European Molecular Biology Laboratory (EMBL) Heidelberg, Heidelberg, Germany.
PLoS Comput Biol. 2013;9(5):e1003073. doi: 10.1371/journal.pcbi.1003073. Epub 2013 May 16.
Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population; this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes.
孟德尔疾病通常是由非致死但导致功能异常的基因突变引起的。在这里，我们研究了可能补偿单基因疾病基因的基因重复的程度。我们通过以下证据证明了人类单基因疾病基因 (MD) 的重复具有普遍的功能冗余性：1) 涉及人类遗传疾病的基因在重复中富集，2) 与具有相似年龄的重复非疾病基因相比，重复疾病基因与其最近的同源基因具有更高的功能相似性。我们提出，基因重复的功能补偿掩盖了有害突变的表型效应，并降低了从人类群体中清除缺陷基因的概率；与非疾病基因相比，疾病基因与其重复以及同源基因之间的更高纯化选择可能进一步增强这种功能补偿。然而，由于个体之间的内在表达随机性，有害突变仍然可能以遗传疾病的形式存在于重复拷贝表达水平较低的某些亚群中。因此，缺陷基因与遗传疾病有关，而它们在人群中仍在继续传播。我们的研究结果为重复疾病基因传播的分子基础提供了深入的见解。
