Ala244Val Is a Common, Probably Ancient Mutation Causing Factor VII Deficiency in Moroccan and Iranian Jews

SummaryWe investigated the molecular basis for factor VII (FVII) deficiency in Israel and found that 13 patients were homozygous and 10 heterozygous for a C to T substitution at nucleotide 10648 of the FVII gene. This predicted an Ala244Val change and was associated with decreased FVII activity and antigen level. Of the 36 Ala244Val positive alleles, 20 were observed in patients of Moroccan origin, 10 in Iranian-Jewish patients and 6 in patients of other origins. A computer model of the serine protease domain of FVII suggested that the Ala244Val substitution may cause distortion of the entire protein structure. Intragenic polymorphic sites analyses disclosed a founder effect for the Moroccan and Iranian-Jewish patients. A survey of the Ala244Val mutation revealed an allele frequency of 1:42.5 in Moroccan Jews and 1:40 in Iranian Jews. As Moroccan Jews have been separated from Iranian Jews for more than two millennia, the data suggest that the Ala244Val mutation occurred in ancient times.

The determination of the age of a clone from characteristics of its geographical distribution

Each point with integer coordinates in d dimensions is occupied by one individual. These individuals produce offspring at a Poisson rate 1, and these offspring migrate and displace other individuals. With probability u (the mutation rate) an offspring is of an entirely new type. A number of points N 0 will be occupied by the same type as the individual at the origin. It is shown that the distribution of N 0 arising from an ancient mutation does not differ greatly from the distribution of N 0 when the mutation is recent. However, the geographical spread is shown to be important, and a central limit theorem is proved for the age of the mutant clone given that a representative is present at a large distance from the origin.

The determination of the age of a clone from characteristics of its geographical distribution

Each point with integer coordinates in d dimensions is occupied by one individual. These individuals produce offspring at a Poisson rate 1, and these offspring migrate and displace other individuals. With probability u (the mutation rate) an offspring is of an entirely new type. A number of points N0 will be occupied by the same type as the individual at the origin. It is shown that the distribution of N0 arising from an ancient mutation does not differ greatly from the distribution of N0 when the mutation is recent. However, the geographical spread is shown to be important, and a central limit theorem is proved for the age of the mutant clone given that a representative is present at a large distance from the origin.