---
OA_place: publisher
OA_type: hybrid
_id: '15362'
abstract:
- lang: eng
  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.
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)].'
article_processing_charge: No
article_type: original
author:
- first_name: Maria A.
  full_name: Andrianova, Maria A.
  last_name: Andrianova
- first_name: Vladimir B.
  full_name: Seplyarskiy, Vladimir B.
  last_name: Seplyarskiy
- first_name: Mariona
  full_name: Terradas, Mariona
  last_name: Terradas
- first_name: Ana Beatriz
  full_name: Sánchez-Heras, Ana Beatriz
  last_name: Sánchez-Heras
- first_name: Pilar
  full_name: Mur, Pilar
  last_name: Mur
- first_name: José Luis
  full_name: Soto, José Luis
  last_name: Soto
- first_name: Gemma
  full_name: Aiza, Gemma
  last_name: Aiza
- first_name: Emma
  full_name: Borràs, Emma
  last_name: Borràs
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
- first_name: Alexey S.
  full_name: Kondrashov, Alexey S.
  last_name: Kondrashov
- first_name: Georgii A.
  full_name: Bazykin, Georgii A.
  last_name: Bazykin
- first_name: Laura
  full_name: Valle, Laura
  last_name: Valle
citation:
  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>
  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>.
  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.
  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.
  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>.
  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.
date_created: 2024-05-05T22:01:04Z
date_published: 2024-07-01T00:00:00Z
date_updated: 2026-04-15T08:51:09Z
day: '01'
ddc:
- '570'
department:
- _id: FyKo
doi: 10.1038/s41431-024-01598-8
ec_funded: 1
external_id:
  isi:
  - '001207703200001'
  pmid:
  - '38658779'
file:
- access_level: open_access
  checksum: e45fc987f4e9ebafdd0ec4f0e9027de4
  content_type: application/pdf
  creator: dernst
  date_created: 2025-01-09T09:21:25Z
  date_updated: 2025-01-09T09:21:25Z
  file_id: '18799'
  file_name: 2024_EJHG_Andrianova.pdf
  file_size: 3060724
  relation: main_file
  success: 1
file_date_updated: 2025-01-09T09:21:25Z
has_accepted_license: '1'
intvolume: '        32'
isi: 1
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '07'
oa: 1
oa_version: Published Version
page: 837-845
pmid: 1
project:
- _id: 9B767A34-BA93-11EA-9121-9846C619BF3A
  grant_number: '429960716'
  name: Evolution of Sensorimotor Transformation Across Diptera
- _id: 26580278-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '771209'
  name: Characterizing the fitness landscape on population and global scales
- _id: 34e076d6-11ca-11ed-8bc3-aec76c41a181
  grant_number: I05127
  name: Evolutionary analysis of gene regulation
publication: European Journal of Human Genetics
publication_identifier:
  eissn:
  - 1476-5438
  issn:
  - 1018-4813
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Discovery of recessive effect of human polymerase δ proofreading deficiency
  through mutational analysis of POLD1-mutated normal and cancer cells
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 32
year: '2024'
...
---
_id: '9910'
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.
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)."
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Sergei A.
  full_name: Slavskii, Sergei A.
  last_name: Slavskii
- first_name: Ivan A.
  full_name: Kuznetsov, Ivan A.
  last_name: Kuznetsov
- first_name: Tatiana I.
  full_name: Shashkova, Tatiana I.
  last_name: Shashkova
- first_name: Georgii A.
  full_name: Bazykin, Georgii A.
  last_name: Bazykin
- first_name: Tatiana I.
  full_name: Axenovich, Tatiana I.
  last_name: Axenovich
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
- first_name: Yurii S.
  full_name: Aulchenko, Yurii S.
  last_name: Aulchenko
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>
  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>.
  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.
date_created: 2021-08-15T22:01:28Z
date_published: 2021-07-01T00:00:00Z
date_updated: 2025-07-10T12:02:05Z
day: '01'
ddc:
- '576'
department:
- _id: FyKo
doi: 10.1038/s41431-021-00836-7
ec_funded: 1
external_id:
  isi:
  - '000625853200001'
  pmid:
  - '33664501'
file:
- access_level: open_access
  checksum: a676d76f91b0dbe0504c63e469129c2a
  content_type: application/pdf
  creator: asandaue
  date_created: 2021-08-16T09:14:36Z
  date_updated: 2021-08-16T09:14:36Z
  file_id: '9921'
  file_name: 2021_EuropeanJournalOfHumanGenetics_Slavskii.pdf
  file_size: 1079395
  relation: main_file
  success: 1
file_date_updated: 2021-08-16T09:14:36Z
has_accepted_license: '1'
intvolume: '        29'
isi: 1
issue: '7'
language:
- iso: eng
month: '07'
oa: 1
oa_version: Published Version
page: 1082-1091
pmid: 1
project:
- _id: 26580278-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '771209'
  name: Characterizing the fitness landscape on population and global scales
publication: European Journal of Human Genetics
publication_identifier:
  eissn:
  - 1476-5438
  issn:
  - 1018-4813
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: The limits of normal approximation for adult height
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 29
year: '2021'
...