Honors & Awards


  • International Student Research Fellowship, Howard Hughes Medical Institute (2015 – 2017)
  • Member, Sigma Pi Sigma (2012)
  • Member, Phi Beta Kappa (2012)
  • Philip Morse Memorial Award, Massachusetts Institute of Technology (2012)
  • Freshman Fellowship, Peking University (2008)
  • Gold Medal, Asian Physics Olympiad (2008)
  • Gold Medal and “the Absolute Winner”, International Physics Olympiad (2008)

Professional Education


  • Bachelor of Science, Massachusetts Institute of Technology, Physics (2012)
  • Doctor of Philosophy, Harvard University (2018)
  • Ph.D., Harvard University, Systems Biology (2018)
  • Summer course, Marine Biological Laboratory, Neurobiology (2014)
  • S.B., Massachusetts Institute of Technology, Physics (minor: Biology) (2012)
  • Freshman student, Peking University, Physics (2009)

Stanford Advisors


Patents


  • Xiaoliang Sunney Xie, Dong Xing, Chi-Han Chang, Longzhi Tan. "United States Patent WO2018217912A1 Multiplex end-tagging amplification of nucleic acids", President And Fellows Of Harvard College, May 23, 2017

All Publications


  • Three-dimensional genome structures of single sensory neurons in mouse visual and olfactory systems NATURE STRUCTURAL & MOLECULAR BIOLOGY Tan, L., Xing, D., Daley, N., Xie, X. 2019; 26 (4): 297-+

    Abstract

    Sensory neurons in the mouse eye and nose have unusual chromatin organization. Here we report their three-dimensional (3D) genome structure at 20-kilobase (kb) resolution, achieved by applying our recently developed diploid chromatin conformation capture (Dip-C) method to 409 single cells from the retina and the main olfactory epithelium of adult and newborn mice. The 3D genome of rod photoreceptors exhibited inverted radial distribution of euchromatin and heterochromatin compared with that of other cell types, whose nuclear periphery is mainly heterochromatin. Such genome-wide inversion is not observed in olfactory sensory neurons (OSNs). However, OSNs exhibited an interior bias for olfactory receptor (OR) genes and enhancers, in clear contrast to non-neuronal cells. Each OSN harbored multiple aggregates of OR genes and enhancers from different chromosomes. We also observed structural heterogeneity of the protocadherin gene cluster. This type of genome organization may provide the structural basis of the 'one-neuron, one-receptor' rule of olfaction.

    View details for DOI 10.1038/s41594-019-0205-2

    View details for Web of Science ID 000463168900011

    View details for PubMedID 30936528

  • Three-dimensional genome structures of single diploid human cells SCIENCE Tan, L., Xing, D., Chang, C., Li, H., Xie, S. 2018; 361 (6405): 924–28

    Abstract

    Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.

    View details for DOI 10.1126/science.aat5641

    View details for Web of Science ID 000443547000040

    View details for PubMedID 30166492

    View details for PubMedCentralID PMC6360088

  • A Near-Complete Spatial Map of Olfactory Receptors in the Mouse Main Olfactory Epithelium CHEMICAL SENSES Tan, L., Xie, X. 2018; 43 (6): 427–32

    Abstract

    Different regions of the mammalian nose smell different odors. In the mouse olfactory system, spatially regulated expression of >1000 olfactory receptors (ORs) along the dorsomedial-ventrolateral (DV) axis forms a topological map in the main olfactory epithelium (MOE). However, the locations of most ORs along the DV axis are currently unknown. By sequencing mRNA of 12 isolated MOE pieces, we mapped out the DV locations-as quantified by "zone indices" on a scale of 1-5-of 1033 OR genes with an estimated error of 0.3 zone indices. Our map covered 81% of all intact OR genes and 99.4% of the total OR mRNA abundance. Spatial regulation tended to vary gradually along chromosomes. We further identified putative non-OR genes that may exhibit spatial expression along the DV axis.

    View details for DOI 10.1093/chemse/bjy030

    View details for Web of Science ID 000438293600005

    View details for PubMedID 29796642

    View details for PubMedCentralID PMC6454507

  • Single-cell whole-genome analyses by Linear Amplification via Transposon Insertion (LIANTI) SCIENCE Chen, C., Xing, D., Tan, L., Li, H., Zhou, G., Huang, L., Xie, X. 2017; 356 (6334): 189–94

    Abstract

    Single-cell genomics is important for biology and medicine. However, current whole-genome amplification (WGA) methods are limited by low accuracy of copy-number variation (CNV) detection and low amplification fidelity. Here we report an improved single-cell WGA method, Linear Amplification via Transposon Insertion (LIANTI), which outperforms existing methods, enabling micro-CNV detection with kilobase resolution. This allowed direct observation of stochastic firing of DNA replication origins, which differs from cell to cell. We also show that the predominant cytosine-to-thymine mutations observed in single-cell genomics often arise from the artifact of cytosine deamination upon cell lysis. However, identifying single-nucleotide variations (SNVs) can be accomplished by sequencing kindred cells. We determined the spectrum of SNVs in a single human cell after ultraviolet radiation, revealing their nonrandom genome-wide distribution.

    View details for DOI 10.1126/science.aak9787

    View details for Web of Science ID 000399013800037

    View details for PubMedID 28408603

    View details for PubMedCentralID PMC5538131

  • Olfactory sensory neurons transiently express multiple olfactory receptors during development MOLECULAR SYSTEMS BIOLOGY Tan, L., Li, Q., Xie, X. 2015; 11 (12): 844

    Abstract

    In mammals, each olfactory sensory neuron randomly expresses one, and only one, olfactory receptor (OR)--a phenomenon called the "one-neuron-one-receptor" rule. Although extensively studied, this rule was never proven for all ~1,000 OR genes in one cell at once, and little is known about its dynamics. Here, we directly tested this rule by single-cell transcriptomic sequencing of 178 cells from the main olfactory epithelium of adult and newborn mice. To our surprise, a subset of cells expressed multiple ORs. Most of these cells were developmentally immature. Our results illustrated how the "one-neuron-one-receptor" rule may have been established: At first, a single neuron temporarily expressed multiple ORs--seemingly violating the rule--and then all but one OR were eliminated. This work provided experimental evidence that epigenetic regulation in the olfactory system selects a single OR by suppressing a few transiently expressed ORs in a single cell during development.

    View details for DOI 10.15252/msb.20156639

    View details for Web of Science ID 000368086600009

    View details for PubMedID 26646940

    View details for PubMedCentralID PMC4704490

  • Single Cell Transcriptome Amplification with MALBAC PLOS ONE Chapman, A. R., He, Z., Lu, S., Yong, J., Tan, L., Tang, F., Xie, X. 2015; 10 (3): e0120889

    Abstract

    Recently, Multiple Annealing and Looping-Based Amplification Cycles (MALBAC) has been developed for whole genome amplification of an individual cell, relying on quasilinear instead of exponential amplification to achieve high coverage. Here we adapt MALBAC for single-cell transcriptome amplification, which gives consistently high detection efficiency, accuracy and reproducibility. With this newly developed technique, we successfully amplified and sequenced single cells from 3 germ layers from mouse embryos in the early gastrulation stage, and examined the epithelial-mesenchymal transition (EMT) program among cells in the mesoderm layer on a single-cell level.

    View details for DOI 10.1371/journal.pone.0120889

    View details for Web of Science ID 000352134700079

    View details for PubMedID 25822772

    View details for PubMedCentralID PMC4378937

  • Rare event of histone demethylation can initiate singular gene expression of olfactory receptors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tan, L., Zong, C., Xie, X. 2013; 110 (52): 21148–52

    Abstract

    Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (∼1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5–10 d-a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression.

    View details for DOI 10.1073/pnas.1321511111

    View details for Web of Science ID 000328858800069

    View details for PubMedID 24344257

    View details for PubMedCentralID PMC3876194

  • Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant CELL Kamberov, Y. G., Wang, S., Tan, J., Gerbault, P., Wark, A., Tan, L., Yang, Y., Li, S., Tang, K., Chen, H., Powell, A., Itan, Y., Fuller, D., Lohmueller, J., Mao, J., Schachar, A., Paymer, M., Hostetter, E., Byrne, E., Burnett, M., McMahon, A. P., Thomas, M. G., Lieberman, D. E., Jin, L., Tabin, C. J., Morgan, B. A., Sabeti, P. C. 2013; 152 (4): 691–702

    Abstract

    An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.

    View details for DOI 10.1016/j.cell.2013.01.016

    View details for Web of Science ID 000314945600006

    View details for PubMedID 23415220

    View details for PubMedCentralID PMC3575602

  • SLOWLY SWITCHING BETWEEN ENVIRONMENTS FACILITATES REVERSE EVOLUTION IN SMALL POPULATIONS EVOLUTION Tan, L., Gore, J. 2012; 66 (10): 3144–54

    Abstract

    Natural populations must constantly adapt to ever-changing environmental conditions. A particularly interesting question is whether such adaptations can be reversed by returning the population to an ancestral environment. Such evolutionary reversals have been observed in both natural and laboratory populations. However, the factors that determine the reversibility of evolution are still under debate. The time scales of environmental change vary over a wide range, but little is known about how the rate of environmental change influences the reversibility of evolution. Here, we demonstrate computationally that slowly switching between environments increases the reversibility of evolution for small populations that are subject to only modest clonal interference. For small populations, slow switching reduces the mean number of mutations acquired in a new environment and also increases the probability of reverse evolution at each of these "genetic distances." As the population size increases, slow switching no longer reduces the genetic distance, thus decreasing the evolutionary reversibility. We confirm this effect using both a phenomenological model of clonal interference and also a Wright-Fisher stochastic simulation that incorporates genetic diversity. Our results suggest that the rate of environmental change is a key determinant of the reversibility of evolution, and provides testable hypotheses for experimental evolution.

    View details for DOI 10.1111/j.1558-5646.2012.01680.x

    View details for Web of Science ID 000309393000012

    View details for PubMedID 23025604

  • Hidden Randomness between Fitness Landscapes Limits Reverse Evolution PHYSICAL REVIEW LETTERS Tan, L., Serene, S., Chao, H., Gore, J. 2011; 106 (19): 198102

    Abstract

    In biological evolution, adaptations to one environment can in some cases reverse adaptations to another environment. To study this "reverse evolution" on a genotypic level, we measured the fitness of E. coli strains with each possible combination of five mutations in an antibiotic-resistance gene in two distinct antibiotic environments. While adaptations to one environment generally lower fitness in the other, we find that reverse evolution is rarely possible and falls as the complexity of adaptations increases, suggesting a probabilistic, molecular form of Dollo's law.

    View details for DOI 10.1103/PhysRevLett.106.198102

    View details for Web of Science ID 000290474100022

    View details for PubMedID 21668204