Ketterling R P, Vielhaber E, Bottema C D, Schaid D J, Cohen M P, Sexauer C L, Sommer S S
Department of Biochemistry and Molecular Biology, Mayo Clinic/Foundation, Rochester, MN 55905.
Am J Hum Genet. 1993 Jan;52(1):152-66.
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.
先前的流行病学和生物化学研究对突变的性别比给出了相互矛盾的估计。直接基因组测序结合单倍型分析扩展了先前的分析，能够在特定家族中确定精确的突变。通过对260个连续的B型血友病家族的因子IX基因进行分析，我们报告了25个家族中生殖系突变的起源。将其与其他人报告的14个突变起源以及我们之前报告的4个起源相结合，共有25个发生在女性生殖系，18个发生在男性生殖系。女性生殖系起源的过量并不意味着女性生殖系中每碱基对的总体突变率过高。对数据的贝叶斯分析表明，性别比随突变类型而变化。单碱基替换的总体显示生殖系突变以男性为主（P <.002）。男性优势的最大似然估计为3.5倍。在单碱基替换中，二核苷酸CpG处的转换显示出最大的男性优势（11倍）。与单碱基替换相反，缺失显示性别比为1。对新突变传递时亲代年龄的分析表明，生殖系突变与女性亲代年龄的小幅增加有关，但与男性亲代年龄的增加关系不大（如果有增加的话）。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，但要准确估计不同突变类别的性别比需要大样本量，并仔细校正多种确定偏倚。本数据中的偏倚导致对男性突变增强的低估。
