Лебедев Юрий Борисович

Личная информация

Лебедев Ю. Б. является первым или ведущим автором свыше 60 оригинальных работ и обзорных статей. Столь же активно он занимается научно-педагогической деятельностью. Ю. Б. Лебедев является постоянным докладчиком на различных школах и конференциях для молодых ученых. За последние 10 лет в его группе успешно выполнены более 20 дипломных работ и защищены под его непосредственным руководством 7 кандидатских диссертаций.

Образование

Период обученияСтрана, городУчебное заведениеДополнительная информация
1973–1978 Москва МГУ

Научные интересы

Руководитель лаборатории доктор биологических наук Юрий Борисович Лебедев является одним из ведущих отечественных специалистов в области изучения структуры, функционирования и эволюции генома млекопитающих. Исследования в этой области начаты Ю. Б. Лебедевым в начале 1990-х, когда он с группой молодых ученых лаборатории академика Е. Д. Свердлова вошли в число первых участников Российской программы «Геном Человека». Как руководитель лаборатории Ю. Б. Лебедев продолжает разрабатывать оригинальное направление эволюционной геномики, связанное с исследованием функциональных последствий распространения и активации ретропозонов в геномах высших приматов.

Премии и заслуги

В 1997 г. стал лауреатом премии им. А. А. Баева «за цикл работ по созданию карты высокого разрешения транскрибируемых и регуляторных участков хромосомы 19 человека».

Основные научные результаты

Результаты функционального картирования отдельных хромосом регулярно представляются Ю. Б. Лебедевым на конгрессах Международной Организации Геном Человека (HUGO) и получают заслуженное признание. С функциональным картированием 19-ой хромосомы связаны и первые работы Ю. Б. Лебедева, посвященные изучению роли ретроэлементов, включая LTR-элементы эндогенных ретровирусов, в эволюции генома человека. Им создается концепция об интеграциях ретроэлементов, приводящих к изменениям систем регуляции экспрессии генов, как важной молекулярно-генетической причине видообразования у приматов. Основные теоретические положения этой концепции подтверждены Ю. Б. Лебедевым в ходе впервые выполненного полногеномного сравнительного анализа геномов человека и шимпанзе, по результатам которого был выявлен и охарактеризован ряд существенных молекулярно-генетических отличий двух близкородственных видов и открыта представительная группа ретроэлементов, специфичных для генома человека. Отдельные достижения этой работы Ю. Б. Лебедева включены в «Важнейшие итоги деятельности РАН» за 2001—2003 гг., а результаты структурно-эволюционного анализа эндогенных ретровирусов человека защищены им в 2004 г. в качестве докторской диссертации.

Членство в научных обществах

В 1996 г. Лебедев Ю. Б. был принят в члены HUGO.

Избранные публикации

  1. Sycheva A.L., Pogorelyy M.V., Komech E.A., Minervina A.A., Zvyagin I.V., Staroverov D.B., Chudakov D.M., Lebedev Y.B., Mamedov I.Z. (2018). Quantitative profiling reveals minor changes of T cell receptor repertoire in response to subunit inactivated influenza vaccine. Vaccine 36 (12), 1599–1605 [+]

    Vaccination against influenza is widely used to protect against seasonal flu epidemic although its effectiveness is debated. Here we performed deep quantitative T cell receptor repertoire profiling in peripheral blood of a healthy volunteer in response to trivalent subunit influenza vaccine. We did not observe significant rebuilding of peripheral blood T cell receptors composition in response to vaccination. However, we found several clonotypes in memory T cell fraction that were undetectable before the vaccination and had a maximum concentration at day 45 after vaccine administration. These cells were found in lower concentration in the course of repertoire monitoring for two years period. Our observation suggests a potential for recruitment of only a limited number of new T cells after each seasonal influenza vaccination.

    ID:2060
  2. Komech E.A., Pogorelyy M.V., Egorov E.S., Britanova O.V., Rebrikov D.V., Bochkova A.G., Shmidt E.I., Shostak N.A., Shugay M., Lukyanov S., Mamedov I.Z., Lebedev Y.B., Chudakov D.M., Zvyagin I.V. (2018). CD8+ T cells with characteristic T cell receptor beta motif are detected in blood and expanded in synovial fluid of ankylosing spondylitis patients. Rheumatology (Oxford) , [+]

    The risk of AS is associated with genomic variants related to antigen presentation and specific cytokine signalling pathways, suggesting the involvement of cellular immunity in disease initiation/progression. The aim of the present study was to explore the repertoire of TCR sequences in healthy donors and AS patients to uncover AS-linked TCR variants.

    ID:2078
  3. Pogorelyy M.V., Elhanati Y., Marcou Q., Sycheva A.L., Komech E.A., Nazarov V.I., Britanova O.V., Chudakov D.M., Mamedov I.Z., Lebedev Y.B., Mora T., Walczak A.M. (2017). Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires. PLoS Comput. Biol. 13 (7), e1005572 [+]

    The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a "public" repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pre-natal life, and survive over long periods, providing the basis of the public repertoire.

    ID:1867
  4. Zvyagin I.V., Mamedov I.Z., Tatarinova O.V., Komech E.A., Kurnikova E.E., Boyakova E.V., Brilliantova V., Shelikhova L.N., Balashov D.N., Shugay M., Sycheva A.L., Kasatskaya S.A., Lebedev Y.B., Maschan A.A., Maschan M.A., Chudakov D.M. (2016). Tracking T-cell immune reconstitution after TCRαβ/CD19-depleted hematopoietic cells transplantation in children. Leukemia , [+]

    αβT-cell-depleted allogeneic hematopoietic cell transplantation holds promise for the safe and accessible therapy of both malignant and non-malignant blood disorders. Here we employed molecular barcoding normalized T-cell receptor (TCR) profiling to quantitatively track T-cell immune reconstitution after TCRαβ-/CD19-depleted transplantation in children. We demonstrate that seemingly early reconstitution of αβT-cell counts 2 months after transplantation is based on only several hundred rapidly expanded clones originating from non-depleted graft cells. In further months, frequency of these hyperexpanded clones declines, and after 1 year the observed T-cell counts and TCRβ diversity are mostly provided by the newly produced T cells. We also demonstrate that high TCRβ diversity at day 60 observed for some of the patients is determined by recipient T cells and intrathymic progenitors that survived conditioning regimen. Our results indicate that further efforts on optimization of TCRαβ-/CD19-depleted transplantation protocols should be directed toward providing more efficient T-cell defense in the first months after transplantation.Leukemia advance online publication, 9 December 2016; doi:10.1038/leu.2016.321.

    ID:1693
  5. Pogorelyy M., Elhanati Y., Marcou Q., Sycheva A., Komech E., Britanova O., Chudakov D., Mamedov I., Lebedev Y., Mora T., Walczak A. (2016). Persisting fetal clonotypes influence the structure and overlap of adult human TCR repertoires. European Journal of Immunology. Abstracts of ICI 2016 International Congress of Immunology, 21-26 August 2016, Melbourne, Australia. , 52 ID:1887
  6. Egorov E.S., Merzlyak E.M., Shelenkov A.A., Britanova O.V., Sharonov G.V., Staroverov D.B., Bolotin D.A., Davydov A.N., Barsova E., Lebedev Y.B., Shugay M., Chudakov D.M. (2015). Quantitative profiling of immune repertoires for minor lymphocyte counts using unique molecular identifiers. J. Immunol. 194 (12), 6155–63 [+]

    Emerging high-throughput sequencing methods for the analyses of complex structure of TCR and BCR repertoires give a powerful impulse to adaptive immunity studies. However, there are still essential technical obstacles for performing a truly quantitative analysis. Specifically, it remains challenging to obtain comprehensive information on the clonal composition of small lymphocyte populations, such as Ag-specific, functional, or tissue-resident cell subsets isolated by sorting, microdissection, or fine needle aspirates. In this study, we report a robust approach based on unique molecular identifiers that allows profiling Ag receptors for several hundred to thousand lymphocytes while preserving qualitative and quantitative information on clonal composition of the sample. We also describe several general features regarding the data analysis with unique molecular identifiers that are critical for accurate counting of starting molecules in high-throughput sequencing applications.

    ID:1313
  7. Nazarov V.I., Pogorelyy M.V., Komech E.A., Zvyagin I.V., Bolotin D.A., Shugay M., Chudakov D.M., Lebedev Y.B., Mamedov I.Z. (2015). tcR: an R package for T cell receptor repertoire advanced data analysis. BMC Bioinformatics 16, 175 [+]

    The Immunoglobulins (IG) and the T cell receptors (TR) play the key role in antigen recognition during the adaptive immune response. Recent progress in next-generation sequencing technologies has provided an opportunity for the deep T cell receptor repertoire profiling. However, a specialised software is required for the rational analysis of massive data generated by next-generation sequencing.

    ID:1299
  8. Kurnosov A.A., Ustyugova S.V., Nazarov V.I., Minervina A.A., Komkov A.Y., Shugay M., Pogorelyy M.V., Khodosevich K.V., Mamedov I.Z., Lebedev Y.B. (2014). The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS ONE 10 (2), e0117854 [+]

    Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic activity. This study aims to expand our understanding of the role retroelements play in generating somatic mosaicism of neural tissues. Whole-genome Alu and L1 profiling of genomic DNA extracted from the cerebellum, frontal cortex, subventricular zone, dentate gyrus, and the myocardium revealed hundreds of somatic insertions in each of the analyzed tissues. Interestingly, the highest concentration of such insertions was detected in the dentate gyrus-the hotspot of adult neurogenesis. Insertions of retroelements and their activity could produce genetically diverse neuronal subsets, which can be involved in hippocampal-dependent learning and memory.

    ID:1274
  9. Zvyagin I.V., Pogorelyy M.V., Ivanova M.E., Komech E.A., Shugay M., Bolotin D.A., Shelenkov A.A., Kurnosov A.A., Staroverov D.B., Chudakov D.M., Lebedev Y.B., Mamedov I.Z. (2014). Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing. Proc. Natl. Acad. Sci. U.S.A. , [+]

    Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individual genetic factors on the formation of the adaptive immunity by analyzing the T-cell receptor (TCR) repertoires of three pairs of monozygous twins by next-generation sequencing. Surprisingly, we found that an overlap between the TCR repertoires of monozygous twins is similar to an overlap between the TCR repertoires of nonrelated individuals. However, the number of identical complementary determining region 3 sequences in two individuals is significantly increased for twin pairs in the fraction of highly abundant TCR molecules, which is enriched by the antigen-experienced T cells. We found that the initial recruitment of particular TCR V genes for recombination and subsequent selection in the thymus is strictly determined by individual genetic factors. J genes of TCRs are selected randomly for recombination; however, the subsequent selection in the thymus gives preference to some α but not β J segments. These findings provide a deeper insight into the mechanism of TCR repertoire generation.

    ID:1015
  10. Mamedov I.Z., Britanova O.V., Zvyagin I.V., Turchaninova M.A., Bolotin D.A., Putintseva E.V., Lebedev Y.B., Chudakov D.M. (2013). Preparing unbiased T-cell receptor and antibody cDNA libraries for the deep next generation sequencing profiling. Front Immunol 4, 456 [+]

    High-throughput sequencing has the power to reveal the nature of adaptive immunity as represented by the full complexity of T-cell receptor (TCR) and antibody (IG) repertoires, but is at present severely compromised by the quantitative bias, bottlenecks, and accumulated errors that inevitably occur in the course of library preparation and sequencing. Here we report an optimized protocol for the unbiased preparation of TCR and IG cDNA libraries for high-throughput sequencing, starting from thousands or millions of live cells in an investigated sample. Critical points to control are revealed, along with tips that allow researchers to minimize quantitative bias, accumulated errors, and cross-sample contamination at each stage, and to enhance the subsequent bioinformatic analysis. The protocol is simple, reliable, and can be performed in 1-2 days.

    ID:995
  11. Shagina I., Bogdanova E., Mamedov I., Lebedev Y., Lukyanov S., Shagin D. (2010). Normalization of genomic DNA using duplex-specific nuclease. BioTechniques 48 (6), 351–355 [+]

    An application of duplex-specific nuclease (DSN) normalization technology to whole-genome shotgun sequencing of genomes with a large proportion of repetitive DNA is described. The method uses a thermostable DSN from the Kamchatka crab that specifically hydrolyzes dsDNA. In model experiments on human genomic DNA, we demonstrated that DSN normalization of double-stranded DNA formed during C0t analysis is effective against abundant repetitive sequences with high sequence identity, while retaining highly divergent repeats and coding regions at baseline levels. Thus, DSN normalization applied to C0t analysis can be used to eliminate evolutionarily young repetitive elements from genomic DNA before sequencing, and should prove invaluable in studies of large eukaryotic genomes, such as those of higher plants.

    ID:339
  12. Mamedov I.Z., Shagina I.A., Kurnikova M.A., Novozhilov S.N., Shagin D.A., Lebedev Y.B. (2010). A new set of markers for human identification based on 32 polymorphic Alu insertions. EJHG , [+]

    A number of genetic systems for human genetic identification based on short tandem repeats or single nucleotide polymorphisms are widely used for crime detection, kinship studies and in analysis of victims of mass disasters. Here, we have developed a new set of 32 molecular genetic markers for human genetic identification based on polymorphic retroelement insertions. Allele frequencies were determined in a group of 90 unrelated individuals from four genetically distant populations of the Russian Federation. The mean match probability and probability of paternal exclusion, calculated based on population data, were 5.53 x 10(-14) and 99.784%, respectively. The developed system is cheap and easy to use as compared to all previously published methods. The application of fluorescence-based methods for allele discrimination allows to use the human genetic identification set in automatic and high-throughput formats.European Journal of Human Genetics advance online publication, 24 February 2010; doi:10.1038/ejhg.2010.22.

    ID:338
  13. Mamedov I.Z., Britanova O.V., Chkalina A.V., Staroverov D.B., Amosova A.L., Mishin A.S., Kurnikova M.A., Zvyagin I.V., Mutovina Z.Y., Gordeev A.V., Khaidukov S.V., Sharonov G.V., Shagin D.A., Chudakov D.M., Lebedev Y.B. (2009). Individual characterization of stably expanded T cell clones in ankylosing spondylitis patients. Autoimmunity 42 (6), 525–36 [+]

    Ankylosing spondylitis (AS) is commonly characterized by clonal expansions of T cells. However, these clonal populations are poorly studied and their role in disease initiation and progression remains unclear. Here, we performed mass sequencing of TCR V beta libraries to search for the expanded T cell clones for two AS patients. A number of clones comprising more than 5% of the corresponding TCR V beta family were identified in both patients. For the first time, expanded clones were shown to be stably abundant in blood samples of AS patients for the prolonged period (1.5 and 2.5 years for two patients, correspondingly). These clones were individually characterized in respect to their differentiation status using fluorescent cell sorting with CD27, CD28, and CD45RA markers followed by quantitative identification of each clone within corresponding fraction using real time PCR analysis. Stable clones differed in phenotype and several were shown to belong to the proinflammatory CD27 - /CD28 - population. Their potentially cytotoxic status was confirmed by staining with perforin-specific antibodies. Search for the TCR V beta CRD3 sequences homologous to the identified clones revealed close matches with the previously reported T cell clones from AS and reactive arthritis patients, thus supporting their role in the disease and proposing consensus TCR V beta CDR3 motifs for AS. Interestingly, these motifs were also found to have homology with earlier reported virus-specific CDR3 variants, indicating that viral infections could play role in development of AS.

    ID:276
  14. Chkalina A.V., Zviagin I.V., Mamedov I.Z., Britanova O.V., Staroverov D.B., Lebedev Iu.B. (2009). [The oligoclonal expansion of T cells: study of its stability over time]. Bioorg. Khim. 36 (2), 206–14 [+]

    A novel experimental approach to the investigation of the repertoire of peripheral T lymphocytes of patients suffering from ankylosing spondylitis (AS) is proposed. This approach is based on the wide-range sequencing of cDNA of the beta-chain of the T-cellular receptor (TcR). The results of the analysis of the diversity of sequences of the TcR antigen-binding domain (CDR3) inside the total pool of one patient with AS are presented by the example of the second V family (BV2) of TcR. The expansion of six independent TcR-expressing clones of T cells with a similar amino acid sequence of the CDR3 domains was proposed based on the results of the comparative structural analysis of the clone libraries of the cDNA of TcR BV2. The long-time stable expansion of these T clones was demonstrated during the development of the disease by specific monitoring.

    ID:405
  15. Lebedev Y.B., Amosova A.L., Mamedov I.Z., Fisunov G.Y., Sverdlov E.D. (2007). Most recent AluY insertions in human gene introns reduce the content of the primary transcripts in a cell type specific manner. Gene 390 (1-2), 122–9 [+]

    Предложена общая стратегия широко масштабного анализа влияния ретроэлементов на функционирование генома приматов, использующая явление инсерционного полиморфизма Alu элементов генома человека. Предложен метод сравнения транскрипционной активности аллельных вариантов генов человека, отличающихся по интронным инсерциям AluY элементов. Открыт ингибиторный эффект диморфных AluY инсерций на экспрессию пораженного аллеля и показан тканеспецифический характер проявления обнаруженного эффекта.

    ID:100
  16. Mamedov I.Z., Arzumanyan E.S., Amosova A.L., Lebedev Y.B., Sverdlov E.D. (2005). Whole-genome experimental identification of insertion/deletion polymorphisms of interspersed repeats by a new general approach. Nucleic Acids Res. 33 (2), e16 [+]

    Разработана уникальная технология экспериментального сравнительно-структурного анализа смесевых образцов геномной ДНК, направленная на полногеномную идентификацию полиморфных инсерций отдельных классов ретроэлементов. Эффективность нового экспериментального подхода к изучению инсерционного полиморфизма ретроэлементов генома человека доказана открытием обширной группы диморфных инсерций AluY элементов, до 40% представителей которой не могли быть идентифицированы биоинформатическими методами анализа.

    ID:99
  17. Buzdin A., Ustyugova S., Gogvadze E., Lebedev Y., Hunsmann G., Sverdlov E. (2003). Genome-wide targeted search for human specific and polymorphic L1 integrations. Hum. Genet. 112 (5-6), 527–33 [+]

    Эффективное применение оригинального метода вычитающей гибридизации геномной ДНК для идентификации видоспецифических инсерций LINE ретропозонов.

    ID:97
  18. Buzdin A., Ustyugova S., Khodosevich K., Mamedov I., Lebedev Y., Hunsmann G., Sverdlov E. (2003). Human-specific subfamilies of HERV-K (HML-2) long terminal repeats: three master genes were active simultaneously during branching of hominoid lineages. Genomics 81 (2), 149–56 [+]

    Полный структурный анализ специфичных для генома человека LTR-элементов. Впервые доказана множественная ретропозиция эндогенных ретровирусов в ходе эволюции генома человека.

    ID:96
  19. Mamedov I., Batrak A., Buzdin A., Arzumanyan E., Lebedev Y., Sverdlov E.D. (2002). Genome-wide comparison of differences in the integration sites of interspersed repeats between closely related genomes. Nucleic Acids Res. 30 (14), e71 [+]

    Представлен окончательный вариант экспериментального подхода к полногеномному сравнительному анализу распределения участков интеграции LTR-элементов в геномах близкородственных видов. Впервые идентифицировано и предварительно охарактеризовано 11 инсерций LTR-элементов, отличающих геном человека от генома шимпанзе.

    ID:18
  20. Buzdin A., Khodosevich K., Mamedov I., Vinogradova T., Lebedev Y., Hunsmann G., Sverdlov E. (2002). A technique for genome-wide identification of differences in the interspersed repeats integrations between closely related genomes and its application to detection of human-specific integrations of HERV-K LTRs. Genomics 79 (3), 413–22 [+]

    В статье опубликован новый метод, позволяющий сравнивать распределение геномных повторов между близкородственными геномами при помощи метода вычитающей гибридизации

    ID:17
  21. Lebedev Y.B., Belonovitch O.S., Zybrova N.V., Khil P.P., Kurdyukov S.G., Vinogradova T.V., Hunsmann G., Sverdlov E.D. (2000). Differences in HERV-K LTR insertions in orthologous loci of humans and great apes. Gene 247 (1-2), 265–77 [+]

    Впервые предложена техника селективной ПЦР-амплификации участков интеграции ретроэлементов. По результатам сравнительно-сруктурного и эволюционного анализа LTR-элементов разработана детальная систематика эндогенных ретровирусов семейства К (HERV-K) и показано существование волн ретропозиций HERV-K в эволюции генома, совпадающих по времени со временем дивергенции основных линий приматов. Доказано существование специфичной для генома человека группы LTR-элементов

    ID:98