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Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.

Paskulin DD, Giacomazzi J, Achatz MI, Costa S, Reis RM, Hainaut P, dos Santos SE, Ashton-Prolla P - PLoS ONE (2015)

Bottom Line: A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil.So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin.Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

View Article: PubMed Central - PubMed

Affiliation: Post-Graduate Program, Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

ABSTRACT
Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

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Related in: MedlinePlus

Age estimation for the p.Arg337His mutation as assessed by DMLE+2.3.Green lines show 95% CIs.
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pone.0143262.g002: Age estimation for the p.Arg337His mutation as assessed by DMLE+2.3.Green lines show 95% CIs.

Mentions: To establish the correct haplotype in which the p.Arg337His allele is present, we used genotype data from the nine STRs analyzed in twelve trios. Observed haplotypes of individuals carrying the p.Arg337His allele are shown in Table 2. Analysis of the nine STR markers in twelve trios using the ESTIAGE software revealed that all extended haplotypes carrying the p.Arg337His mutation included in this study derive from a common ancestor haplotype which was introduced in the population 84 generations ago (95% CI: 54–135). For estimating the generation distance using the DMLE+2.3 software, the haplotype frequencies from the Portuguese control population were constructed using ARLEQUIN as a reference. Analysis of linkage disequilibrium in carriers and non-carriers estimated that the p.Arg337His mutation was present on a haplotype that might have been introduced 72 generations ago (95% CI 50–105) (Fig 2). Based on these two approaches and using a pre-established 25-year intergeneration interval, the age of the TP53 p.Arg337His mutation appears to be of approximately of 2000 years.


Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.

Paskulin DD, Giacomazzi J, Achatz MI, Costa S, Reis RM, Hainaut P, dos Santos SE, Ashton-Prolla P - PLoS ONE (2015)

Age estimation for the p.Arg337His mutation as assessed by DMLE+2.3.Green lines show 95% CIs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664269&req=5

pone.0143262.g002: Age estimation for the p.Arg337His mutation as assessed by DMLE+2.3.Green lines show 95% CIs.
Mentions: To establish the correct haplotype in which the p.Arg337His allele is present, we used genotype data from the nine STRs analyzed in twelve trios. Observed haplotypes of individuals carrying the p.Arg337His allele are shown in Table 2. Analysis of the nine STR markers in twelve trios using the ESTIAGE software revealed that all extended haplotypes carrying the p.Arg337His mutation included in this study derive from a common ancestor haplotype which was introduced in the population 84 generations ago (95% CI: 54–135). For estimating the generation distance using the DMLE+2.3 software, the haplotype frequencies from the Portuguese control population were constructed using ARLEQUIN as a reference. Analysis of linkage disequilibrium in carriers and non-carriers estimated that the p.Arg337His mutation was present on a haplotype that might have been introduced 72 generations ago (95% CI 50–105) (Fig 2). Based on these two approaches and using a pre-established 25-year intergeneration interval, the age of the TP53 p.Arg337His mutation appears to be of approximately of 2000 years.

Bottom Line: A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil.So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin.Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

View Article: PubMed Central - PubMed

Affiliation: Post-Graduate Program, Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

ABSTRACT
Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

Show MeSH
Related in: MedlinePlus