Germline origins in the human F9 gene: Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age

Rhett P. Ketterling, Erica Vielhaber, Xuemin Li, Joni Drost, Daniel J Schaid, Carol K. Kasper, John A. Phillips, Arion A. Koerper, Hugh Kim, Charles Sexauer, Ralph Gruppo, Raul Ambriz, Rogelio Paredes, Steve S. Sommer

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)629-640
Number of pages12
JournalHuman Genetics
Volume105
Issue number6
DOIs
StatePublished - 1999

Fingerprint

Mosaicism
Maternal Age
Paternal Age
Mutation
Mutation Rate
Genes
Factor IX
Bayes Theorem
Germ-Line Mutation
DNA Sequence Analysis
Embryonic Development
Leukocytes
Mothers

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Germline origins in the human F9 gene : Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age. / Ketterling, Rhett P.; Vielhaber, Erica; Li, Xuemin; Drost, Joni; Schaid, Daniel J; Kasper, Carol K.; Phillips, John A.; Koerper, Arion A.; Kim, Hugh; Sexauer, Charles; Gruppo, Ralph; Ambriz, Raul; Paredes, Rogelio; Sommer, Steve S.

In: Human Genetics, Vol. 105, No. 6, 1999, p. 629-640.

Research output: Contribution to journalArticle

Ketterling, RP, Vielhaber, E, Li, X, Drost, J, Schaid, DJ, Kasper, CK, Phillips, JA, Koerper, AA, Kim, H, Sexauer, C, Gruppo, R, Ambriz, R, Paredes, R & Sommer, SS 1999, 'Germline origins in the human F9 gene: Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age', Human Genetics, vol. 105, no. 6, pp. 629-640. https://doi.org/10.1007/s004390051155
Ketterling, Rhett P. ; Vielhaber, Erica ; Li, Xuemin ; Drost, Joni ; Schaid, Daniel J ; Kasper, Carol K. ; Phillips, John A. ; Koerper, Arion A. ; Kim, Hugh ; Sexauer, Charles ; Gruppo, Ralph ; Ambriz, Raul ; Paredes, Rogelio ; Sommer, Steve S. / Germline origins in the human F9 gene : Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age. In: Human Genetics. 1999 ; Vol. 105, No. 6. pp. 629-640.
@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.}",
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",

}

TY - JOUR

T1 - Germline origins in the human F9 gene

T2 - Frequent G:C→A:T mosaicism and increased mutations with advanced maternal age

AU - Ketterling, Rhett P.

AU - Vielhaber, Erica

AU - Li, Xuemin

AU - Drost, Joni

AU - Schaid, Daniel J

AU - Kasper, Carol K.

AU - Phillips, John A.

AU - Koerper, Arion A.

AU - Kim, Hugh

AU - Sexauer, Charles

AU - Gruppo, Ralph

AU - Ambriz, Raul

AU - Paredes, Rogelio

AU - Sommer, Steve S.

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=18744422146&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18744422146&partnerID=8YFLogxK

U2 - 10.1007/s004390051155

DO - 10.1007/s004390051155

M3 - Article

C2 - 10647899

AN - SCOPUS:18744422146

VL - 105

SP - 629

EP - 640

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 6

ER -