Population genetics of EWSR1, a highly conserved chromosome 22 breakpoint region. N. Orr¹, S. Savage², G. Thomas^2,3, S. Chanock^1,2,3. 1) Pediatric Oncology Branch, NCI, Bethesda, MD; 2) Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD; 3) Core Genotyping Facility, NCI, Gaithersburg, MD.
   Ewings Sarcoma (ES) is characterised by the presence of a small number of highly specific somatic translocations resulting in fusion of the transactivation domain of the EWS gene with the RNA binding domain from one of five members of the ETS gene family. Distributions of EWS breakpoint junctions are confined to a 6 kb region termed EWSR1. The incidence of ES is significantly higher in Caucasians than in African Americans suggesting that population specific susceptibility and/or protective factors are implicated. We present a detailed population genetics analysis of EWSR1 as a step towards understanding the ethnic bias of the genetic lesion driving these pathogenic translocations.
   We detected a 3.7 kb region of EWSR1 whose evolutionary conservation between 17 species was estimated at 0.752 using the phastCons17way algorithm, suggesting an area of functional or structural significance. We characterised common genetic variation within the EWSR1 region by resequencing in the SNP500 Cancer population (32 Caucasians, 24 African Americans, 23 admixed/Hispanic and 23 Pacific Rim individuals). A total of 16 SNPs were detected; of these, 14 were population private, 11 were singletons, only three had a minor allele frequency of greater than 5% and all were intronic. Nucleotide diversity, as calculated using the pi statistic, was 4x10^-5 and the population mutation frequency, theta, was 42x10^-5. We observed the same predominant ancestral haplotype in all populations accompanied by a low number of singletons. Tajimas D statistic was marginally significant (p<0.05) in the African American (-1.866) and admixed (-1.820) populations, suggesting recent selection. Fst, a measure of genetic distance between populations was unremarkable (0.019). Comparison of HapMap phase II data indicates that there may be a region of high recombination in EWS in the Yoruba which is not present in Caucasians. These data form the foundation for further genetic studies of ES in order to investigate the marked population bias of this early onset malignancy.