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Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

Heaton MP, Kalbfleisch TS, Petrik DT, Simpson B, Kijas JW, Clawson ML, Chitko-McKown CG, Harhay GP, Leymaster KA, International Sheep Genomics Consorti - PLoS ONE (2013)

Bottom Line: Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep.Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation.A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154.

View Article: PubMed Central - PubMed

Affiliation: U.S. Meat Animal Research Center (USMARC), Clay Center, Nebraska, USA. mike.heaton@ars.usda.gov

ABSTRACT
In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

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Evidence for TMEM154 missense mutations in whole genome sequences data from an international panel of 75 sheep.Computer screen images of Integrated Genome Viewer software [18] and showing next generation sequencing reads for animals with previously unreported SNPs affecting the TMEM154 coding sequence. Numbers shown on the reads indicated the most distal identification number on the read name when viewed in the IGV software. Direct public links to these data are provided: OCAN1 F74/F74, OCAN2 F74/F74, OCAN3F74/F74, ODAL2 I74/F74, CHA02 A13/V13, BSI4 I102/T102, BSI4N70/I70, ODAL2 E31/Q31.
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pone-0055490-g003: Evidence for TMEM154 missense mutations in whole genome sequences data from an international panel of 75 sheep.Computer screen images of Integrated Genome Viewer software [18] and showing next generation sequencing reads for animals with previously unreported SNPs affecting the TMEM154 coding sequence. Numbers shown on the reads indicated the most distal identification number on the read name when viewed in the IGV software. Direct public links to these data are provided: OCAN1 F74/F74, OCAN2 F74/F74, OCAN3F74/F74, ODAL2 I74/F74, CHA02 A13/V13, BSI4 I102/T102, BSI4N70/I70, ODAL2 E31/Q31.

Mentions: The A13V variant was observed as a heterozygote in a single Changthangi sheep, a local breed in the Changthang area of Leh district of Jammu and Kashmir state (CHA02, Figure 3A). Although the A13V variant was observed in only one animal, five of the seven mapped reads contain the GTC codon for valine. This animal was also homozygous for the TMEM154 haplotype 9, suggesting that this mutation arose on a haplotype that contained the N33 mutation (Figure 2C, haplotype 13).


Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

Heaton MP, Kalbfleisch TS, Petrik DT, Simpson B, Kijas JW, Clawson ML, Chitko-McKown CG, Harhay GP, Leymaster KA, International Sheep Genomics Consorti - PLoS ONE (2013)

Evidence for TMEM154 missense mutations in whole genome sequences data from an international panel of 75 sheep.Computer screen images of Integrated Genome Viewer software [18] and showing next generation sequencing reads for animals with previously unreported SNPs affecting the TMEM154 coding sequence. Numbers shown on the reads indicated the most distal identification number on the read name when viewed in the IGV software. Direct public links to these data are provided: OCAN1 F74/F74, OCAN2 F74/F74, OCAN3F74/F74, ODAL2 I74/F74, CHA02 A13/V13, BSI4 I102/T102, BSI4N70/I70, ODAL2 E31/Q31.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569457&req=5

pone-0055490-g003: Evidence for TMEM154 missense mutations in whole genome sequences data from an international panel of 75 sheep.Computer screen images of Integrated Genome Viewer software [18] and showing next generation sequencing reads for animals with previously unreported SNPs affecting the TMEM154 coding sequence. Numbers shown on the reads indicated the most distal identification number on the read name when viewed in the IGV software. Direct public links to these data are provided: OCAN1 F74/F74, OCAN2 F74/F74, OCAN3F74/F74, ODAL2 I74/F74, CHA02 A13/V13, BSI4 I102/T102, BSI4N70/I70, ODAL2 E31/Q31.
Mentions: The A13V variant was observed as a heterozygote in a single Changthangi sheep, a local breed in the Changthang area of Leh district of Jammu and Kashmir state (CHA02, Figure 3A). Although the A13V variant was observed in only one animal, five of the seven mapped reads contain the GTC codon for valine. This animal was also homozygous for the TMEM154 haplotype 9, suggesting that this mutation arose on a haplotype that contained the N33 mutation (Figure 2C, haplotype 13).

Bottom Line: Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep.Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation.A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154.

View Article: PubMed Central - PubMed

Affiliation: U.S. Meat Animal Research Center (USMARC), Clay Center, Nebraska, USA. mike.heaton@ars.usda.gov

ABSTRACT
In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

Show MeSH
Related in: MedlinePlus