Ohnologs in the human genome are dosage balanced and frequently associated with disease
Ohnologs in the human genome are dosage balanced and frequently associated with disease
复制标题
DOI：
10.1073/pnas.0914697107
复制
发表时间：
2010-05-18
影响因子：
11.1
通讯作者：
McLysaght, Aoife
中科院分区：
文献类型：
--
作者：
Makino, Takashi;McLysaght, Aoife
人类基因组中约30%的蛋白质编码基因通过两次全基因组复制（WGD）事件相关。虽然WGD通常被认为具有很大的进化重要性，但这些基因的保留过程及其生物学意义仍不清楚。一个越来越流行的假设是，剂量平衡限制是重复基因保留的主要决定因素。我们测试了这一假设，并表明WGD重复基因（ohnologs）很少经历随后的小规模重复（SSD），并且在人群中也不受拷贝数变异（CNV）的影响，因此可能对相对量敏感（即，它们是剂量平衡的）。相比之下，在脊椎动物谱系中经历SSD的基因更可能也显示CNV。这支持了WGD后剂量平衡基因的偏倚保留的假设。我们还表明，ohnologs与人类疾病有很强的相关性。特别是，由21三体引起的唐氏综合征（DS）被广泛认为是由剂量效应引起的，并且先前报道的用于该综合征的候选基因中有75%是没有经历其他拷贝数变化的同源基因。我们建议21号染色体上剩余的剂量平衡的ohnologs作为候选DS基因。这些观察结果清楚地表明，WGD复制的基因对剂量变化具有持久抗性。剂量平衡的限制，同时解释重复基因保留和必要性后WGD。
About 30% of protein-coding genes in the human genome are related through two whole genome duplication (WGD) events. Although WGD is often credited with great evolutionary importance, the processes governing the retention of these genes and their biological significance remain unclear. One increasingly popular hypothesis is that dosage balance constraints are a major determinant of duplicate gene retention. We test this hypothesis and show that WGD-duplicated genes (ohnologs) have rarely experienced subsequent small-scale duplication (SSD) and are also refractory to copy number variation (CNV) in human populations and are thus likely to be sensitive to relative quantities (i.e., they are dosage-balanced). By contrast, genes that have experienced SSD in the vertebrate lineage are more likely to also display CNV. This supports the hypothesis of biased retention of dosage-balanced genes after WGD. We also show that ohnologs have a strong association with human disease. In particular, Down Syndrome (DS) caused by trisomy 21 is widely assumed to be caused by dosage effects, and 75% of previously reported candidate genes for this syndrome are ohnologs that experienced no other copy number changes. We propose the remaining dosage-balanced ohnologs on chromosome 21 as candidate DS genes. These observations clearly show a persistent resistance to dose changes in genes duplicated by WGD. Dosage balance constraints simultaneously explain duplicate gene retention and essentiality after WGD.