Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability
Abstract Background Recessive deleterious variants are known to segregate in livestock populations, as in humans, and some may be lethal in the homozygous state. Results We used phased 50 k single nucleotide polymorphism (SNP) genotypes and pedigree data to scan the genome of 6845 Manech Tête Rousse...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | deu |
| Published: |
BMC
2024-02-01
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| Series: | Genetics Selection Evolution |
| Online Access: | https://doi.org/10.1186/s12711-024-00886-7 |
| _version_ | 1797276193613938688 |
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| author | Maxime Ben Braiek Carole Moreno-Romieux Céline André Jean-Michel Astruc Philippe Bardou Arnaud Bordes Frédéric Debat Francis Fidelle Itsasne Granado-Tajada Chris Hozé Florence Plisson-Petit François Rivemale Julien Sarry Némuel Tadi Florent Woloszyn Stéphane Fabre |
| author_facet | Maxime Ben Braiek Carole Moreno-Romieux Céline André Jean-Michel Astruc Philippe Bardou Arnaud Bordes Frédéric Debat Francis Fidelle Itsasne Granado-Tajada Chris Hozé Florence Plisson-Petit François Rivemale Julien Sarry Némuel Tadi Florent Woloszyn Stéphane Fabre |
| author_sort | Maxime Ben Braiek |
| collection | DOAJ |
| description | Abstract Background Recessive deleterious variants are known to segregate in livestock populations, as in humans, and some may be lethal in the homozygous state. Results We used phased 50 k single nucleotide polymorphism (SNP) genotypes and pedigree data to scan the genome of 6845 Manech Tête Rousse dairy sheep to search for deficiency in homozygous haplotypes (DHH). Five Manech Tête Rousse deficient homozygous haplotypes (MTRDHH1 to 5) were identified, with a homozygous deficiency ranging from 84 to 100%. These haplotypes are located on Ovis aries chromosome (OAR)1 (MTRDHH2 and 3), OAR10 (MTRDHH4), OAR13 (MTRDHH5), and OAR20 (MTRDHH1), and have carrier frequencies ranging from 7.8 to 16.6%. When comparing at-risk matings between DHH carriers to safe matings between non-carriers, two DHH (MTRDHH1 and 2) were linked with decreased insemination success and/or increased stillbirth incidence. We investigated the MTRDHH1 haplotype, which substantially increased stillbirth rate, and identified a single nucleotide variant (SNV) inducing a premature stop codon (p.Gln409*) in the methylmalonyl-CoA mutase (MMUT) gene by using a whole-genome sequencing approach. We generated homozygous lambs for the MMUT mutation by at-risk mating between heterozygous carriers, and most of them died within the first 24 h after birth without any obvious clinical symptoms. Reverse transcriptase-qPCR and western blotting on post-mortem liver and kidney biological samples showed a decreased expression of MMUT mRNA in the liver and absence of a full-length MMUT protein in the mutant homozygous lambs. Conclusions We identified five homozygous deficient haplotypes that are likely to harbor five independent deleterious recessive variants in sheep. One of these was detected in the MMUT gene, which is associated with lamb lethality in the homozygous state. A specific management of these haplotypes/variants in the MTR dairy sheep selection program would help enhance the overall fertility and lamb survival. |
| first_indexed | 2024-03-07T15:23:57Z |
| format | Article |
| id | doaj.art-7b1755e444a340379fc3b8e77ff22cc4 |
| institution | Directory Open Access Journal |
| issn | 1297-9686 |
| language | deu |
| last_indexed | 2024-03-07T15:23:57Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genetics Selection Evolution |
| spelling | doaj.art-7b1755e444a340379fc3b8e77ff22cc42024-03-05T17:25:05ZdeuBMCGenetics Selection Evolution1297-96862024-02-0156111610.1186/s12711-024-00886-7Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viabilityMaxime Ben Braiek0Carole Moreno-Romieux1Céline André2Jean-Michel Astruc3Philippe Bardou4Arnaud Bordes5Frédéric Debat6Francis Fidelle7Itsasne Granado-Tajada8Chris Hozé9Florence Plisson-Petit10François Rivemale11Julien Sarry12Némuel Tadi13Florent Woloszyn14Stéphane Fabre15GenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTCDEOInstitut de l’ElevageINRAEGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTCDEODepartment of Animal Production, NEIKER-BRTA Basque Institute of Agricultural Research and DevelopmentElianceGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTGenPhySE, Université de Toulouse, INRAE, ENVTAbstract Background Recessive deleterious variants are known to segregate in livestock populations, as in humans, and some may be lethal in the homozygous state. Results We used phased 50 k single nucleotide polymorphism (SNP) genotypes and pedigree data to scan the genome of 6845 Manech Tête Rousse dairy sheep to search for deficiency in homozygous haplotypes (DHH). Five Manech Tête Rousse deficient homozygous haplotypes (MTRDHH1 to 5) were identified, with a homozygous deficiency ranging from 84 to 100%. These haplotypes are located on Ovis aries chromosome (OAR)1 (MTRDHH2 and 3), OAR10 (MTRDHH4), OAR13 (MTRDHH5), and OAR20 (MTRDHH1), and have carrier frequencies ranging from 7.8 to 16.6%. When comparing at-risk matings between DHH carriers to safe matings between non-carriers, two DHH (MTRDHH1 and 2) were linked with decreased insemination success and/or increased stillbirth incidence. We investigated the MTRDHH1 haplotype, which substantially increased stillbirth rate, and identified a single nucleotide variant (SNV) inducing a premature stop codon (p.Gln409*) in the methylmalonyl-CoA mutase (MMUT) gene by using a whole-genome sequencing approach. We generated homozygous lambs for the MMUT mutation by at-risk mating between heterozygous carriers, and most of them died within the first 24 h after birth without any obvious clinical symptoms. Reverse transcriptase-qPCR and western blotting on post-mortem liver and kidney biological samples showed a decreased expression of MMUT mRNA in the liver and absence of a full-length MMUT protein in the mutant homozygous lambs. Conclusions We identified five homozygous deficient haplotypes that are likely to harbor five independent deleterious recessive variants in sheep. One of these was detected in the MMUT gene, which is associated with lamb lethality in the homozygous state. A specific management of these haplotypes/variants in the MTR dairy sheep selection program would help enhance the overall fertility and lamb survival.https://doi.org/10.1186/s12711-024-00886-7 |
| spellingShingle | Maxime Ben Braiek Carole Moreno-Romieux Céline André Jean-Michel Astruc Philippe Bardou Arnaud Bordes Frédéric Debat Francis Fidelle Itsasne Granado-Tajada Chris Hozé Florence Plisson-Petit François Rivemale Julien Sarry Némuel Tadi Florent Woloszyn Stéphane Fabre Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability Genetics Selection Evolution |
| title | Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability |
| title_full | Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability |
| title_fullStr | Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability |
| title_full_unstemmed | Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability |
| title_short | Searching for homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant in the MMUT gene affecting newborn lamb viability |
| title_sort | searching for homozygous haplotype deficiency in manech tete rousse dairy sheep revealed a nonsense variant in the mmut gene affecting newborn lamb viability |
| url | https://doi.org/10.1186/s12711-024-00886-7 |
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