The evolution of sex chromosome dosage compensation in animals

The evolution of heteromorphic sex chromosomes shall lead to gene expression dosage problems,as in at least one of the sexes,the sex-linked gene dose has been reduced by half.It has been proposed that the transcriptional output of the whole X or Z chromosome should be doubled for complete dosage compensation in heterogametic sex.However,owing to the variability of the existing methods to determine the transcriptional differences between sex chromosomes and autosomes(S:A ratios)in different studies,we collected more than 500 public RNA-Seq data set from multiple tissues and species in major clades and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species.We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes.We found that in mammals and birds,the S:A ratio is approximately 0.5,whereas in insects,fishes,and flatworms,the S:A ratio is approximately 1.0.Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the X/Z chromosome is significantly correlated with the S:A ratio.In addition,the degree of degeneration of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage compensation mechanism.Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that dosage sensitivity states of sex chromosomes are a major factor underlying different evolutionary strategies of dosage compensation.

The expression tractability of biological traits shaped by natural selection

Understanding how gene expression is translated to phenotype is central to modern molecular biology,and the success is contingent on the intrinsic tractability of the specific traits under examination.However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable.Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate(S_T)by gauging the number(N) of expression states that underlie the same trait abnormality, with large S_T corresponding to large N. By analyzing over 200 yeast morphological traits, we show that S_T predicts the tractability of an expression-trait relationship. We further show that S_T is ultimately determined by natural selection, which builds co-regulated gene modules to minimize possible expression states.

Development of a high-fidelity Cas9-dependent adenine base editor (ABE) system for genome editing with high-fidelity Cas9 variants

One of the main reasons that hinders the application of base editors in the clinic is the trade-off between editing efficiency and editing fidelity.The off-target base editing includes Cas9-independent and Cas9-dependent manners.1 The Cas9-independent off-target results from the intrinsic deamination activity of the deaminase domain of a base editor,which affects random RNA or DNA molecules.

大流行起源及早期演化的理论探索

能引起全球疫情的病毒,从生物进化的观点来看不会是一步到位,而是一个逐步进化的过程.因此我们需要一个理论架构,以指导关于病毒起源的研究.在此,我们提出了病毒和宿主共进化的适应性模型.在该模型中,宿主分三类:野生动物宿主、附近的人口和较远的人口.基于数学理论,我们推衍病毒起源地(PL_(0))具备如下特性:(1)野生动物丰富度大;(2)邻近人口密度低;(3)野生动物与人类长期接触;(4)起源地的动物与人类均有一定的群体免疫.该模型表明病毒在早期可能会多次从PL_(0)入侵到其它地方,但这种入侵通常会以失败告终,从而导致零星的早期感染病例.与起源地不同,第一个疫情区(PL_(1)),应该是群体免疫较弱,人口较密的地方.溯源研究,必须先建立理论架构.本研究提出一个非常好的理论模型,可以指导对SARS-CoV-2起源的探索.

Defining endogenous barcoding sites for CRISPR/Cas9-based cell lineage tracing in zebrafish

There is a growing interest in developing experimental methods for tracking the developmental cell lineages of a complex organism.The recently developed CRISPR/Cas9-based barcoding method is,although highly promising,difficult to scale up because it relies on exogenous barcoding sequences that are engineered into the genome.In this study,we characterized 78 high-quality endogenous sites in the zebrafish genome that can be used as CRISPR/Cas9-based barcoding sites.The 78 sites are all highly expressed in most of the cell types according to single-cell RNA sequencing(scRNA-seq)data.Hence,the barcoding information of the 78 endogenous sites is recovered by the available scRNA-seq platforms,enabling simultaneous characterization of cell type and cell lineage information.

An instantaneous coalescent method insensitive to population structure

Conventional coalescent inferences of population history make the critical assumption that the population under examination is panmictic.However,most populations are structured.This complicates the prevailing coalescent analyses and sometimes leads to inaccurate estimates.To develop a coalescent method unhampered by population structure,we perform two analyses.First,we demonstrate that the coalescent probability of two randomly sampled alleles from the immediate preceding generation(one generation back)is independent of population structure.Second,motivated by this finding,we propose a new coalescent method:i-coalescent analysis.The i-coalescent analysis computes the instantaneous coalescent rate by using a phylogenetic tree of sampled alleles.Using simulated data,we broadly demonstrate the capability of i-coalescent analysis to accurately reconstruct population size dynamics of highly structured populations,although we find this method often requires larger sample sizes for structured populations than for panmictic populations.Overall,our results indicate i-coalescent analysis to be a useful tool,especially for the inference of population histories with intractable structure such as the developmental history of cell populations in the organs of complex organisms.