DLX5/6 GABAergic Expression Affects Social Vocalization: Implications for Human Evolution

Mol Biol Evol. 2021 Oct 27;38(11):4748-4764. doi: 10.1093/molbev/msab181.

Abstract

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated with neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioral and metabolic phenotypes notably increasing lifespan by 33%. Here, we show that Dlx5/6VgatCre mice present a hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10 min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1,400 calls/10 min with a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals. The characters affected by Dlx5/6 in the mouse (sociability, vocalization, skull, and brain shape…) overlap those affected in the "domestication syndrome". We therefore explored the possibility that DLX5/6 played a role in human evolution and "self-domestication" comparing DLX5/6 genomic regions from Neanderthal and modern humans. We identified an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype includes the binding site for GTF2I, a gene associated with Williams-Beuren syndrome, a hyper-sociability and hyper-vocalization neurodevelopmental disorder. The DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105 years of age), a well-established human model of healthy aging and longevity, suggesting their involvement in the coevolution of longevity, sociability, and speech.

Keywords: DLX5/6 genes; aging; human evolution; self-domestication; social behavior; ultrasonic vocalization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genes, Homeobox
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Neanderthals* / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors, TFII* / genetics
  • Vocalization, Animal

Substances

  • DLX5 protein, human
  • Dlx5 protein, mouse
  • Gtf2i protein, mouse
  • Homeodomain Proteins
  • Transcription Factors
  • Transcription Factors, TFII