--- OA_type: closed access _id: '882' abstract: - lang: eng text: Some mutations in human mitochondrial tRNAs are severely pathogenic. The available computational methods have a poor record of predicting the impact of a tRNA mutation on the phenotype and fitness. Here patterns of evolution at tRNA sites that harbor pathogenic mutations and at sites that harbor phenotypically cryptic polymorphisms were compared. Mutations that are pathogenic to humans occupy more conservative sites, are only rarely fixed in closely related species, and, when located in stem structures, often disrupt Watson-Crick pairing and display signs of compensatory evolution. These observations make it possible to classify ∼90% of all known pathogenic mutations as deleterious together with only ∼30% of polymorphisms. These polymorphisms segregate at frequencies that are more than two times lower than frequencies of polymorphisms classified as benign, indicating that at least ∼30% of known polymorphisms in mitochondrial tRNAs affect fitness negatively. acknowledgement: "The author thanks P. Andolfatto, D. Bachtrog, N. Esipova, S. Makeev, A. Kondrashov, V. Ramensky, V. Tumanyan and P. Vlasov for a critical reading of the manuscript. The author is an NSF Graduate Research Fellow. This work was supported by a Contract of the Russian Ministry of Science and Education (02.434.11.1008) and a grant on Molecular and Cellular Biology from RAS.\r\n" article_processing_charge: No article_type: original author: - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Kondrashov F. Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Human Molecular Genetics. 2005;14(16):2415-2419. doi:10.1093/hmg/ddi243 apa: Kondrashov, F. (2005). Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Human Molecular Genetics. Oxford University Press. https://doi.org/10.1093/hmg/ddi243 chicago: Kondrashov, Fyodor. “Prediction of Pathogenic Mutations in Mitochondrially Encoded Human TRNAs.” Human Molecular Genetics. Oxford University Press, 2005. https://doi.org/10.1093/hmg/ddi243. ieee: F. Kondrashov, “Prediction of pathogenic mutations in mitochondrially encoded human tRNAs,” Human Molecular Genetics, vol. 14, no. 16. Oxford University Press, pp. 2415–2419, 2005. ista: Kondrashov F. 2005. Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Human Molecular Genetics. 14(16), 2415–2419. mla: Kondrashov, Fyodor. “Prediction of Pathogenic Mutations in Mitochondrially Encoded Human TRNAs.” Human Molecular Genetics, vol. 14, no. 16, Oxford University Press, 2005, pp. 2415–19, doi:10.1093/hmg/ddi243. short: F. Kondrashov, Human Molecular Genetics 14 (2005) 2415–2419. date_created: 2018-12-11T11:49:00Z date_published: 2005-08-15T00:00:00Z date_updated: 2026-08-14T11:46:18Z day: '15' doi: 10.1093/hmg/ddi243 extern: '1' external_id: pmid: - '16014637' fulldoi: https://doi.org/10.1093/hmg/ddi243 intvolume: ' 14' issue: '16' language: - iso: eng month: '08' oa_version: None page: 2415 - 2419 pmid: 1 publication: Human Molecular Genetics publication_identifier: eissn: - 1460-2083 issn: - 0964-6906 publication_status: published publisher: Oxford University Press publist_id: '6767' status: public title: Prediction of pathogenic mutations in mitochondrially encoded human tRNAs type: journal_article user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345 volume: 14 year: '2005' ... --- OA_type: closed access _id: '843' abstract: - lang: eng text: The impact of an amino acid replacement on the organism's fitness can vary from lethal to selectively neutral and even, in rare cases, beneficial. Substantial data are available on either pathogenic or acceptable replacements. However, the whole distribution of coefficients of selection against individual replacements is not known for any organism. To ascertain this distribution for human proteins, we combined data on pathogenic missense mutations, on human non-synonymous SNPs and on human-chimpanzee divergence of orthologous proteins. Fractions of amino acid replacements which reduce fitness by >10-2, 10-2-10-4, 10-4-10-5 and <10-5 are 25, 49, 14 and 12%, respectively. On average, the strength of selection against a replacement is substantially higher when chemically dissimilar amino acids are involved, and the Grantham's index of a replacement explains 35% of variance in the average logarithm of selection coefficients associated with different replacements. Still, the impact of a replacement depends on its context within the protein more than on its own nature. Reciprocal replacements are often associated with rather different selection coefficients, in particular, replacements of non-polar amino acids with polar ones are typically much more deleterious than replacements in the opposite direction. However, differences between evolutionary fluxes of reciprocal replacements are only weakly correlated with the differences between the corresponding selection coefficients. article_processing_charge: No article_type: original author: - first_name: Lev full_name: Yampolsky, Lev last_name: Yampolsky - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 - first_name: Alexey full_name: Kondrashov, Alexey last_name: Kondrashov citation: ama: Yampolsky L, Kondrashov F, Kondrashov A. Distribution of the strength of selection against amino acid replacements in human proteins. Human Molecular Genetics. 2005;14(21):3191-3201. doi:10.1093/hmg/ddi350 apa: Yampolsky, L., Kondrashov, F., & Kondrashov, A. (2005). Distribution of the strength of selection against amino acid replacements in human proteins. Human Molecular Genetics. Oxford University Press. https://doi.org/10.1093/hmg/ddi350 chicago: Yampolsky, Lev, Fyodor Kondrashov, and Alexey Kondrashov. “Distribution of the Strength of Selection against Amino Acid Replacements in Human Proteins.” Human Molecular Genetics. Oxford University Press, 2005. https://doi.org/10.1093/hmg/ddi350. ieee: L. Yampolsky, F. Kondrashov, and A. Kondrashov, “Distribution of the strength of selection against amino acid replacements in human proteins,” Human Molecular Genetics, vol. 14, no. 21. Oxford University Press, pp. 3191–3201, 2005. ista: Yampolsky L, Kondrashov F, Kondrashov A. 2005. Distribution of the strength of selection against amino acid replacements in human proteins. Human Molecular Genetics. 14(21), 3191–3201. mla: Yampolsky, Lev, et al. “Distribution of the Strength of Selection against Amino Acid Replacements in Human Proteins.” Human Molecular Genetics, vol. 14, no. 21, Oxford University Press, 2005, pp. 3191–201, doi:10.1093/hmg/ddi350. short: L. Yampolsky, F. Kondrashov, A. Kondrashov, Human Molecular Genetics 14 (2005) 3191–3201. date_created: 2018-12-11T11:48:48Z date_published: 2005-11-01T00:00:00Z date_updated: 2026-08-14T12:13:44Z day: '01' doi: 10.1093/hmg/ddi350 extern: '1' external_id: pmid: - '16174645' fulldoi: https://doi.org/10.1093/hmg/ddi350 intvolume: ' 14' issue: '21' language: - iso: eng month: '11' oa_version: None page: 3191 - 3201 pmid: 1 publication: Human Molecular Genetics publication_identifier: eissn: - 1460-2083 issn: - 0964-6906 publication_status: published publisher: Oxford University Press publist_id: '6807' status: public title: Distribution of the strength of selection against amino acid replacements in human proteins type: journal_article user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345 volume: 14 year: '2005' ... --- OA_type: closed access _id: '847' abstract: - lang: eng text: The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed. acknowledgement: We are grateful to Alexey Kondrashov and Alison Wellman for the careful reading of the manuscript and providing us with their valuable comments. article_processing_charge: No article_type: original author: - first_name: Shamil full_name: Sunyaev, Shamil last_name: Sunyaev - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 - first_name: Peer full_name: Bork, Peer last_name: Bork - first_name: Vasily full_name: Ramensky, Vasily last_name: Ramensky citation: ama: Sunyaev S, Kondrashov F, Bork P, Ramensky V. Impact of selection, mutation rate and genetic drift on human genetic variation. Human Molecular Genetics. 2003;12(24):3325-3330. doi:10.1093/hmg/ddg359 apa: Sunyaev, S., Kondrashov, F., Bork, P., & Ramensky, V. (2003). Impact of selection, mutation rate and genetic drift on human genetic variation. Human Molecular Genetics. Oxford Academic. https://doi.org/10.1093/hmg/ddg359 chicago: Sunyaev, Shamil, Fyodor Kondrashov, Peer Bork, and Vasily Ramensky. “Impact of Selection, Mutation Rate and Genetic Drift on Human Genetic Variation.” Human Molecular Genetics. Oxford Academic, 2003. https://doi.org/10.1093/hmg/ddg359. ieee: S. Sunyaev, F. Kondrashov, P. Bork, and V. Ramensky, “Impact of selection, mutation rate and genetic drift on human genetic variation,” Human Molecular Genetics, vol. 12, no. 24. Oxford Academic, pp. 3325–3330, 2003. ista: Sunyaev S, Kondrashov F, Bork P, Ramensky V. 2003. Impact of selection, mutation rate and genetic drift on human genetic variation. Human Molecular Genetics. 12(24), 3325–3330. mla: Sunyaev, Shamil, et al. “Impact of Selection, Mutation Rate and Genetic Drift on Human Genetic Variation.” Human Molecular Genetics, vol. 12, no. 24, Oxford Academic, 2003, pp. 3325–30, doi:10.1093/hmg/ddg359. short: S. Sunyaev, F. Kondrashov, P. Bork, V. Ramensky, Human Molecular Genetics 12 (2003) 3325–3330. date_created: 2018-12-11T11:48:49Z date_published: 2003-12-15T00:00:00Z date_updated: 2026-05-28T14:13:45Z day: '15' doi: 10.1093/hmg/ddg359 extern: '1' external_id: pmid: - '14570704 ' fulldoi: https://doi.org/10.1093/hmg/ddg359 intvolume: ' 12' issue: '24' language: - iso: eng month: '12' oa_version: None page: 3325 - 3330 pmid: 1 publication: Human Molecular Genetics publication_identifier: eissn: - 1460-2083 issn: - 0964-6906 publication_status: published publisher: Oxford Academic publist_id: '6803' quality_controlled: '1' scopus_import: '1' status: public title: Impact of selection, mutation rate and genetic drift on human genetic variation type: journal_article user_id: ba8df636-2132-11f1-aed0-ed93e2281fdd volume: 12 year: '2003' ...