[{"publisher":"Springer Nature","project":[{"name":"Evolution of Sensorimotor Transformation Across Diptera","grant_number":"429960716","_id":"9B767A34-BA93-11EA-9121-9846C619BF3A"},{"grant_number":"771209","call_identifier":"H2020","name":"Characterizing the fitness landscape on population and global scales","_id":"26580278-B435-11E9-9278-68D0E5697425"},{"name":"Evolutionary analysis of gene regulation","grant_number":"I05127","_id":"34e076d6-11ca-11ed-8bc3-aec76c41a181"}],"ddc":["570"],"year":"2024","date_published":"2024-07-01T00:00:00Z","pmid":1,"article_processing_charge":"No","page":"837-845","intvolume":"        32","volume":32,"_id":"15362","external_id":{"isi":["001207703200001"],"pmid":["38658779"]},"author":[{"last_name":"Andrianova","full_name":"Andrianova, Maria A.","first_name":"Maria A."},{"last_name":"Seplyarskiy","full_name":"Seplyarskiy, Vladimir B.","first_name":"Vladimir B."},{"full_name":"Terradas, Mariona","last_name":"Terradas","first_name":"Mariona"},{"first_name":"Ana Beatriz","full_name":"Sánchez-Heras, Ana Beatriz","last_name":"Sánchez-Heras"},{"full_name":"Mur, Pilar","last_name":"Mur","first_name":"Pilar"},{"first_name":"José Luis","last_name":"Soto","full_name":"Soto, José Luis"},{"full_name":"Aiza, Gemma","last_name":"Aiza","first_name":"Gemma"},{"first_name":"Emma","full_name":"Borràs, Emma","last_name":"Borràs"},{"full_name":"Kondrashov, Fyodor","id":"44FDEF62-F248-11E8-B48F-1D18A9856A87","last_name":"Kondrashov","orcid":"0000-0001-8243-4694","first_name":"Fyodor"},{"full_name":"Kondrashov, Alexey S.","last_name":"Kondrashov","first_name":"Alexey S."},{"full_name":"Bazykin, Georgii A.","last_name":"Bazykin","first_name":"Georgii A."},{"full_name":"Valle, Laura","last_name":"Valle","first_name":"Laura"}],"isi":1,"status":"public","file":[{"creator":"dernst","file_size":3060724,"date_updated":"2025-01-09T09:21:25Z","file_name":"2024_EJHG_Andrianova.pdf","file_id":"18799","date_created":"2025-01-09T09:21:25Z","checksum":"e45fc987f4e9ebafdd0ec4f0e9027de4","relation":"main_file","content_type":"application/pdf","access_level":"open_access","success":1}],"citation":{"ieee":"M. A. Andrianova <i>et al.</i>, “Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells,” <i>European Journal of Human Genetics</i>, vol. 32. Springer Nature, pp. 837–845, 2024.","ama":"Andrianova MA, Seplyarskiy VB, Terradas M, et al. Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells. <i>European Journal of Human Genetics</i>. 2024;32:837-845. doi:<a href=\"https://doi.org/10.1038/s41431-024-01598-8\">10.1038/s41431-024-01598-8</a>","apa":"Andrianova, M. A., Seplyarskiy, V. B., Terradas, M., Sánchez-Heras, A. B., Mur, P., Soto, J. L., … Valle, L. (2024). Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells. <i>European Journal of Human Genetics</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41431-024-01598-8\">https://doi.org/10.1038/s41431-024-01598-8</a>","mla":"Andrianova, Maria A., et al. “Discovery of Recessive Effect of Human Polymerase δ Proofreading Deficiency through Mutational Analysis of POLD1-Mutated Normal and Cancer Cells.” <i>European Journal of Human Genetics</i>, vol. 32, Springer Nature, 2024, pp. 837–45, doi:<a href=\"https://doi.org/10.1038/s41431-024-01598-8\">10.1038/s41431-024-01598-8</a>.","chicago":"Andrianova, Maria A., Vladimir B. Seplyarskiy, Mariona Terradas, Ana Beatriz Sánchez-Heras, Pilar Mur, José Luis Soto, Gemma Aiza, et al. “Discovery of Recessive Effect of Human Polymerase δ Proofreading Deficiency through Mutational Analysis of POLD1-Mutated Normal and Cancer Cells.” <i>European Journal of Human Genetics</i>. Springer Nature, 2024. <a href=\"https://doi.org/10.1038/s41431-024-01598-8\">https://doi.org/10.1038/s41431-024-01598-8</a>.","short":"M.A. Andrianova, V.B. Seplyarskiy, M. Terradas, A.B. Sánchez-Heras, P. Mur, J.L. Soto, G. Aiza, E. Borràs, F. Kondrashov, A.S. Kondrashov, G.A. Bazykin, L. Valle, European Journal of Human Genetics 32 (2024) 837–845.","ista":"Andrianova MA, Seplyarskiy VB, Terradas M, Sánchez-Heras AB, Mur P, Soto JL, Aiza G, Borràs E, Kondrashov F, Kondrashov AS, Bazykin GA, Valle L. 2024. Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells. European Journal of Human Genetics. 32, 837–845."},"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png"},"acknowledgement":"This study was funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigación), co-funded by FEDER funds a way to build Europe [PID2020-112595RB-I00 (LV)], Instituto de Salud Carlos III [CIBERONC CB16/12/00234 (LV); ISCIII-AES-2017 PI17/01082 (JLS), PMP22/00064], Government of Catalonia [AGAUR 2021SGR01112, CERCA Program for institutional support (LV)], Scientific Foundation Asociación Española Contra el Cáncer [AECC Investigador (MT)], Austrian Science Fund FWF [Grant Agreement # I5127-B (FK)], German Research Foundation DFG [Grant Agreement # 429960716 (FK)], and ERC Consolidator [Grant Agreement # 771209 ChrFL (FK)].","scopus_import":"1","month":"07","doi":"10.1038/s41431-024-01598-8","ec_funded":1,"day":"01","department":[{"_id":"FyKo"}],"publication_status":"published","oa_version":"Published Version","quality_controlled":"1","language":[{"iso":"eng"}],"abstract":[{"text":"Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation in the exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.","lang":"eng"}],"publication_identifier":{"eissn":["1476-5438"],"issn":["1018-4813"]},"publication":"European Journal of Human Genetics","date_created":"2024-05-05T22:01:04Z","file_date_updated":"2025-01-09T09:21:25Z","date_updated":"2026-04-15T08:51:09Z","type":"journal_article","OA_place":"publisher","article_type":"original","OA_type":"hybrid","title":"Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"has_accepted_license":"1"},{"article_processing_charge":"Yes (in subscription journal)","page":"1082-1091","pmid":1,"date_published":"2021-07-01T00:00:00Z","year":"2021","project":[{"grant_number":"771209","name":"Characterizing the fitness landscape on population and global scales","call_identifier":"H2020","_id":"26580278-B435-11E9-9278-68D0E5697425"}],"publisher":"Springer Nature","ddc":["576"],"isi":1,"author":[{"full_name":"Slavskii, Sergei A.","last_name":"Slavskii","first_name":"Sergei A."},{"last_name":"Kuznetsov","full_name":"Kuznetsov, Ivan A.","first_name":"Ivan A."},{"last_name":"Shashkova","full_name":"Shashkova, Tatiana I.","first_name":"Tatiana I."},{"first_name":"Georgii A.","last_name":"Bazykin","full_name":"Bazykin, Georgii A."},{"full_name":"Axenovich, Tatiana I.","last_name":"Axenovich","first_name":"Tatiana I."},{"orcid":"0000-0001-8243-4694","first_name":"Fyodor","last_name":"Kondrashov","full_name":"Kondrashov, Fyodor","id":"44FDEF62-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Yurii S.","full_name":"Aulchenko, Yurii S.","last_name":"Aulchenko"}],"_id":"9910","external_id":{"isi":["000625853200001"],"pmid":["33664501"]},"issue":"7","volume":29,"intvolume":"        29","language":[{"iso":"eng"}],"quality_controlled":"1","oa_version":"Published Version","month":"07","publication_status":"published","department":[{"_id":"FyKo"}],"ec_funded":1,"doi":"10.1038/s41431-021-00836-7","day":"01","acknowledgement":"We are grateful to Marianna Bevova and Pavel Borodin for fruitful discussion and help with conceptualising our findings and to Lennart C. Karssen for help with handling the UK Biobank data.\r\n\r\nFunding\r\nThis research has been conducted using the UK Biobank Resource (project # 41601, “Non-additive effects in control of complex human traits”). The work of SAS, IAK, and TIS were supported by Russian Ministry of Science and Education under the 5–100 Excellence Programme. The work of YSA and TIA was supported by the Ministry of Education and Science of the RF via the Institute of Cytology and Genetics SB RAS (project number 0324-2019-0040-C-01/AAAA-A17-117092070032-4). FAK is supported by the ERC Consolidator Grant (ChrFL: 771209).","scopus_import":"1","status":"public","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png"},"citation":{"ama":"Slavskii SA, Kuznetsov IA, Shashkova TI, et al. The limits of normal approximation for adult height. <i>European Journal of Human Genetics</i>. 2021;29(7):1082-1091. doi:<a href=\"https://doi.org/10.1038/s41431-021-00836-7\">10.1038/s41431-021-00836-7</a>","apa":"Slavskii, S. A., Kuznetsov, I. A., Shashkova, T. I., Bazykin, G. A., Axenovich, T. I., Kondrashov, F., &#38; Aulchenko, Y. S. (2021). The limits of normal approximation for adult height. <i>European Journal of Human Genetics</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41431-021-00836-7\">https://doi.org/10.1038/s41431-021-00836-7</a>","ieee":"S. A. Slavskii <i>et al.</i>, “The limits of normal approximation for adult height,” <i>European Journal of Human Genetics</i>, vol. 29, no. 7. Springer Nature, pp. 1082–1091, 2021.","ista":"Slavskii SA, Kuznetsov IA, Shashkova TI, Bazykin GA, Axenovich TI, Kondrashov F, Aulchenko YS. 2021. The limits of normal approximation for adult height. European Journal of Human Genetics. 29(7), 1082–1091.","mla":"Slavskii, Sergei A., et al. “The Limits of Normal Approximation for Adult Height.” <i>European Journal of Human Genetics</i>, vol. 29, no. 7, Springer Nature, 2021, pp. 1082–91, doi:<a href=\"https://doi.org/10.1038/s41431-021-00836-7\">10.1038/s41431-021-00836-7</a>.","short":"S.A. Slavskii, I.A. Kuznetsov, T.I. Shashkova, G.A. Bazykin, T.I. Axenovich, F. Kondrashov, Y.S. Aulchenko, European Journal of Human Genetics 29 (2021) 1082–1091.","chicago":"Slavskii, Sergei A., Ivan A. Kuznetsov, Tatiana I. Shashkova, Georgii A. Bazykin, Tatiana I. Axenovich, Fyodor Kondrashov, and Yurii S. Aulchenko. “The Limits of Normal Approximation for Adult Height.” <i>European Journal of Human Genetics</i>. Springer Nature, 2021. <a href=\"https://doi.org/10.1038/s41431-021-00836-7\">https://doi.org/10.1038/s41431-021-00836-7</a>."},"file":[{"access_level":"open_access","success":1,"content_type":"application/pdf","checksum":"a676d76f91b0dbe0504c63e469129c2a","relation":"main_file","date_created":"2021-08-16T09:14:36Z","file_id":"9921","file_name":"2021_EuropeanJournalOfHumanGenetics_Slavskii.pdf","date_updated":"2021-08-16T09:14:36Z","creator":"asandaue","file_size":1079395}],"has_accepted_license":"1","oa":1,"article_type":"original","title":"The limits of normal approximation for adult height","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file_date_updated":"2021-08-16T09:14:36Z","type":"journal_article","date_updated":"2025-07-10T12:02:05Z","abstract":[{"lang":"eng","text":"Adult height inspired the first biometrical and quantitative genetic studies and is a test-case trait for understanding heritability. The studies of height led to formulation of the classical polygenic model, that has a profound influence on the way we view and analyse complex traits. An essential part of the classical model is an assumption of additivity of effects and normality of the distribution of the residuals. However, it may be expected that the normal approximation will become insufficient in bigger studies. Here, we demonstrate that when the height of hundreds of thousands of individuals is analysed, the model complexity needs to be increased to include non-additive interactions between sex, environment and genes. Alternatively, the use of log-normal approximation allowed us to still use the additive effects model. These findings are important for future genetic and methodologic studies that make use of adult height as an exemplar trait."}],"date_created":"2021-08-15T22:01:28Z","publication":"European Journal of Human Genetics","publication_identifier":{"eissn":["1476-5438"],"issn":["1018-4813"]}}]