HUMAN SPERM ANEUPLOIDY: GENETIC AND ENVIRONMENTAL CAUSES

我们和其他调查人员已经证明，有一些亲属有一个 非整倍体后代的非随机复发。基于这些观察 我们可以假定人类在这一点上与其他真核生物相似 遗传因素导致了一些不分离的病例。我们计划正式 通过估计人类的变异比例来检验这一假设 可归因于遗传和/或环境因素的非整倍体。 这将通过对人类精子中的非整倍体水平进行评分来完成 同卵双胞胎和异卵双胞胎的多色荧光原位检测 杂交(FISH)技术共有100对双胞胎(50对同卵 配对和50对双合子)将被研究。观察到的非整倍体水平 对于200对双胞胎精子中的24条染色体中的每一条 得分了。非整倍体中个体差异的程度 由累加遗传、共同环境和特定因素决定 将使用稳健方差方法来估计环境影响 成分估计(在Fisher数量遗传学中实现 包)。精子的非整倍体频率也将被用来比较 差异：(1)男性；(2)染色体；(3)内部染色体 雄性；(4)射精之间的雄性内的染色体；和(5) 精子形态异常。男性被确认为患有 显著高水平的非整倍体将被进一步研究， 与他们的同卵双胞胎(他们可能是和谐的或不和谐的) 非整倍体水平)和对照，以测试阿尔法卫星的差异 DNA序列、着丝粒相关蛋白(CENPs)或早产 着丝粒分裂与升高的非整倍体相关 频率。此外，对于这一双胞胎子集，非整倍体水平 配子(精子)将与体细胞中的水平进行比较。 (淋巴细胞)。后一种比较将提供有关 体细胞在筛选试验中的应用 环境或遗传因素对配子非整倍体的影响。总体而言， 这项研究的结果不仅将使我们能够提供第一个 遗传因素在糖尿病发病中作用的定量估计 非整倍体，但也可以为设计人类提供重要的见解 诱变剂筛选测试，并为家庭提供遗传咨询 有一个非整倍体的孩子。

We and other investigators have shown that there are kindreds who have a nonrandom recurrence of aneuploid offspring. Based on these observations one can postulate that humans are similar to other eukaryotes in that genetic factors cause some cases of nondisjunction. We plan to formally test this hypothesis by estimating the proportion of variation in human aneuploidy that is attributable to genetic and/or environmental factors. This will be done by scoring the levels of aneuploidy in human sperm from identical and fraternal twins using a multi-color fluorescence in situ hybridization (FISH) technique. A total of 100 twin pairs (50 monozygotic pairs and 50 dizygotic pairs) will be studied. Levels of aneuploidy seen for each of the 24 chromosomes in sperm from each of the 200 twins will be scored. The extent to which individual differences in aneuploidy are determined by additive genetic, common environmental, and specific environment effects will be estimated using a method of robust variance component estimation (implemented in the FISHER quantitative genetics package). The sperm aneuploidy frequencies will also be used to compare differences between: (1) males; (2) chromosomes; (3) chromosomes within males; (4) chromosomes within males between ejaculates; and (5) levels of sperm morphological abnormalities. Males identified as having significantly high levels of aneuploidy will be further studied, along with their co-twins (who may be concordant or discordant for high aneuploidy levels) and controls, to test if differences in alpha-satellite DNA sequences, centromere associated proteins (CENPs), or premature centromere division are correlated with the elevated aneuploidy frequencies. Also, for this subset of twins the level of aneuploidy in gametes (sperm) will be compared to levels seen in somatic cells (lymphocytes). This latter comparison will provide information about the utility of somatic cells in screening tests to estimate the effects of environmental or genetic agents on gametic aneuploidy. Collectively, the results of this study will not only allow us to provide the first quantitative estimate of the role of genetic factors in the incidence of aneuploidy, but could also provide important insight for designing human mutagen screening tests, and providing genetic counseling to families having a child with an aneuploid condition.