Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.
Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.
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基因表达变化的组合模式有助于发育延迟相关的16p12.1缺失的可变表达性。
DOI：
10.1186/s13073-021-00982-z
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发表时间：
2021-10-18
期刊：
影响因子：
12.3
通讯作者：
Girirajan S
中科院分区：
文献类型：
--
作者：
Jensen M;Tyryshkina A;Pizzo L;Smolen C;Das M;Huber E;Krishnan A;Girirajan S
最近的研究表明，个体变异不足以解释复杂疾病中观察到的表型的可变表达性。例如，16p12.1缺失与受影响个体的发育迟缓和神经精神病学特征相关，但在> 90%的病例中，16p12.1缺失是从轻度受影响的父母遗传的。虽然有缺失的儿童比他们的父母更有可能携带额外的“二次打击”变异，但这些变异如何导致表型变异的机制尚不清楚。我们进行了详细的临床评估，全基因组测序，和RNA测序的淋巴母细胞样细胞系的32个人在5个大家庭与多个成员携带16p12.1缺失。我们确定了16p12.1缺失和“二次命中”变体对缺失携带者及其家族成员的一系列表达变化的贡献，包括差异表达、离群表达、可变剪接、等位基因特异性表达和表达定量性状基因座分析。我们发现，这种缺失会使多个自闭症和大脑发育基因（如FOXP 1、ANK 3和MEF 2）失调。携带者儿童与父母一方或双方相比，平均有5323个基因表达变化，与观察到的39个发育表型中的33个相匹配。我们发现，在表达变化的基因中，13/25类“二次打击”变异显著富集，其中4/25的变异类型仅在从非携带者亲本遗传时富集，包括功能丧失的SNV和大重复。在11个例子中，包括ZEB 2和SYNJ 1，基因表达被携带者儿童中的缺失和遗传“二次命中”协同改变。最后，脑特异性相互作用网络分析显示携带“二次命中”的基因与缺失携带者中转录组改变的基因之间存在强连接。我们的研究结果表明了一个潜在的机制，如何“二次打击”的变体调节复杂的疾病，如16p12.1缺失的表达，通过转录干扰的基因网络的重要早期发展。我们的工作进一步表明，基于家族的转录组数据评估与理解与复杂疾病相关的遗传机制高度相关。在线版本包含补充材料，可通过10.1186/s13073-021-00982-z获得。
Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders. The online version contains supplementary material available at 10.1186/s13073-021-00982-z.