Bio

Honors & Awards


  • Dean's Postdoctoral Fellowship, Stanford (2012)
  • National Excellent 100 Doctoral Dissertation nomination paper, China (2011)
  • Excellent Doctorial Dissertation, Yunnan Province, China (2011)
  • Excellent Doctorial Dissertation, Chinese Academy of Sciences (2010)
  • President Scholarship, Chinese Academy of Sciences (2009)
  • Liu Yong-Ling Scholarship, Chinese Academy of Sciences (2007)

Professional Education


  • Ph.D., Chinese Academy of Sciences, Genetics (2009)
  • B.S., Sichuan University, Biology (2003)

Stanford Advisors


  • Jin Li, Postdoctoral Faculty Sponsor

Research & Scholarship

Current Research and Scholarly Interests


My research goal is to combine theoretical and experimental approaches to decode RNA regulatory networks. My current research focuses on RNA editing, a post-transcriptional-processing mechanism that contributes to the diversity of gene products.

Publications

Journal Articles


  • Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing. Nature methods Zhang, R., Li, X., Ramaswami, G., Smith, K. S., Turecki, G., Montgomery, S. B., Li, J. B. 2014; 11 (1): 51-54

    Abstract

    We developed a targeted RNA sequencing method that couples microfluidics-based multiplex PCR and deep sequencing (mmPCR-seq) to uniformly and simultaneously amplify up to 960 loci in 48 samples independently of their gene expression levels and to accurately and cost-effectively measure allelic ratios even for low-quantity or low-quality RNA samples. We applied mmPCR-seq to RNA editing and allele-specific expression studies. mmPCR-seq complements RNA-seq for studying allelic variations in the transcriptome.

    View details for DOI 10.1038/nmeth.2736

    View details for PubMedID 24270603

  • The evolution of evolvability in microRNA target sites in vertebrates GENOME RESEARCH Xu, J., Zhang, R., Shen, Y., Liu, G., Lu, X., Wu, C. 2013; 23 (11): 1810-1816

    Abstract

    The lack of long-term evolutionary conservation of microRNA (miRNA) target sites appears to contradict many analyses of their functions. Several hypotheses have been offered, but an attractive one-that the conservation may be a function of taxonomic hierarchy (vertebrates, mammals, primates, etc.)-has rarely been discussed. For such an analysis, we cannot use evolutionary conservation as a criterion of target identification, and hence, have used high confidence target sites in the cross-linking immunoprecipitation (CLIP) data. Assuming that a proportion, p, of target sites in the CLIP data are conserved, we define the evolvability of miRNA targets as 1-p. Genomic data from vertebrate species show that the evolvability between human and fish is very high, at more than 90%. The evolvability decreases to 50% between birds and mammals, 20% among mammalian orders, and only 6% between human and chimpanzee. Within each taxonomic hierarchy, there is a set of targets that are conserved only at that level of evolution. Extrapolating the evolutionary trend, we find the evolvability in any single species to be close to 0%. Thus, all miRNA target sites identified by the CLIP method are evolutionarily conserved in one species, but the conservation is lost step by step in larger taxonomic groups. The changing evolvability of miRNA targets suggests that miRNA-target interactions may play a role in the evolution of organismal diversity.

    View details for DOI 10.1101/gr.148916.112

    View details for Web of Science ID 000326642500005

    View details for PubMedID 24077390

  • Identifying RNA editing sites using RNA sequencing data alone NATURE METHODS Ramaswami, G., Zhang, R., Piskol, R., Keegan, L. P., Deng, P., O'Connell, M. A., Li, J. B. 2013; 10 (2): 128-132

    Abstract

    We show that RNA editing sites can be called with high confidence using RNA sequencing data from multiple samples across either individuals or species, without the need for matched genomic DNA sequence. We identified many previously unidentified editing sites in both humans and Drosophila; our results nearly double the known number of human protein recoding events. We also found that human genes harboring conserved editing sites within Alu repeats are enriched for neuronal functions.

    View details for DOI 10.1038/NMETH.2330

    View details for Web of Science ID 000314623900018

    View details for PubMedID 23291724

  • Overlapping functions of microRNAs in control of apoptosis during Drosophila embryogenesis CELL DEATH AND DIFFERENTIATION Ge, W., Chen, Y., Weng, R., Lim, S. F., Buescher, M., Zhang, R., Cohen, S. M. 2012; 19 (5): 839-846

    Abstract

    Regulation of apoptosis is crucial for tissue homeostasis under normal development and environmental stress. In Drosophila, cell death occurs in different developmental processes including embryogenesis. Here, we report that two members of the miR-2 seed family of microRNAs, miR-6 and miR-11, function together to limit the level of apoptosis during Drosophila embryonic development. Mutants lacking both miR-6 and miR-11 show embryonic lethality and defects in the central nervous system (CNS). We provide evidence that miR-6/11 functions through regulation of the proapoptotic genes, reaper (rpr), head involution defective (hid), grim and sickle (skl). Upregulation of these proapoptotic genes is responsible for the elevated apoptosis and the CNS defects in the mutants. These findings demonstrate that the activity of the proapoptotic genes is kept in check by miR-6/11 to ensure normal development.

    View details for DOI 10.1038/cdd.2011.161

    View details for Web of Science ID 000302784400012

    View details for PubMedID 22095284

  • Testing hypotheses on the rate of molecular evolution in relation to gene expression using microRNAs PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shen, Y., Lv, Y., Huang, L., Liu, W., Wen, M., Tang, T., Zhang, R., Hungate, E., Shi, S., Wu, C. 2011; 108 (38): 15942-15947

    Abstract

    There exists an inverse relationship between the rate of molecular evolution and the level of gene expression. Among the many explanations, the "toxic-error" hypothesis is a most general one, which posits that processing errors may often be toxic to the cells. However, toxic errors that constrain the evolution of highly expressed genes are often difficult to measure. In this study, we test the toxic-error hypothesis by using microRNA (miRNA) genes because their processing errors can be directly measured by deep sequencing. A miRNA gene consists of a small mature product (?22 nt long) and a "backbone." Our analysis shows that (i) like the mature miRNA, the backbone is highly conserved; (ii) the rate of sequence evolution in the backbone is negatively correlated with expression; and (iii) although conserved between distantly related species, the error rate in miRNA processing is also negatively correlated with the expression level. The observations suggest that, as a miRNA gene becomes more highly (or more ubiquitously) expressed, its sequence evolves toward a structure that minimizes processing errors.

    View details for DOI 10.1073/pnas.1110098108

    View details for Web of Science ID 000295030000057

    View details for PubMedID 21911382

  • Genome sequence and global sequence variation map with 5.5 million SNPs in Chinese rhesus macaque GENOME BIOLOGY Fang, X., Zhang, Y., Zhang, R., Yang, L., Li, M., Ye, K., Guo, X., Wang, J., Su, B. 2011; 12 (7)

    Abstract

    Rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate animal in biomedical research. A global map of genetic variations in rhesus macaque is valuable for both evolutionary and functional studies.Using next-generation sequencing technology, we sequenced a Chinese rhesus macaque genome with 11.56-fold coverage. In total, 96% of the reference Indian macaque genome was covered by at least one read, and we identified 2.56 million homozygous and 2.94 million heterozygous SNPs. We also detected a total of 125,150 structural variations, of which 123,610 were deletions with a median length of 184 bp (ranging from 25 bp to 10 kb); 63% of these deletions were located in intergenic regions and 35% in intronic regions. We further annotated 5,187 and 962 nonsynonymous SNPs to the macaque orthologs of human disease and drug-target genes, respectively. Finally, we set up a genome-wide genetic variation database with the use of Gbrowse.Genome sequencing and construction of a global sequence variation map in Chinese rhesus macaque with the concomitant database provide applicable resources for evolutionary and biomedical research.

    View details for DOI 10.1186/gb-2011-12-7-r63

    View details for Web of Science ID 000296648400002

    View details for PubMedID 21733155

  • Proteomic Analysis of Proteins Involved in Spermiogenesis in Mouse JOURNAL OF PROTEOME RESEARCH Guo, X., Shen, J., Xia, Z., Zhang, R., Zhang, P., Zhao, C., Xing, J., Chen, L., Chen, W., Lin, M., Huo, R., Su, B., Zhou, Z., Sha, J. 2010; 9 (3): 1246-1256

    Abstract

    Spermiogenesis is a unique process in mammals during which haploid round spermatids mature into spermatozoa in the testis. Its successful completion is necessary for fertilization and its malfunction is an important cause of male infertility. Here, we report the high-confidence identification of 2116 proteins in mouse haploid germ cells undergoing spermiogenesis: 299 of these were testis-specific and 155 were novel. Analysis of these proteins showed many proteins possibly functioning in unique processes of spermiogenesis. Of the 84 proteins annotated to be involved in vesicle-related events, VAMP4 was shown to be important for acrosome biogenesis by in vivo knockdown experiments. Knockdown of VAMP4 caused defects of acrosomal vesicle fusion and significantly increased head abnormalities in spermatids from testis and sperm from the cauda epididymis. Analysis of chromosomal distribution of the haploid genes showed underrepresentation on the X chromosome and overrepresentation on chromosome 11, which were due to meiotic sex chromosome inactivation and expansion of testis-expressed gene families, respectively. Comparison with transcriptional data showed translational regulation during spermiogenesis. This characterization of proteins involved in spermiogenesis provides an inventory of proteins useful for understanding the mechanisms of male infertility and may provide candidates for drug targets for male contraception and male infertility.

    View details for DOI 10.1021/pr900735k

    View details for Web of Science ID 000275088100008

    View details for PubMedID 20099899

  • MicroRNA regulation and the variability of human cortical gene expression NUCLEIC ACIDS RESEARCH Zhang, R., Su, B. 2008; 36 (14): 4621-4628

    Abstract

    Understanding the driving forces of gene expression variation within human populations will provide important insights into the molecular basis of human phenotypic variation. In the genome, the gene expression variability differs among genes, and at present, most research has focused on identifying the genetic variants responsible for the within population gene expression variation. However, little is known about whether microRNAs (miRNAs), which are small noncoding RNAs modulating expression of their target genes, could have impact on the variability of gene expression. Here we demonstrate that miRNAs likely lead to the difference of expression variability among genes. With the use of the genome-wide expression data in 193 human brain samples, we show that the increased variability of gene expression is concomitant with the increased number of the miRNA seeds interacting with the target genes, suggesting a direct influence of miRNA on gene expression variability. Compared with the non-miRNA-target genes, genes targeted by more than two miRNA seeds have increased expression variability, independent of the miRNA types. In addition, single-nucleotide polymorphisms (SNPs) located in the miRNA binding sites could further increase the gene expression variability of the target genes. We propose that miRNAs are one of the driving forces causing expression variability in the human genome.

    View details for DOI 10.1093/nar/gkn431

    View details for Web of Science ID 000258330900017

    View details for PubMedID 18617573

  • Molecular evolution of a primate-specific microRNA family MOLECULAR BIOLOGY AND EVOLUTION Zhang, R., Wang, Y., Su, B. 2008; 25 (7): 1493-1502

    Abstract

    Lineage-specific microRNA (miRNA) families may contribute to developmental novelties during evolution. However, little is known about the origin and evolution of new miRNA families. We report evidence of an Alu-mediated rapid expansion of miRNA genes in a previously identified primate-specific miRNA family, drawn from sequencing and comparative analysis of 9 diverse primate species. Evolutionary analysis reveals similar divergence among miRNA copies whether they are within or between species, lineage-specific gain and loss of miRNAs, and gene pseudolization in multiple species. These observations support a birth-and-death process of miRNA genes in this family, implicating functional diversification during primate evolution. In addition, both secondary structure conservation and reduced single nucleotide polymorphisms density attest to functional constraint of this family in primates. Finally, we observed preferential expression of miRNAs in human placenta and fetal brain, suggesting a functional importance of this family for primate development.

    View details for DOI 10.1093/molbev/msn094

    View details for Web of Science ID 000256979100025

    View details for PubMedID 18417486

  • Rapid evolution of an X-linked microRNA cluster in primates GENOME RESEARCH Zhang, R., Peng, Y., Wang, W., Su, B. 2007; 17 (5): 612-617

    Abstract

    MicroRNAs (miRNAs) are a growing class of small RNAs (about 22 nt) that play crucial regulatory roles in the genome by targeting mRNAs for cleavage or translational repression. Most of the identified miRNAs are highly conserved among species, indicating strong functional constraint on miRNA evolution. However, nonconserved miRNAs may contribute to functional novelties during evolution. Recently, an X-linked miRNA cluster was reported with multiple copies in primates but not in rodents or dog. Here we sequenced and compared this miRNA cluster in major primate lineages including human, great ape, lesser ape, Old World monkey, and New World monkey. Our data indicate rapid evolution of this cluster in primates including frequent tandem duplications and nucleotide substitutions. In addition, lineage-specific substitutions were observed in human and chimpanzee, leading to the emergence of potential novel mature miRNAs. The expression analysis in rhesus monkeys revealed a strong correlation between miRNA expression changes and male sexual maturation, suggesting regulatory roles of this miRNA cluster in testis development and spermatogenesis. We propose that, like protein-coding genes, miRNA genes involved in male reproduction are subject to rapid adaptive changes that may contribute to functional novelties during evolution.

    View details for DOI 10.1101/gr.6146507

    View details for Web of Science ID 000246297900008

    View details for PubMedID 17416744

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