Original American Sin in the Form of an AFAP Mutation

A recent article authored by investigators at the University of Utah features an all-time favorite pastime: genealogic digging. The authors examined 2 large kindreds, one in Utah and one in New York, that share an identical autosomal-dominant (AD) deletion mutation, c.426_427delAT, which determines an attenuated form of familial adenomatous polyposis (FAP). FAP and its attenuated forms (AFAP) are associated with substantially increased risks of colonic polyps and colorectal cancer, FAP moreso than AFAP, but phenotypic variance appears to be considerable, particularly in individuals with the attenuated conditions.

By using genealogic records at the massively stocked LDS* library and matching surnames between the 2 pedigrees, the investigators identified a common ancestral couple who emigrated from England to America in the early 1600s: George Frye and his nameless wife, aka Mrs. George Frye. The interesting thing about this couple is that the c.426_427delAT mutation appears to have spontaneously originated with one of them, because it has not been identified in England or elsewhere in Europe, according to the authors.

The big question the article generates is How many Americans currently alive have inherited the original deletion mutation? The authors indicate that genealogic data are presently not sufficient to identify the full extent of descendants of the founding couple; however, there are at least 11 other American families with the exact allele haplotype who have been identified in Texas, Nebraska, Washington, Vermont, or Michigan and 2 additional families in Wisconsin with a slightly different genotype, mostly likely due to recombination events. Whether this tally is complete is difficult to know, until all progeny lines from Mr. and Mrs. George Frye have been traced, and genetic analyses of living descendants have been performed. The absence of colorectal cancer in a particular lineage is unlikely to preclude the presence of the mutation, because of substantial phenotypic variance. Among the 2 studied kindreds, approximately 37% of mutation-positive members had fewer than 10 colonic adenomatous polyps, and only approximately 7% of these individuals were diagnosed with colorectal cancer.

According to records at familysearch.org and ancestry.com, George Sr. and wife produced at least 4 children, 2 of which, George Frye, Jr, and Elizabeth Frye, passed on their acquired mutations to the New York and Utah families, respectively. Now it is certainly possible, despite the 50% probability of passing on the AD mutation, that the 2 other children of the founding couple were also affected and passed on the allele haplotype to their descendents.

In any event, it is recorded that George, Jr, had at least 4 children, and that Elizabeth had 9 children. Therefore the minimum probability is that 6 individuals of the third Frye generation (b. circa 1640-1660) carried the mutation, and half of those children passed it onto their children, and so forth (providing that the mutation is not subject to selective pressure, which it does not appear to be). For the sake of further argument, if each couple of each successive generation had 4 children, with 2 of those 4 children acquiring the mutation, then by the thirteenth generation (those individuals b. 1920s-40s), more than 6000 individuals carried the c.426_427delAT mutation. The mutation incidence, in this scenario, is then doubled for the fourteenth generation, at 12,000—which suggests a considerable mountain of genealogic and genetic data to dig through.

*Latter-day Saints.