Genetic anthropology of the colorectal cancer-susceptibility allele APC I1307K: evidence of genetic drift within the Ashkenazim

Abstract

The adenomatous polyposis coli (APC) I1307K allele is found in 6% of the Ashkenazi Jewish population and in 1%-2% of Sephardi Jews; it confers a relative risk of 1.5-2.0 for colorectal cancer (CRC) on all carriers. Within the Ashkenazim, the existence of numerous high-prevalence mutations, including I1307K, has sparked controversy over whether genetic drift or selection is the underlying cause. For the present population-based case-control study of CRC in Israel, we tested whether selection has operated at I1307K. We also estimated the age of the I1307K allele, to understand its origin in the context of the Jewish diasporas and subsequent founder events. We genotyped 83 matched pairs, in which one or both members of the pair carried I1307K, at three microsatellites and two SNPs. Haplotypes were statistically constructed using PHASE software. Single-marker age estimates for I1307K were calculated using the approach described by Risch et al. A common progenitor haplotype spanned across APC I1307K from the centromeric marker D5S135 to the telomeric marker D5S346 and was observed in individuals of Ashkenazi, Sephardi, and Arab descent. The ancestor of modern I1307K alleles existed 87.9-118 generations ago ( approximately 2,200-2,950 years ago). This age estimate indicates that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. Our data do not indicate that selection operated at I1307K (D5S346, P=.114; D5S135, P=.373), providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection. This research underscores the importance of the migratory patterns of ancestral populations in the ethnic and geographic distribution of APC I1307K.

Figure 1

Representative genotypes of APC I1307K carriers. A, Conserved allele at D5S346 among I1307K carriers observed among Ashkenazi Jews (lanes 1–3), Sephardi Jews (lanes 4–6), and Arabs (lanes 7–9) (arrow). B, Absence of conserved genotype at D5S82 among Ashkenazi Jews (lanes 1–3), Sephardi Jews (lanes 4–6), or Arabs (lanes 7–9).

Figure 2

Conserved alleles at markers linked to I1307K. These alleles, shown for homozygous positive individuals, construct a putative progenitor haplotype of the most recent common ancestor of I1307K.

Figure 3

Timeline of selected events in the history of the Jewish peoples

Figure 4

The Jewish diasporas. The existence of APC I1307K prior to the Jewish diasporas explains its presence in non-Ashkenazi peoples residing in geographic locales populated by the diasporas. Adapted from Barnavi (1992).