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Title: Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

Journal Article · · American Journal of Human Genetics; (United States)
OSTI ID:6616025
; ; ; ;  [1];  [2];  [3]
  1. Mayo Clinic/Foundation, Rochester, MN (United States)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. Children's Hospital, Oklahoma City, OK (United States)

Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

OSTI ID:
6616025
Journal Information:
American Journal of Human Genetics; (United States), Vol. 52:1; ISSN 0002-9297
Country of Publication:
United States
Language:
English