HUMAN SPERM ANEUPLOIDY: GENETIC AND ENVIRONMENTAL CAUSES

我们和其他研究人员已经证明，有一种Kinematic， 非整倍体后代的非随机复发。 基于这些观察 我们可以假设人类与其他真核生物相似， 遗传因素导致某些不分离的情况。 我们计划正式 通过估计人类中变异的比例来检验这一假设。 非整倍性可归因于遗传和/或环境因素。 这将通过对人类精子中的非整倍体水平进行评分来完成， 同卵和异卵双胞胎使用多色荧光原位 杂交（FISH）技术。 共100对双胞胎（50个单卵 对和50个双合子对）将被研究。 观察到的非整倍体水平 200对双胞胎精子中24条染色体的每一条， 得分了 非整倍体的个体差异程度 由加性遗传、共同环境和特定 将使用稳健方差方法估计环境影响 成分估计（在FISHER定量遗传学中实施） package）。 精子非整倍体频率也将用于比较 差异：（1）男性;（2）染色体;（3）染色体内 男性;（4）射精之间男性体内的染色体;（5） 精子形态异常。 被确定为患有 显著高水平的非整倍体将被进一步研究，沿着 与他们的双胞胎（谁可能是一致的或不一致的高 非整倍性水平）和对照，以测试α-卫星 DNA序列，着丝粒相关蛋白（CENP），或早熟 着丝粒分裂与非整倍体增多有关 频率. 此外，对于双胞胎的这个子集， 将配子（精子）与体细胞中观察到的水平进行比较 （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，以评估 环境或遗传因素对配子非整倍性的影响。 统称 这项研究的结果不仅使我们能够提供第一个 定量估计遗传因素在发病率中的作用 非整倍体，但也可以提供重要的见解，设计人类 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.