A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.

Accelerated evolution of an Lhx2 enhancer shapes mammalian social hierarchies.

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 knock-out 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.

Large numbers of vertebrates began rapid population decline in the late 19th century.

Accelerated losses of biodiversity are a hallmark of the current era. Large declines of population size have been widely observed and currently 22,176 species are threatened by extinction. The time at which a threatened species began rapid population decline (RPD) and the rate of RPD provide important clues about the driving forces of population decline and anticipated extinction time. However, these parameters remain unknown for the vast majority of threatened species. Here we analyzed the genetic diversity data of nuclear and mitochondrial loci of 2,764 vertebrate species and found that the mean genetic diversity is lower in threatened species than in related nonthreatened species. Our coalescence-based modeling suggests that in many threatened species the RPD began ∼123 y ago (a 95% confidence interval of 20-260 y). This estimated date coincides with widespread industrialization and a profound change in global living ecosystems over the past two centuries. On average the population size declined by ∼25% every 10 y in a threatened species, and the population size was reduced to ∼5% of its ancestral size. Moreover, the ancestral size of threatened species was, on average, ∼22% smaller than that of nonthreatened species. Because the time period of RPD is short, the cumulative effect of RPD on genetic diversity is still not strong, so that the smaller ancestral size of threatened species may be the major cause of their reduced genetic diversity; RPD explains 24.1-37.5% of the difference in genetic diversity between threatened and nonthreatened species.

LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration.

Parkinson's disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration.