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The relative fitness of the de novo variants in general Lithuanian population vs. in individuals with intellectual disability

European Journal of Human Genetics volume 30, pages 332–338 (2022)Cite this article

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Abstract

The effect of a variant on an organism is always multifaceted and can be considered from multiple perspectives—biochemical, medical, or evolutionary. However, the relationship between the effects of amino acid substitution on protein activity, human health, and an individual’s evolutionary fitness is not trivial. We uncover that the general Lithuanian population is characterized by a “mirror reflection“ of the de novo variant fitness effect, confirming the theory of neutrality. Meanwhile, in the group of individuals with intellectual disability, compared with the reference exome de novo variants significantly changed the composition of the amino acid. Therefore, it predicts that, both in terms of the number of amino acids and changes in their relative fitness, the structure of the proteins encoded by the studied amino acids undergo significant changes following the de novo variant, leading to possible changes in protein function associated with phenotypic traits. These results suggest that the analysis of relative fitness of exome sequences with de novo variants can predict the future phenotype. Therefore even in those cases, then only a few of all functional prediction analysis tools predict a variant as damaging, the negative relative fitness or even adaptability of the genome variant should be carefully evaluated considering both its direct function and the global background of the possible disease-associated mechanism regardless of the phenotype being studied.

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Fig. 1: Distribution of relative fitness coefficient S in the genes for which the determined dnV.
Fig. 2: Summarized estimates of relative fitness in the group of the general population of Lithuania.
Fig. 3: Summarized estimates of relative fitness in the group of individuals with intellectual disability.

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Acknowledgements

The authors are grateful: to Ambrozaitytė L, Kavaliauskienė I, Domarkienė I, Meškienė R, Rančelis T for sequencing of trios exomes; to prof. Jakaitienė A who helped calculate the rate of dnVs; to dr. Preikšaitienė E for descriptions of phenotypes of patients with ID; to dr. Siavrienė E who performed functional assay and analysis of the patient’s cDNA sample (de novo variant in ARID1B gene).

Funding

This study was supported by the ANELGEMIA project, which has received funding from the Research Council of Lithuania (LMTLT), agreement No. S-MIP-20–34.

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  1. Institute of Biomedical Sciences, Department of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania

    Laura Pranckėnienė & Vaidutis Kučinskas

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  1. Laura Pranckėnienė
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  2. Vaidutis Kučinskas
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Contributions

LP performed data analysis and prepared the manuscript. VK was the principal investigator, contributed to the conception and design of the whole experiment, and critically revised the manuscript.

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Correspondence to Laura Pranckėnienė.

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Pranckėnienė, L., Kučinskas, V. The relative fitness of the de novo variants in general Lithuanian population vs. in individuals with intellectual disability. Eur J Hum Genet 30, 332–338 (2022). https://doi.org/10.1038/s41431-021-00915-9

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