Laboratory of comparative and functional genomics

Department of Genomics of Adaptive Immunity

Head: Yuri Lebedev, D.Sc, professor

Human genome, genome evolution and variability, retroelements, regulation of gene expression, transcriptome of human lymphocytes, autoimmune diseases

The laboratory was formed early in 2006 and was joined by those of young scientists and PhD students from Laboratory of structure and functions of human genes (LSFHG, laboratory head — academician E.D. Sverdlov) who studied retroposon’s impact on human genome evolution and functioning. On March 2009, Laboratory of comparative and functional genomics includes: laboratory head Y.B. Lebedev, D.Sci., researchers I.Z. Mamedov, Ph.D. and A.L. Amosova, Ph.D., junior researcher S.V. Ustyugova, Ph.D., PhD students A.V. Chkalina, I.V. Zvyagin, A.Y. Komkov, and three undergraduate students from Moscow State University who work on their bachelor’s theses. Ongoing laboratory projects are supported by the Institute, by Russ. Acad. Sci. Presidium programs, by RFBR grants and by other grants, including:

  • Studies of human genome variability and genetic basis of inherited diseases;
  • New approach to identification and selective suppression of expanded T-cell clones in patients with autoimmune and oncological diseases;
  • Role of retroposon’s insertional polymorphism in oncological diseases;
  • Large-scale functional analysis of human specific and polymorphic retroelement insertions;
  • Advanced molecular-genetic markers and their application for people genetic services and records;
  • Molecular-genetic analysis of eneolithic/bronze age inhabitants of Thrace valley and South-Russian steppe.

The laboratory carries out a wide range of molecular genetic research applying newly developed techniques and approaches to comparative analysis of genomic DNAs and cDNA pools of various origins. Ongoing research includes the following directions:

  1. genetics of distinct types of autoimmune diseases associated with clonal T-cell expansion; comparative transcriptome analysis of various subpopulations of peripheral blood lymphocytes;
  2. transposable elements impact on the eukaryotic genome evolution; investigation of genomic variability of individuals and within human population forming by retroelements activity; studies on the interaction between species-specific and polymorphic retroelements and gene expression systems;
  3. development of new aproaches for analysis of individual T-cell repertoires;
  4. studying of clonal diversity dynamic of human T- and B-lymphocytes in normal state and during development of autoimmune or oncological diseases.

All publications (show selected)


Yuri Lebedev

Dynamics and phenotypes of memory T cell clones in response to anti-viral vaccination

In collaboration with Laboratory of immunosequencing methods

Using TCR alpha and beta repertoire sequencing for T-cell subsets, as well as single-cell RNAseq and TCRseq, we track the concentrations and phenotypes of individual T-cell clones in response to primary and secondary yellow fever immunization — the model for acute infection in humans — showing their large diversity. We confirm the secondary response is an order of magnitude weaker, albeit ~10 days faster than the primary one. Estimating the fraction of the T-cell response directed against the single immunodominant epitope, we identify the sequence features of TCRs that define the high precursor frequency of the two major TCR motifs specific for this particular epitope. We also show the consistency of clonal expansion dynamics between bulk alpha and beta repertoires, using a new methodology to reconstruct alpha-beta pairings from clonal trajectories.

- two functionally distinct subpopulations of CD8 + memory stem cells described.

- a new approach developed to assess the clonal heterogeneity of tumor-infiltrating T-lymphocytes.

-  stably clonal T cell response was shown to be associated with a response to anti-PD1 immunotherapy.

- the T-cell repertoire of nickel-specific CD4 + T-lymphocytes was characterized.

- the repertoire of gamma-delta T lymphocytes involved in the antitumor response was investigated.

- a comparative analysis of the repertoire of follicular helper T-lymphocytes was carried out.

- a deep comparative study of methods for analyzing the repertoire of T-cell receptors was carried out.


  1. Galletti G, De Simone G, Mazza EMC, Puccio S, Mezzanotte C, Bi TM, Davydov AN, Metsger M, Scamardella E, Alvisi G, De Paoli F, Zanon V, Scarpa A, Camisa B, Colombo FS, Anselmo A, Peano C, Polletti S, Mavilio D, Gattinoni L, Boi SK, Youngblood BA, Jones RE, Baird DM, Gostick E, Llewellyn-Lacey S, Ladell K, Price DA, Chudakov DM, Newell EW, Casucci M, Lugli E (2020). Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nat Immunol ,
  2. Yuzhakova DV, Volchkova LN, Pogorelyy MV, Serebrovskaya EO, Shagina IA, Bryushkova EA, Nakonechnaya TO, Izosimova AV, Zavyalova DS, Karabut MM, Izraelson M, Samoylenko IV, Zagainov VE, Chudakov DM, Zagaynova EV, Sharonov GV (2020). Measuring Intratumoral Heterogeneity of Immune Repertoires. Front Oncol 10, 512
  3. Zhigalova EA, Izosimova AI, Yuzhakova DV, Volchkova LN, Shagina IA, Turchaninova MA, Serebrovskaya EO, Zagaynova EV, Chudakov DM, Sharonov GV (2020). RNA-Seq-Based TCR Profiling Reveals Persistently Increased Intratumoral Clonality in Responders to Anti-PD-1 Therapy. Front Oncol 10, 385
  4. Aparicio-Soto M, Riedel F, Leddermann M, Bacher P, Scheffold A, Kuhl H, Timmermann B, Chudakov DM, Molin S, Worm M, Heine G, Thierse HJ, Luch A, Siewert K (2020). TCRs with segment TRAV9-2 or a CDR3 histidine are overrepresented among nickel-specific CD4+ T cells. Allergy 75 (10), 2574–2586
  5. Janssen A, Villacorta Hidalgo J, Beringer DX, van Dooremalen S, Fernando F, van Diest E, Terrizi AR, Bronsert P, Kock S, Schmitt-Gräff A, Werner M, Heise K, Follo M, Straetemans T, Sebestyen Z, Chudakov DM, Kasatskaya SA, Frenkel FE, Ravens S, Spierings E, Prinz I, Küppers R, Malkovsky M, Fisch P, Kuball J (2020). γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity. Cancer Immunol Res 8 (4), 530–543
  6. Brenna E, Davydov AN, Ladell K, McLaren JE, Bonaiuti P, Metsger M, Ramsden JD, Gilbert SC, Lambe T, Price DA, Campion SL, Chudakov DM, Borrow P, McMichael AJ (2020). CD4 T Follicular Helper Cells in Human Tonsils and Blood Are Clonally Convergent but Divergent from Non-Tfh CD4 Cells. Cell Rep 30 (1), 137–152.e5
  7. Barennes P, Quiniou V, Shugay M, Egorov ES, Davydov AN, Chudakov DM, Uddin I, Ismail M, Oakes T, Chain B, Eugster A, Kashofer K, Rainer PP, Darko S, Ransier A, Douek DC, Klatzmann D, Mariotti-Ferrandiz E (2020). Benchmarking of T cell receptor repertoire profiling methods reveals large systematic biases. Nat Biotechnol 39 (2), 236–245
  8. De Simone G, Mazza EMC, Cassotta A, Davydov AN, Kuka M, Zanon V, De Paoli F, Scamardella E, Metsger M, Roberto A, Pilipow K, Colombo FS, Tenedini E, Tagliafico E, Gattinoni L, Mavilio D, Peano C, Price DA, Singh SP, Farber JM, Serra V, Cucca F, Ferrari F, Orrù V, Fiorillo E, Iannacone M, Chudakov DM, Sallusto F, Lugli E (2019). CXCR3 Identifies Human Naive CD8 T Cells with Enhanced Effector Differentiation Potential. J Immunol 203 (12), 3179–3189

A new approach to the functional analysis of sequencing data for T-lymphocyte repertoires

In collaboration with Laboratory of immunosequencing methods,  Group of Immunosequencing Algorithms

In order to extract clinically relevant information from large high-throughput sequencing of TCR repertoires we create a new statistical approach - Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE) /fig a/. We applied our algorithm to distinguish naïve from the effector memory cells in available TCR beta repertoires /fig b/, to identify reactive T-cell clones in mixed lymphocyte reaction (MLR) assay /fig c, d/, to fractionate TCR repertoires of patients with autoimmune disease or ones being under cancer immunotherapy, or subject to an acute viral infection. In summary, implementation of ALICE facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.

Clonal profiling of T cell response to antiviral vaccination

T cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed an experimental approach with a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framework to data from three pairs of identical twins immunized with the yellow fever vaccine. We identified 600 to 1,700 responding TCRs in each donor and validated them using three independent assays. While the responding TCRs were mostly private, albeit with higher overlap between twins, they could be well-predicted using a classifier based on sequence similarity. Our method can also be applied to samples obtained postinfection, making it suitable for systematic discovery of new infection-specific TCRs in the clinic.

T cell immune response to the flu vaccination

Deep quantitative T cell receptors profiling of peripheral lymphocytes have been performed to investigate T cell impact on the human immune response to the trivalent subunit influenza vaccine. Besides the fact that the flu vaccination does not lead to a significant rebuilding of T-lymphocytes repertoire, we founded small oligoclonal subpopulation bearing T cell memory phenotype. The subpopulation appears at 45th day after vaccine administration and then decreases its proportion of T cell clones in the repertoire. These “new memory” T cell clones suggest a potential for recruitment of a limited number of new T cells after each seasonal influenza vaccination.