The diversity profile of TP53 is influenced by positive selection on the immediately upstream locus WDR79.
OBJECTIVE
TP53 is an efficient central node in a signal transduction network that responds to minimize cancer. However, over 50% of tumors show some mutation in TP53. Thus, one might argue that this single central node network lacks robustness. Therefore, we wanted to investigate if natural selection has played a role in shaping the genomic region containing TP53.


METHODS
We have analyzed the HapMap data for evidence of selection using F(ST) pairwise comparisons and the extended haplotype homozygosity test on a 200-kb region encompassing TP53. We have also resequenced 4 kb upstream TP53 in Europeans (including melanoma patients), Asians, Australian Aborigines and Africans.


RESULTS
Genetic hitchhiking by a linked, positively selected allele at the nearby gene WDR79 may be partly responsible for the sequence diversity profile of TP53. It can help explain why the TP53 Arg72 allele is the major allele in Europeans even when the alternative allele, 72Pro, has been reported to offer an increased longevity after disease.


CONCLUSIONS
Despite the important role of TP53, a complex interplay with other evolutionary forces, which are extrinsic to TP53 function, may have driven the genetic diversity pattern of this locus, and, as a consequence, its structure and function.
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Barrio Sarriena s/n, ES-48940 Leioa, Bizkaia, Spain. santos.alonso@ehu.es
Santos
S
Alonso
Neskuts
N
Izagirre
Saioa
S
López
Isabel
I
Smith-Zubiaga
Montse
M
Hervella
María Dolores
MD
Boyano
Yoana
Y
Arroyo-Berdugo
Jesús
J
Gardeazabal
José Luís
JL
Díaz-Ramón
Ana
A
Sánchez Díez
Jesus María
JM
Careaga
Concepción
C
de la Rúa
D000483:Alleles; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008545:Melanoma / Q000208:ethnology / Q000235:genetics; D018832:Molecular Chaperones; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012641:Selection, Genetic; D019098:Telomerase; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044465:White People / Q000235:genetics
D018832:Molecular Chaperones; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; C535133:WRAP53 protein, human