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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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Estimating the frequency of highly-susceptible TMEM154 alleles in global sheep populations.The “c” allele of SNP OAR17_5388531 is in linkage disequilibrium with the “g” nucleotide allele in codon 35 (gaa) of TMEM154. Genotypes for OAR17_5388531 were derived from the ISGC ovine SNP50k data set [11]. Numbers in parentheses for each breed group indicate the number of animals genotyped. The 11 breed groups with asterisks were genotyped for TMEM154 E35 by Sanger sequencing [9] and were included for comparison with the 74 ISGC breed groups.
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pone-0055490-g001: Estimating the frequency of highly-susceptible TMEM154 alleles in global sheep populations.The “c” allele of SNP OAR17_5388531 is in linkage disequilibrium with the “g” nucleotide allele in codon 35 (gaa) of TMEM154. Genotypes for OAR17_5388531 were derived from the ISGC ovine SNP50k data set [11]. Numbers in parentheses for each breed group indicate the number of animals genotyped. The 11 breed groups with asterisks were genotyped for TMEM154 E35 by Sanger sequencing [9] and were included for comparison with the 74 ISGC breed groups.

Mentions: In a collection of 2,759 sheep DNAs from 74 breeds from around the world, the frequency of the “c” nucleotide allele of the c/t SNP OAR17_5388531 ranged from 0.0 to 1.0 with a mean of 0.51 and median of 0.50 among breeds (Figure 1). Breed groups with the highest “c” allele frequencies are predicted to have high frequencies of TMEM154 E35 (haplotypes 2 and 3) and larger proportions of highly-susceptible animals. Conversely, breed groups with low “c” allele frequencies are predicted to have more homozygous K35 animals (haplotype 1) and be less susceptible to OPPV. The results indicated that the highly-susceptible TMEM154 alleles are present in breeds throughout the world.


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)

Estimating the frequency of highly-susceptible TMEM154 alleles in global sheep populations.The “c” allele of SNP OAR17_5388531 is in linkage disequilibrium with the “g” nucleotide allele in codon 35 (gaa) of TMEM154. Genotypes for OAR17_5388531 were derived from the ISGC ovine SNP50k data set [11]. Numbers in parentheses for each breed group indicate the number of animals genotyped. The 11 breed groups with asterisks were genotyped for TMEM154 E35 by Sanger sequencing [9] and were included for comparison with the 74 ISGC breed groups.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0055490-g001: Estimating the frequency of highly-susceptible TMEM154 alleles in global sheep populations.The “c” allele of SNP OAR17_5388531 is in linkage disequilibrium with the “g” nucleotide allele in codon 35 (gaa) of TMEM154. Genotypes for OAR17_5388531 were derived from the ISGC ovine SNP50k data set [11]. Numbers in parentheses for each breed group indicate the number of animals genotyped. The 11 breed groups with asterisks were genotyped for TMEM154 E35 by Sanger sequencing [9] and were included for comparison with the 74 ISGC breed groups.
Mentions: In a collection of 2,759 sheep DNAs from 74 breeds from around the world, the frequency of the “c” nucleotide allele of the c/t SNP OAR17_5388531 ranged from 0.0 to 1.0 with a mean of 0.51 and median of 0.50 among breeds (Figure 1). Breed groups with the highest “c” allele frequencies are predicted to have high frequencies of TMEM154 E35 (haplotypes 2 and 3) and larger proportions of highly-susceptible animals. Conversely, breed groups with low “c” allele frequencies are predicted to have more homozygous K35 animals (haplotype 1) and be less susceptible to OPPV. The results indicated that the highly-susceptible TMEM154 alleles are present in breeds throughout the world.

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