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Genes & Diseases 2023年第3期10卷 705-707页

作者： Ruisha Hong xionglei he State Key Laboratory of Biocontrol School of Life SciencesSun Yat-Sen UniversityGuangzhouGuangdong 510275China

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.

关键词： base fidelity adenine

Mutation signatures inform the natural host of SARS-CoV-2

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National Science Review 2022年第2期9卷 9-12页

作者： Shanjun Deng Ke Xing xionglei he State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-Sen University School of Life Sciences Guangzhou University

The origin of SARS-CoV-2,the causative virus of COVID-19,has been a mystery since the beginning of the outbreak and has been heavily debated lately.One of the main reasons for this is that RaTG13,the closest relative found to date [1](in the horseshoe bat Rhinolophus affinis),has only 96.1% nucleotide similarity to SARS-CoV-2 (with～1200 nucleotide differences).

关键词： CORONAVIRUS

The twin-beginnings of COVID-19 in Asia and Europe—one prevails quickly

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National Science Review 2022年第4期9卷 51-59页

作者： Yongsen Ruan Haijun Wen Mei Hou Ziwen he Xuemei Lu Yongbiao Xue xionglei he Ya-Ping Zhang Chung-I Wu State Key Laboratory of Biocontrol School of Life SciencesSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat-sen University Department of Ecology and Evolution University of Chicago State Key Laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of Sciences Beijing Institute of Genomics Chinese Academy of Sciencesand China National Centre for Bioinformation

In the spread of SARS-C oV-2,there have been multiple waves of replacement between strains,each of which having a distinct set of mutations.The first wave is a group of four mutations(C241 T,C3037 T,C14408 T and A23403 G [this being the amino acid change D614 G];all designated 0 to 1 below).This DG(D614 G) group,fixed at the start of the pandemic,is the foundation of all subsequent waves of strains.Curiously,the DG group is absent in early Asian samples but present(and likely common) in Europe from the beginning.European data show that the high fitness of DG1111 requires the synergistic effect of all four mutations.However,the European strains would have had no time to evolve the four DG mutations(0 to1),had they come directly from the early Asian DG0000 strain.Very likely,the European DG1111 strain had acquired the highly adaptive DG mutations in pre-pandemic Europe and had been spreading in parallel with the Asian strains.Two recent reports further support this twin-beginning interpretation.There was a period of two-way spread between Asia and Europe but,by May 2020,the European strains had supplanted the Asian strains globally.This large-scale replacement of one set of mutations for another has since been replayed many times as COVID-19 progresses.

关键词： COVID-19 D614G SARS-CoV-2 fitness advantage twin-beginnings

An instantaneous coalescent method insensitive to population structure

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Journal of Genetics and Genomics 2021年第3期48卷 219-224页

作者： Zeqi Yao Kehui Liu Shanjun Deng xionglei he State Key Laboratory of Biocontrol School of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

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.

关键词： Coalescent Population structure Demographic history Population size Phylogenetic tree

On the low reproducibility of cancer studies

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National Science Review 2018年第5期5卷 619-624页

作者： Haijun Wen Hurng-Yi Wang xionglei he Chung-I Wu State Key Laboratory of Biocontrol College of Ecology and EvolutionSun Yat-Sen University Graduate Institute of Clinical Medicine and hepatitis Research Center Taiwan University and Hospital Department of Ecology and Evolution University of Chicago

INTRODUCTION Previous reports have suggested that close to 90%of cancer biology publications are irreproducible. The low number has recently been corroborated by five detailed replication studies in e Life, which have been commented on in Nature (Replication studies offer much more than technical details.Nature 2017;541:259–60). While the irreproducibility is often attributed to human factors, which are remediable, the

关键词： On the low reproducibility of cancer studies

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

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Journal of Genetics and Genomics 2020年第2期47卷 85-91页

作者： Chang Ye Zhuoxin Chen Zhan Liu Feng Wang xionglei he State Key Laboratory of Biocontrol School of Life SciencesSun Yat-sen UniversityGuangzhou510275China

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.

关键词： Zebrafish CRISPR/Cas9 Cell lineage Development Single-cell RNA sequencing

The evolution of sex chromosome dosage compensation in animals

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Journal of Genetics and Genomics 2020年第11期47卷 681-693页

作者： Jiabi Chen Menghan Wang xionglei he Jian-Rong Yang Xiaoshu Chen Department of Biology and Medical Genetics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina State Key Laboratory of Biocontrol College of Life SciencesSun Yat-sen UniversityGuangzhouChina Department of Biomedical Informatics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina RNA Biomedical Institute Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina Program in Cancer Research Zhongshan School of MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

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.

关键词： Dosage compensation Sex chromosome Genomic evolution

The expression tractability of biological traits shaped by natural selection

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Journal of Genetics and Genomics 2019年第8期46卷 397-404页

作者： Li Liu Jianguo Wang Jian-Rong Yang Feng Wang xionglei he State Key Laboratory of Bio-control School of Life SciencesSun Yat-sen UniversityGuangzhou510275China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou510080China

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.

关键词： Natural selection Tractability Expression state Complex trait

Decoupling gene functions from knockout effects by evolutionary analyses

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National Science Review 2020年第7期7卷 1169-1180页

作者： Li Liu Mengdi Liu Di Zhang Shanjun Deng Piaopiao Chen Jing Yang Yunhan Xie xionglei he State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-sen University

Genic functions have long been confounded by pleiotropic mutational effects. To understand such genetic effects, we examine HAP4, a well-studied transcription factor in Saccharomyces cerevisiae that functions by forming a tetramer with HAP2, HAP3 and HAP5. Deletion of HAP4 results in highly pleiotropic gene expression responses, some of which are clustered in related cellular processes(clustered effects) while most are distributed randomly across diverse cellular processes(distributed effects). Strikingly, the distributed effects that account for much of HAP4 pleiotropy tend to be non-heritable in a population,suggesting they have few evolutionary consequences. Indeed, these effects are poorly conserved in closely related yeasts. We further show substantial overlaps of clustered effects, but not distributed effects, among the four genes encoding the HAP2/3/4/5 tetramer. This pattern holds for other biochemically characterized yeast protein complexes or metabolic pathways. Examination of a set of cell morphological traits of the deletion lines yields consistent results. hence, only some deletion effects of a gene support related biochemical understandings with the rest being often pleiotropic and evolutionarily decoupled from the gene's normal functions. This study suggests a new framework for reverse genetic analysis.

关键词： pleiotropy mutational effects heritability reverse genetics gene function

On the founder effect in COVID-19 outbreaks:how many infected travelers may have started them all?

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National Science Review 2021年第1期8卷 30-39页

作者： Yongsen Ruan Zhida Luo Xiaolu Tang Guanghao Li Haijun Wen xionglei he Xuemei Lu Jian Lu Chung-I Wu State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-sen University State Key Laboratory of Protein and Plant Gene Research Center for Bioinformatics School of Life SciencesPeking University CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences State Key Laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyCenter for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences

How many incoming travelers（I;at time 0, equivalent to the ‘founders’ in evolutionary genetics） infected with SARS-CoV-2 who visit or return to a region could have started the epidemic of that region? I;would be informative about the initiation and progression of epidemics. To obtain I;, we analyze the genetic divergence among viral populations of different regions. By applying the ‘individual-output’ model of genetic drift to the SARS-CoV-2 diversities, we obtain I;he conclusion is robust regardless of the source population, the continuation of inputs（I;for t > 0） or the fitness of the variants. With such a tiny trickle of human movement igniting many outbreaks, the crucial stage of repressing an epidemic in any region should,therefore, be the very first sign of local contagion when positive cases first become identifiable. The implications of the highly ‘portable’ epidemics, including their early evolution prior to any outbreak, are explored in the companion study（Ruan et al., personal communication）.

关键词： SARS-CoV-2 COVID-19 population genetics genetic drift founder effect