins from Tetrapoda, regarding protein disorder content and evolutionary rate. We also predicted the number and type of short linear motifs (SLIMs) in the IDRs. Similar levels of protein disorder (approximately 70%) were found for FOXP1, FOXP2, and FOXP4. However, for FOXP3, which is shorter in length and has a more specific function, the disordered content was lower (30%). Mammals showed higher protein disorders for FOXP1 and FOXP4 than non-mammals. Specific analyses related to linear motifs in the four genes showed also a clear differentiation between FOXPs in mammals and non-mammals. We predicted for the first time the role of IDRs and SLIMs in the FOXP gene family associated with possible adaptive novelties within Tetrapoda. For instance, we found gain and loss of important phosphorylation sites in the Homo sapiens FOXP2 IDR regions, with possible implication for the evolution of human speech.

After a brief review of the most recent findings in the study of human evolution, an extensive comparison of the complete genomes of our nearest relative, the chimpanzee (Pan troglodytes), of extant Homo sapiens, archaic Homo neanderthalensis and the Denisova specimen were made. The focus was on non-synonymous mutations, which consequently had an impact on protein levels and these changes were classified according to degree of effect. A total of 10,447 non-synonymous substitutions were found in which the derived allele is fixed or nearly fixed in humans as compared to chimpanzee. Their most frequent location was on chromosome 21. Their presence was then searched in the two archaic genomes. Mutations in 381 genes would imply radical amino acid changes, with a fraction of these related to olfaction and other important physiological processes. Eight new alleles were identified in the Neanderthal and/or Denisova genetic pools. Four others, possibly affecting cognition, occured both in the sapiens and two other archaic genomes. The selective sweep that gave rise to Homo sapiens could, therefore, have initiated before the modern/archaic human divergence.

Genetic studies have long suggested the important role of the DRD2 gene in psychiatric disorders and behavior. Further research has shown a conjoined effect of genes in the Chr11q22-23 region, which includes the NCAM1, TTC12, ANKK1 and DRD2 genes, or NTAD cluster. Despite a growing need to unravel the role of this cluster, few studies have taken into account interspecies and evolutionary approaches. This study shows that behaviorally relevant SNPs from the NTAD cluster, such as rs1800497 (Taq1A) and rs6277, are ancient polymorphisms that date back to the common ancestor between modern humans and Neanderthals/Denisovans. Conserved synteny and neighborhood indicate the NTAD cluster seems to have been established at least 400 million years ago, when the first Sarcopterygians emerged. The NTAD genes are apparently co-regulated and this could be attributed to adaptive functional properties, including those that emerged when the central nervous system became more complex. Finally, our findings indicate that NTAD genes, which are related to neurogenesis and dopaminergic neurotransmission, should be approached as a unit in behavioral and psychiatric genetic studies.

The TP53 gene, first described in 1979, was identified as a tumor suppressor gene in 1989, when it became clear that its product, the p53 nuclear phosphoprotein, was frequently inactivated in many different forms of cancers. Nicknamed "guardian of the genome", TP53 occupies a central node in stress response networks. The p53 protein has a key role as transcription factor in limiting oncogenesis through several growth suppressive functions, such as initiating apoptosis, senescence, or cell cycle arrest. The p53 protein is directly inactivated in about 50% of all tumors as a result of somatic gene mutations or deletions, and over 80% of tumors demonstrate dysfunctional p53 signaling. Beyond the undeniable importance of p53 as a tumor suppressor, an increasing number of new functions for p53 have been reported, including its ability to regulate energy metabolism, to control autophagy, and to participate in various aspects of differentiation and development. Recently, studies on genetic variations in TP53 among different populations have led to the notion that the p53 protein might play an important role in regulating fertility. This review summarizes current knowledge on the basic functions of different genes of the TP53 family and TP53 pathway with respect to fertility. We also provide original analyses based on genomic and genotype databases, providing further insights into the possible roles of the TP53 pathway in human reproduction.