Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions
Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions
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DOI：
10.1136/jmedgenet-2011-100440
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发表时间：
2011-12-01
影响因子：
4
通讯作者：
Bassett, Anne S.
中科院分区：
文献类型：
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作者：
Costain, Gregory;Chow, Eva W. C.;Bassett, Anne S.
背景 22q11.2 缺失综合征 (22q11.2DS) 是人类最常见的微缺失综合征。在少数患者中，潜在的 22q11.2 缺失被发现是遗传的，通常来自受影响的母亲。严重的神经精神疾病通常与 22q11.2DS 特征相关，可能会严重影响男性的生殖成功。 方法 本研究比较了 141 名患有 22q11.2DS 的加拿大成年人（病例）及其 200 名未受影响的兄弟姐妹（对照）的生殖健康标准测量值（活产后代的平均数量和无子女比例）。使用多变量回归模型来识别 22q11.2DS 适合度的表型预测因子。结果 患有 22q11.2DS 的成年人的子女数量明显少于其兄弟姐妹（p < 0.0001，相对适合度 = 0.28）； 85.8% 没有孩子。正如预期的那样，年龄较小（p < 0.0001）、智力低下（p = 0.0211）和精神分裂症（p = 0.0046）是 22q11.2DS 生殖健康的显着负预测因子；然而，严重的先天性心脏病则不然。女性成为独立于主要神经精神表型的健康的显着正预测因子（p = 0.0082）。事后分析证实了这些性别差异。值得注意的是，患有 22q11.2DS 且既无智力低下也无精神分裂症的女性的健康状况与未受影响的女性兄弟姐妹没有显着差异。结论 22q11.2 缺失存在很强的负选择压力。这似乎主要是由神经精神表型的严重性和独立的性选择效应介导的。后者也导致了观察到的传播母亲过多。这些结果可能对这种结构重排的进化生物学以及针对 22q11.2DS 青少年和成人的遗传咨询和生殖服务产生影响。
Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. In a minority of patients, the underlying 22q11.2 deletion is found to have been inherited, usually from an affected mother. Serious neuropsychiatric conditions that are commonly associated features of 22q11.2DS could disproportionately affect reproductive success in males.Methods This study compared standard measures of reproductive fitness (mean number of liveborn offspring and proportion childless) in 141 Canadian adults with 22q11.2DS (cases) and their 200 unaffected siblings (controls). Multivariate regression models were used to identify phenotypic predictors of fitness in 22q11.2DS.Results The adults with 22q11.2DS had significantly fewer children than their siblings (p < 0.0001, relative fitness = 0.28); 85.8% were childless. As expected, younger age (p < 0.0001), mental retardation (p = 0.0211), and schizophrenia (p = 0.0046) were significant negative predictors of reproductive fitness in 22q11.2DS; however, serious congenital heart disease was not. Female sex emerged as a significant positive predictor of fitness independent of the major neuropsychiatric phenotypes (p = 0.0082). Post-hoc analyses corroborated these sex differences. Notably, fitness in women with 22q11.2DS with neither mental retardation nor schizophrenia was not significantly different from that of unaffected female siblings.Conclusions There is a strong negative selective pressure against 22q11.2 deletions. This appears to be primarily mediated by the severity of the neuropsychiatric phenotype and an independent sexual selection effect. The latter also contributes to the observed excess of transmitting mothers. These results may have implications both for the evolutionary biology of this structural rearrangement and for genetic counselling and reproductive services for adolescents and adults with 22q11.2DS.