vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-14vavilov-4483Research ArticleГЕНЕТИКА ЖИВОТНЫХANIMAL GENETICSАссоциация двух миссенс-мутаций в генах MSS51 и KAT6B с массой тела в разном возрасте у коров ярославской породыAssociation of two missense mutations in the MSS51 and KAT6B genes with body weight at different ages in cows of the Yaroslavl breedhttps://orcid.org/0000-0002-1896-0072ИгошинА. В.IgoshinA. V.

Новосибирск

Novosibirsk

igoshin@bionet.nsc.ruhttps://orcid.org/0000-0002-1947-5554ЮдинН. С.YudinN. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-7859-6201ЛаркинД. М.LarkinD. M.

Лондон

London

dmlarkin@gmail.comФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences,Russian FederationКоролевский ветеринарный колледжВеликобританияUniversity of London, Royal Veterinary CollegeUnited Kingdom202504032025291122127Copyright © Игошин А.В., Юдин Н.С., Ларкин Д.М., 20252025Игошин А.В., Юдин Н.С., Ларкин Д.М.Igoshin A.V., Yudin N.S., Larkin D.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4483

   Ярославская порода крупного рогатого скота – отечественная порода молочного направления продуктивности, выведенная в XIX в. на основе северного великорусского скота, адаптированного к суровому климату и скудному рациону. Ранее у животных этой породы мы обнаружили две высокочастотные почти породоспецифичные миссенс-мутации в генах MSS51 (Ala415Glu) и KAT6B (Val105Met), которые имели отрицательную связь с массой тела на выборке из 30 животных.

   Целью работы было подтверждение ассоциации миссенс-мутаций в генах MSS51 и KAT6B, а также мутантного гаплотипа, содержащего обе мутации, с живой массой в разном возрасте у коров ярославской породы на расширенной выборке животных.

   Мы генотипировали 113 коров по вышеупомянутым миссенс-вариантам и на объединенной с предыдущими данными выборке в 143 животных провели анализ ассоциаций с живой массой в возрасте 0, 6, 10, 12, 15 и 18 мес. с использованием линейной регрессии и однофакторного дисперсионного анализа. С помощью линейной регрессии для мутации в гене KAT6B были выявлены значимые ассоциации с живой массой в возрасте 6, 12 и 18 мес. Мутация в гене MSS51 была ассоциирована с живой массой в возрасте 6, 12, 15 и 18 мес. Гаплотип с обеими мутациями был ассоциирован с живой массой во всех возрастах, от 6 до 18 мес. включительно. По результатам однофакторного дисперсионного анализа значимые ассоциации живой массы с генотипами по мутации в гене KAT6B были обнаружены только в возрасте 6 мес. Для мутации в гене MSS51, как и для мутантного гаплотипа, ассоциации имелись в возрасте 6, 12, 15 и 18 мес. В обоих статистических тестах наибольшей значимости достигла ассоциация не с отдельными вариантами, а с мутантным гаплотипом. Полученные данные могут быть использованы при селекции для производства говядины за счет откормочного контингента молодняка, а также помесей ярославской породы с быками мясных пород.

   The Yaroslavl cattle is a native Russian dairy breed developed in the 19th century from the Northern Great Russian cattle, which were adapted to withstand harsh climates and poor forage conditions. Previous studies identified two breed-specific missense mutations in the MSS51 (Ala415Glu) and KAT6B (Val105Met) genes that negatively impact the body weight of the animals.

   This study aimed to confirm the association of these missense mutations in the MSS51 and KAT6B genes, along with the mutant haplotype containing both mutations, with live weight at various ages in the Yaroslavl breed using an expanded sample set.

   We genotyped 113 cows for these missense variants and analyzed their associations with live weight at birth, as well as at 6, 10, 12, 15, and 18 months in a combined sample of 143 animals, which includes earlier data. We employed linear regression and one-way ANOVA for statistical analysis. The results from linear regression indicated significant associations with live weight at 6, 12, and 18 months for the mutation in the KAT6B gene. The MSS51 gene mutation was associated with live weight at 6, 12, 15, and 18 months. Notably, the mutant haplotype was linked to live weight across all ages from 6 to 18 months. One-way ANOVA revealed significant associations of live weight with KAT6B genotypes only at 6 months. For the MSS51 gene mutation and the mutant haplotype, significant associations were found at 6, 12, 15, and 18 months. In both statistical tests, the most significant association was observed for the mutant haplotype rather than for the individual variants. These findings could be instrumental in enhancing the live weight of beef hybrids utilising the Yaroslavl cattle breed.

ярославская породаживая массавозрастген KAT6Bген MSS51миссенс-мутациягаплотипселекцияYaroslavl breedlive weightageKAT6B geneMSS51 genemissense mutationhaplotypeselectionРабота выполнена при поддержке бюджетного проекта № FWNR-2024-0012.This work was supported by State Budget Project No. FWNR-2024-0012ReferencesAbdelmanova A.S., Kharzinova V.R., Volkova V.V., Mishina A.I., Dotsev A.V., Sermyagin A.A., Boronetskaya O.I., Petrikeeva L.V., Chinarov R.Y., Brem G., Zinovieva N.A. Genetic diversity of historical and modern populations of Russian cattle breeds revealed by microsatellite analysis. Genes (Basel). 2020;11(8):940. doi: 10.3390/genes11080940Abdelmanova A.S., Kharzinova V.R., Volkova V.V., Mishina A.I., Dotsev A.V., Sermyagin A.A., Boronetskaya O.I., Petrikeeva L.V., Chinarov R.Y., Brem G., Zinovieva N.A. Genetic diversity of historical and modern populations of Russian cattle breeds revealed by microsatellite analysis. Genes (Basel). 2020;11(8):940. doi: 10.3390/genes11080940Bergamasco M.I., Abeysekera W., Garnham A.L., Hu Y., Li-Wai-Suen C.S.N., Sheikh B.N., Smyth G.K., Thomas T., Voss A.K. KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain. Life Sci Alliance. 2024a;8(2): e202402969. doi: 10.26508/lsa.202402969Bergamasco M.I., Abeysekera W., Garnham A.L., Hu Y., Li-Wai-Suen C.S.N., Sheikh B.N., Smyth G.K., Thomas T., Voss A.K. KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain. Life Sci Alliance. 2024a;8(2): e202402969. doi: 10.26508/lsa.202402969Bergamasco M.I., Vanyai H.K., Garnham A.L., Geoghegan N.D., Vogel A.P., Eccles S., Rogers K.L., Smyth G.K., Blewitt M.E., Hannan A.J., Thomas T., Voss A.K. Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice. J Clin Invest. 2024b;134(7):e167672. doi: 10.1172/JCI167672Bergamasco M.I., Vanyai H.K., Garnham A.L., Geoghegan N.D., Vogel A.P., Eccles S., Rogers K.L., Smyth G.K., Blewitt M.E., Hannan A.J., Thomas T., Voss A.K. Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice. J Clin Invest. 2024b;134(7):e167672. doi: 10.1172/JCI167672Burmistrov V.A., Pogosyan G.A., Asianin V., Golubeva A.I. Cross-breeding to thorough-bred Galloway bulls improves beef-making qualities of cattle bred in the Yaroslavl region. Molochnoye i Myasnoye Skotovodstvo = Dairy and Meat Cattle Breed. 2013;7:17-19 (in Russian)Burmistrov V.A., Pogosyan G.A., Asianin V., Golubeva A.I. Cross-breeding to thorough-bred Galloway bulls improves beef-making qualities of cattle bred in the Yaroslavl region. Molochnoye i Myasnoye Skotovodstvo = Dairy and Meat Cattle Breed. 2013;7:17-19 (in Russian)Chen S., He T., Chen J., Wen D., Wang C., Huang W., Yang Z., Yang M., Li M., Huang S., Huang Z., Zhu H. Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1. J Cachexia Sarcopenia Muscle. 2024;15(5):2104-2117. doi: 10.1002/jcsm.13558Chen S., He T., Chen J., Wen D., Wang C., Huang W., Yang Z., Yang M., Li M., Huang S., Huang Z., Zhu H. Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1. J Cachexia Sarcopenia Muscle. 2024;15(5):2104-2117. doi: 10.1002/jcsm.13558Colombi D., Perini F., Bettini S., Mastrangelo S., Abeni F., Conte G., Marletta D., Cassandro M., Bernabucci U., Ciampolini R., Lasagna E. Genomic responses to climatic challenges in beef cattle : a review. Anim Genet. 2024;55(6):854-870. doi: 10.1111/age.13474Colombi D., Perini F., Bettini S., Mastrangelo S., Abeni F., Conte G., Marletta D., Cassandro M., Bernabucci U., Ciampolini R., Lasagna E. Genomic responses to climatic challenges in beef cattle : a review. Anim Genet. 2024;55(6):854-870. doi: 10.1111/age.13474Curone G., Filipe J., Cremonesi P., Piccioli-Cappelli F., Trevisi E., Amadori M. Relevance of the dairy cow biodiversity in the development of a profitable and environmentally sustainable livestock. CABI Rev. 2019;14:1-11. doi: 10.1079/PAVSNNR201914024Curone G., Filipe J., Cremonesi P., Piccioli-Cappelli F., Trevisi E., Amadori M. Relevance of the dairy cow biodiversity in the development of a profitable and environmentally sustainable livestock. CABI Rev. 2019;14:1-11. doi: 10.1079/PAVSNNR201914024Dmitriev N.G., Ernst L.K. Animal Genetics Resources of the USSR. Rome: Food and Agriculture Organization of the United Nations, 1989Dmitriev N.G., Ernst L.K. Animal Genetics Resources of the USSR. Rome: Food and Agriculture Organization of the United Nations, 1989FAO. Status and Trends of Animal Genetic Resources. Rome: Commission on Genetic Resources for Food and Agriculture, 2024FAO. Status and Trends of Animal Genetic Resources. Rome: Commission on Genetic Resources for Food and Agriculture, 2024Gonzalez Y.I.R., Moyer A.L., LeTexier N.J., Bratti A.D., Feng S., Sun C., Liu T., Mula J., Jha P., Iyer S.R., Lovering R.M., O’Rourke B., Noh H.L., Suk S., Kim J.K., Essien Umanah G.K., Wagner K.R. Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice. JCI Insight. 2019;4(20):e122247. doi: 10.1172/jci.insight.122247Gonzalez Y.I.R., Moyer A.L., LeTexier N.J., Bratti A.D., Feng S., Sun C., Liu T., Mula J., Jha P., Iyer S.R., Lovering R.M., O’Rourke B., Noh H.L., Suk S., Kim J.K., Essien Umanah G.K., Wagner K.R. Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice. JCI Insight. 2019;4(20):e122247. doi: 10.1172/jci.insight.122247Iso-Touru T., Tapio M., Vilkki J., Kiseleva T., Ammosov I., Ivanova Z., Popov R., Ozerov M., Kantanen J. Genetic diversity and genomic signatures of selection among cattle breeds from Siberia, eastern and northern Europe. Anim Genet. 2016;47(6):647-657. doi: 10.1111/age.12473Iso-Touru T., Tapio M., Vilkki J., Kiseleva T., Ammosov I., Ivanova Z., Popov R., Ozerov M., Kantanen J. Genetic diversity and genomic signatures of selection among cattle breeds from Siberia, eastern and northern Europe. Anim Genet. 2016;47(6):647-657. doi: 10.1111/age.12473Kochetkov A.A. Use of world and Russian breed resources of beef cattle to increase the production of high-quality meat in the North Caucasus and the central zone of Russia: Dr. (Agricultural Sci.) Dissertation. 2011 (in Russian)Kochetkov A.A. Use of world and Russian breed resources of beef cattle to increase the production of high-quality meat in the North Caucasus and the central zone of Russia: Dr. (Agricultural Sci.) Dissertation. 2011 (in Russian)Korenev M.M., Furaeva N.S., Khrustaleva V.I., Ursol A.Yu., Vorobyova S.S., Konovalov A.V., Kosyachenko N.M., Ilyina A.V., Muratova N.S., Gvazava D.G., Tarasenkova N.A., Malyukova M.A. Breeding Measures for the Preservation and Improvement of the Yaroslavl Cattle Breed for 2013–2020. Yaroslavl: Kantsler Publ., 2013 (in Russian)Korenev M.M., Furaeva N.S., Khrustaleva V.I., Ursol A.Yu., Vorobyova S.S., Konovalov A.V., Kosyachenko N.M., Ilyina A.V., Muratova N.S., Gvazava D.G., Tarasenkova N.A., Malyukova M.A. Breeding Measures for the Preservation and Improvement of the Yaroslavl Cattle Breed for 2013–2020. Yaroslavl: Kantsler Publ., 2013 (in Russian)Lu G., Moriyama E.N. Vector NTI, a balanced all-in-one sequence analysis suite. Brief Bioinform. 2004;5(4):378-388. doi: 10.1093/bib/5.4.378Lu G., Moriyama E.N. Vector NTI, a balanced all-in-one sequence analysis suite. Brief Bioinform. 2004;5(4):378-388. doi: 10.1093/bib/5.4.378Monoenkov M.I. Yaroslavl Breed of Cattle. Yaroslavl, 1974 (in Russian)Monoenkov M.I. Yaroslavl Breed of Cattle. Yaroslavl, 1974 (in Russian)Moyer A.L., Wagner K.R. Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism. J Neuromuscul Dis. 2015;2(4):371-385. doi: 10.3233/JND-150119Moyer A.L., Wagner K.R. Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism. J Neuromuscul Dis. 2015;2(4):371-385. doi: 10.3233/JND-150119Ota M., Fukushima H., Kulski J.K., Inoko H. Single nucleotide polymorphism detection by polymerase chain reaction-restriction fragment length polymorphism. Nat Protoc. 2007;2(11):2857-2864. doi: 10.1038/nprot.2007.407Ota M., Fukushima H., Kulski J.K., Inoko H. Single nucleotide polymorphism detection by polymerase chain reaction-restriction fragment length polymorphism. Nat Protoc. 2007;2(11):2857-2864. doi: 10.1038/nprot.2007.407Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira M.A.R., Bender D., Maller J., Sklar P., de Bakker P.I.W., Daly M.J., Sham P.C. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575. doi: 10.1086/519795Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira M.A.R., Bender D., Maller J., Sklar P., de Bakker P.I.W., Daly M.J., Sham P.C. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575. doi: 10.1086/519795Ruvinskiy D., Igoshin A., Yurchenko A., Ilina A.V., Larkin D.M. Resequencing the Yaroslavl cattle genomes reveals signatures of selection and a rare haplotype on BTA28 likely to be related to breed phenotypes. Anim Genet. 2022;53(5):680-684. doi: 10.1111/age.13230Ruvinskiy D., Igoshin A., Yurchenko A., Ilina A.V., Larkin D.M. Resequencing the Yaroslavl cattle genomes reveals signatures of selection and a rare haplotype on BTA28 likely to be related to breed phenotypes. Anim Genet. 2022;53(5):680-684. doi: 10.1111/age.13230Sambrook J., Russell D.W. The Condensed Protocols from Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, 2006Sambrook J., Russell D.W. The Condensed Protocols from Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, 2006Tamarova R.V. Will we save our Yaroslavl wet nurse? On the 140<sup>th</sup> anniversary of the creation of the Yaroslavl breed. Vestnik APK Verkhnevolzh’ya = Agroindustrial Complex of Upper Volga Region Herald. 2009;3(7):20-23 (in Russian)Tamarova R.V. Will we save our Yaroslavl wet nurse? On the 140<sup>th</sup> anniversary of the creation of the Yaroslavl breed. Vestnik APK Verkhnevolzh’ya = Agroindustrial Complex of Upper Volga Region Herald. 2009;3(7):20-23 (in Russian)van der Heide E.M.M., Lourenco D.A.L., Chen C.Y., Herring W.O., Sapp R.L., Moser D.W., Tsuruta S., Masuda Y., Ducro B.J., Misztal I. Sexual dimorphism in livestock species selected for economically important traits. J Anim Sci. 2016;94(9):3684-3692. doi: 10.2527/jas.2016-0393van der Heide E.M.M., Lourenco D.A.L., Chen C.Y., Herring W.O., Sapp R.L., Moser D.W., Tsuruta S., Masuda Y., Ducro B.J., Misztal I. Sexual dimorphism in livestock species selected for economically important traits. J Anim Sci. 2016;94(9):3684-3692. doi: 10.2527/jas.2016-0393Ye J., Coulouris G., Zaretskaya I., Cutcutache I., Rozen S., Madden T.L. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13:134. doi: 10.1186/1471-2105-13-134Ye J., Coulouris G., Zaretskaya I., Cutcutache I., Rozen S., Madden T.L. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13:134. doi: 10.1186/1471-2105-13-134Yudin N.S., Larkin D.M. Whole genome studies of origin, selection and adaptation of the Russian cattle breeds. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov J Genet Breed. 2019;23(5):559-568. doi: 10.18699/VJ19.525 (in Russian)Yudin N.S., Larkin D.M. Whole genome studies of origin, selection and adaptation of the Russian cattle breeds. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov J Genet Breed. 2019;23(5):559-568. doi: 10.18699/VJ19.525 (in Russian)Yurchenko A., Yudin N., Aitnazarov R., Plyusnina A., Brukhin V., Soloshenko V., Lhasaranov B., Popov R., Paronyan I.A., Plemyashov K.V., Larkin D.M. Genome-wide genotyping uncovers genetic profiles and history of the Russian cattle breeds. Heredity (Edinb). 2018;120(2):125-137. doi: 10.1038/s41437-017-0024-3Yurchenko A., Yudin N., Aitnazarov R., Plyusnina A., Brukhin V., Soloshenko V., Lhasaranov B., Popov R., Paronyan I.A., Plemyashov K.V., Larkin D.M. Genome-wide genotyping uncovers genetic profiles and history of the Russian cattle breeds. Heredity (Edinb). 2018;120(2):125-137. doi: 10.1038/s41437-017-0024-3Zhang L.X., Lemire G., Gonzaga-Jauregui C., Molidperee S., Galaz-Montoya C., Liu D.S., Verloes A., … Bamshad M.J., Lee B.H., Yang X.-J., Lupski J.R., Campeau P.M. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants. Genet Med. 2020;22(8):1338-1347. doi: 10.1038/s41436-020-0811-8Zhang L.X., Lemire G., Gonzaga-Jauregui C., Molidperee S., Galaz-Montoya C., Liu D.S., Verloes A., … Bamshad M.J., Lee B.H., Yang X.-J., Lupski J.R., Campeau P.M. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants. Genet Med. 2020;22(8):1338-1347. doi: 10.1038/s41436-020-0811-8Zhu L., Lv L., Wu D., Shao J. KAT6B genetic variant identified in a short stature chinese infant: a report of physical growth in clinical spectrum of KAT6B-related disorders. Front Pediatr. 2020;8:124. doi: 10.3389/fped.2020.00124Zhu L., Lv L., Wu D., Shao J. KAT6B genetic variant identified in a short stature chinese infant: a report of physical growth in clinical spectrum of KAT6B-related disorders. Front Pediatr. 2020;8:124. doi: 10.3389/fped.2020.00124

The authors declare that there are no conflicts of interest present.