Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation.
Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation.
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发表时间：
1993
影响因子：
9.8
通讯作者：
R. Ketterling;E. Vielhaber;C. Bottema;D. Schaid;Melinda P. Cohen;Charles L. Sexauer;Steve S. Sommer
中科院分区：
文献类型：
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作者：
R. Ketterling;E. Vielhaber;C. Bottema;D. Schaid;Melinda P. Cohen;Charles L. Sexauer;Steve S. Sommer
以前的流行病学和生物化学研究对突变的性别比例产生了相互矛盾的估计。直接基因组测序与单倍型分析相结合，通过允许在给定家庭中确定精确的突变，扩展了先前的分析。通过对260个B型血友病连续家族的IX因子基因分析，报道了25个家族突变的种系起源。结合前人报道的14个突变源和我们之前报道的4个突变源，共有25个突变源发生在雌性种系，18个突变源发生在雄性种系。雌性生殖系起源的过剩并不意味着雌性生殖系中每个碱基对的总体突变率过高。对数据的贝叶斯分析表明，性别比随突变类型的不同而变化。单碱基置换的总和显示雄性在种系突变中占优势（P < 0.002）。男性优势的最大似然估计是3.5倍。在单碱基取代中，二核苷酸CpG的转变显示出最大的雄性优势（11倍）。与单碱基取代相比，缺失显示出统一的性别比例。对新突变传播时父母年龄的分析表明，生殖系突变与女性父母年龄的小幅增加有关，但与男性父母年龄的增加几乎没有关系。尽管直接基因组测序为确定特定家族中突变的起源提供了一种通用方法，但准确估计不同突变类别的性别比例需要大样本量，并仔细校正确定的多重偏差。目前数据中的偏差导致低估了男性突变的增强。
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, we 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 us, 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, transitions at the dinucleotide CpG show the largest male predominance (11-fold). In contrast to 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.