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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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Short Tandem Repeats position used for haplotype analysis and their respective position in chromosome 17p.
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pone.0143262.g001: Short Tandem Repeats position used for haplotype analysis and their respective position in chromosome 17p.

Mentions: Genomic DNA was extracted from peripheral blood leukocytes using the Ilustra blood genomic Prep Mini spin Kit (GE Healthcare, Piscataway, NJ, USA) as described by the manufacturer. DNA concentration was measured with Nano-Drop 1000 (Thermo Fisher Scientific, Waltham, MA, USA) and diluted to a final concentration of 10 ng/μl. Direct sequencing of TP53 exons 2 to 11 and flanking splice site junctions was performed in all members of the trios as previously described [24]. For haplotype analysis, we selected nine short tandem repeat (STRs) markers spanning a region of 8Mb extending on both sides of the TP53 gene at 17p13 (Fig 1). STR1 to STR9 markers were PCR amplified using fluorescently end-labeled primers (Table 1), analyzed on an ABI3130 DNA analyzer and scored using ABI GeneScan Analysis Software (Thermo Fisher Scientific, Waltham,MA, USA).


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)

Short Tandem Repeats position used for haplotype analysis and their respective position in chromosome 17p.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143262.g001: Short Tandem Repeats position used for haplotype analysis and their respective position in chromosome 17p.
Mentions: Genomic DNA was extracted from peripheral blood leukocytes using the Ilustra blood genomic Prep Mini spin Kit (GE Healthcare, Piscataway, NJ, USA) as described by the manufacturer. DNA concentration was measured with Nano-Drop 1000 (Thermo Fisher Scientific, Waltham, MA, USA) and diluted to a final concentration of 10 ng/μl. Direct sequencing of TP53 exons 2 to 11 and flanking splice site junctions was performed in all members of the trios as previously described [24]. For haplotype analysis, we selected nine short tandem repeat (STRs) markers spanning a region of 8Mb extending on both sides of the TP53 gene at 17p13 (Fig 1). STR1 to STR9 markers were PCR amplified using fluorescently end-labeled primers (Table 1), analyzed on an ABI3130 DNA analyzer and scored using ABI GeneScan Analysis Software (Thermo Fisher Scientific, Waltham,MA, USA).

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