P53 mutation selected for

A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection

By Jorge Zeron-Medina, Xuting Wang, et al.

In Cell – 10 October 2013 (Vol. 155, Issue 2, pp. 410-422)

An accessible overview by Brett Smith is in RedOrbit here

The article provides evidence for positive selection for a mutation in p53, KITLG,  that causes testicular cancer.  They note that this same allele influences the rate of replication of melanin producing cells in response to UV radiation.  This allele is much more common in Caucasians than Africans, and testicular cancer is 4-5 times more common in Caucasian men.

Summary

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, andp53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans

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