@article{15362,
  abstract     = {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.},
  author       = {Andrianova, Maria A. and Seplyarskiy, Vladimir B. and Terradas, Mariona and Sánchez-Heras, Ana Beatriz and Mur, Pilar and Soto, José Luis and Aiza, Gemma and Borràs, Emma and Kondrashov, Fyodor and Kondrashov, Alexey S. and Bazykin, Georgii A. and Valle, Laura},
  issn         = {1476-5438},
  journal      = {European Journal of Human Genetics},
  pages        = {837--845},
  publisher    = {Springer Nature},
  title        = {{Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells}},
  doi          = {10.1038/s41431-024-01598-8},
  volume       = {32},
  year         = {2024},
}

@article{9910,
  abstract     = {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.},
  author       = {Slavskii, Sergei A. and Kuznetsov, Ivan A. and Shashkova, Tatiana I. and Bazykin, Georgii A. and Axenovich, Tatiana I. and Kondrashov, Fyodor and Aulchenko, Yurii S.},
  issn         = {1476-5438},
  journal      = {European Journal of Human Genetics},
  number       = {7},
  pages        = {1082--1091},
  publisher    = {Springer Nature},
  title        = {{The limits of normal approximation for adult height}},
  doi          = {10.1038/s41431-021-00836-7},
  volume       = {29},
  year         = {2021},
}