Human germline mutation in the factor IX gene

The molecular epidemiology of factor IX germline mutations in patients with hemophilia B has been studied in detail because it is an advantageous mode l for analyzing recent germline mutations in humans. It is estimated that m utations have been defined in the majority of nucleotides that are the targ et for mutation. The likelihood that a factor IX missense mutation will cau se disease correlates with the degree of evolutionary conservation of the a mino acid. Mutation rates per base-pair have been estimated after careful c onsideration and correction for biases, predicting about 76 de novo mutatio ns per generation per individual resulting in 0.3 deleterious changes. The male-to-female sex ratio of mutation varies with the type of mutation. Ther e is evidence for a maternal age effect and an excess of non-CpG G:C to A:T transitions. The factor IX mutation pattern is similar among geographicall y, racially and ethnically diverse human populations. The data support prim arily endogenous mechanisms of germline mutation in the factor IX gene. Mut ations at splice junctions are compatible with simple rules for predicting disease causing mutations. (C) 2001 Published by Elsevier Science B.V.