@article{ae5a218c574640d69f7dd774a0a2b8a0,
title = "Germline origins in the human F9 gene: Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age",
abstract = "The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ('r') in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall 'r' in F9 was estimated at 3.75. The 'r's varied with the type of mutation. The 'r's ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (> 1 kb), respectively. The 'r' for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P = 0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.",
author = "Ketterling, {Rhett P.} and Erica Vielhaber and Xuemin Li and Joni Drost and Schaid, {Daniel J.} and Kasper, {Carol K.} and Phillips, {John A.} and Koerper, {Arion A.} and Hugh Kim and Charles Sexauer and Ralph Gruppo and Raul Ambriz and Rogelio Paredes and Sommer, {Steve S.}",
note = "Funding Information: Acknowledgements We thank the many individuals who have helped with this study. We should like to thank Kim Viker, Antje Kn{\"o}ll, M.D., Vicky Koenig, Tammy Lind, David P. Jacobson, Bobbie Gostout, M.D., Erik Thorland, Jing-Zhong Liu, Ph.D., and Hong-Sup Yoon, M.D. for contributing to the sequence analysis, and Amy Groszbach, Victoria Tillotson, and Tristi Muir, M.D. for contributing to the haplotype analysis. We thank Mary Johnson for excellent secretarial assistance, and Kathleen Hill for helping to revise the manuscript. We should also like to thank the following people for submitting one or more of the families included in these analyses: Joan Eisele, R.N. of Robert Wood Johnson Medical School, New Brunswick, N.J.; Mary Peterman, M.S. of Children{\textquoteright}s Hospital, Oklahoma City, OK; Melinda Cohen, M.S. of Vanderbilt University School of Medicine, Nashville, TN; Susan Karp, R.N., University of California, San Francisco, CA; Peter Mockary of the University of Southern California, Los Angeles, CA; Eleanor Geller, M.S., David Flanney, M.D. of Medical College of Georgia, Augusta, GA; Joleen Visont, M.S., Haynes B. Robinson, M.D., of Toledo Hospital, Toledo, OH; Betsy Glaser, R.N., Joseph Hersh, M.D., of Children{\textquoteright}s Evaluation Center, Louisville, Ky.; Linda Schornstein of the Hemophilia Foundation of Hawaii, Honolulu, HI; Lissa Kraus, M.S., Doreen Brettler, M.D., Medical Center of Central Massachusetts, Worcester, MA; Sandy Jacques, R.N., Leticia Valdez, M.D., of Children{\textquoteright}s Medical Center, Dayton, OH; Betty Schmalz, R.N., Bonnie Koenig, R.N., Virginia Michels, M.D. of the Mayo Clinic, Rochester, MN; Leonard Valentino, M.D., Rush Presbyterian, Chicago, IL; Billie Sullivan, M.S., Jerry Powell, M.D., University of California at Davis, Sacramento, CA; Thomas W. Loew, M.D. of Southern Illinois University, Springfield, IL; Deidre Grimes, Maurice J. Mahoney, M.D., of Yale University, New Haven, CT; Karen Wulff, R.N., Cindy Leissinger, M.D., Louisiana Comprehensive Hemophilia Care Center, New Orleans, LA; Bonnie LeRoy, M.S., Roger Edson, M.D., University of Minnesota, Minneapolis, MN; and Sarah Neagely, R.N.,M.A., M. Elaine Eyster, M.D., of Hershey Medical Center, Hershey, PA. R.P.K. is a Howard Hughes Medical Institute Medical Student Research Training Fellow. This work was supported by HL39762.",
year = "1999",
doi = "10.1007/s004390051155",
language = "English (US)",
volume = "105",
pages = "629--640",
journal = "Human genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "6",
}