Accelerated evolution of an Lhx2 enhancer shapes mammalian social hierarchies

Abstract

Social hierarchies emerged during evolution, and social rank influences behavior and health of individuals. However, the evolutionary mechanisms of social hierarchy are still unknown in amniotes. Here we developed a new method and performed a genome-wide screening for identifying regions with accelerated evolution in the ancestral lineage of placental mammals, where mammalian social hierarchies might have initially evolved. Then functional analyses were conducted for the most accelerated region designated as placental-accelerated sequence 1 (PAS1, P = 3.15 × 10 −18). Multiple pieces of evidence show that PAS1 is an enhancer of the transcription factor gene Lhx2 involved in brain development. PAS1s isolated from various amniotes showed different cis-regulatory activity in vitro, and affected the expression of Lhx2 differently in the nervous system of mouse embryos. PAS1 knockout mice lack social stratification. PAS1 knock-in mouse models demonstrate that PAS1s determine the social dominance and subordinate of adult mice, and that social ranks could even be turned over by mutated PAS1. All homozygous mutant mice had normal huddled sleeping behavior, motor coordination and strength. Therefore, PAS1-Lhx2 modulates social hierarchies and is essential for establishing social stratification in amniotes, and positive Darwinian selection on PAS1 plays pivotal roles in the occurrence of mammalian social hierarchies.

New exon ignites accelerated evolution of placental gene Nrk in the ancestral lineage of eutherians

“…A phylogenetic tree of 16 amniotes (12 placental mammals, 1 marsupial, 2 aves, and 1 reptile) was constructed, and the length of each branch was determined as in the previous study [12] (Figure 1A). Then, using the Kung-Fu Panda (KFP) software [12], we screened the chrX to detect the regions with accelerated evolution in the ancestral lineage of eutherians. A total of 99,106 windows were scanned, and 13 of them were identified ( P < 1.01 × 10 −7 ) (Figure 1B) after Bonferroni correction [18] for multiple tests (the desired overall Type I error rate, i.e.…”

“…The multi-genome alignments were scanned by Kung-Fu Panda (KFP) software [12]. The window size and sliding step were set as 100bp and 20bp, respectively.…”

“…A previous study was carried out to screen the autosomal regions that have undergone an accelerated evolution in the ancestral lineage of eutherians [12]; however, the identified accelerated regions in the autosomes are unlikely to be related to the development and function of placenta since their nearest genes do not highly express in the placenta. The X chromosome (chrX) was not investigated because the evolution rate of chrX is lower than that of the autosomes [13].…”

Revealing the transcription factor regulatory context of human specific cortical development using single-cell multi-omics

“…LHX2 is a particularly interesting TF as it shows strong fetal HGE motif enrichment in neuronal progenitors (RG, ipEx) across both datasets, and is known to be a key regulator of forebrain development 37 . Prior studies have also found that an LHX2 enhancer showed accelerated evolution in placental mammals and was critical to social stratification in mice 41 . Thus, by looking for cell type specific TF motif enrichment in fetal HGEs, we found that these regions have the potential to influence forebrain development and social behavior by activating LHX2 binding sites in neuronal progenitors.…”

Advances in understanding neural mechanisms of social and emotional behavior

“…将神 dmPFC) [28] , 其他团队鉴定出下丘脑腹侧前乳核(hypothalamic ventral premammillary nucleus, PMv) [36] 、 腹侧被盖区(ventral tegmental area, VTA) [37] 、NAc [34] 等 与调控社会等级密切相关的脑区. 最近, 中国科学院上 海营养与健康研究所的李海鹏团队 [38] [44] 、钾-氯协同转运蛋白KCC2 [45] 、 Npy1r受体 [46] [53] . 这一发现被认为是精神疾病领域半个世纪内最 重要的发现 [53,54] .…”