Human Monogenic Disease Genes Have Frequently Functionally Redundant Paralogs

Wei-Hua Chen,Vera Van Noort,Xing-Ming Zhao,Peer Bork,Thomas Lengauer

doi:10.1371/journal.pcbi.1003073

Abstract

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.

Highlights

Elucidating the molecular basis of human genetic disorders is one of the most important tasks in medical biology
The corresponding phenotypes would manifest themselves when mutations occur in singletons, since functional compensation is rare among non-duplicated genes
How could the stronger functional compensation among duplicates increase their likelihood to associate with diseases? We propose that due to functional compensation in duplicates, disease-causing mutations are less likely to be removed from a human population in large scale since the phenotypes are masked; the functional compensation could be lost in a subpopulation, perhaps due to intrinsic variation in gene expression, and lead to diseases

Summary

Introduction

Elucidating the molecular basis of human genetic disorders is one of the most important tasks in medical biology. The accepted hypothesis was that disease genes tend to be singletons with fewer paralogs [15] since duplication can lead to functional redundancy [16,17,18] and thereby mask the effect of deleterious mutations [15,19]; disease genes were found surprisingly enriched in duplicates [8]. In duplicates (i.e. more recent ones) whose functional redundancy is resilient enough to mask some disease-causing mutations in one of the copies, the proportion of disease genes would be lower compared with that of overall singletons; for duplicates (i.e. older ones) whose compensation capacity is partial or no longer effective, they would be purged from the human genome at the same rate as singletons; combined together, the overall proportion of disease genes in duplicates would still be lower. Summarizing recent literature, we realized that the duplication-functional redundancy theory alone is perhaps insufficient in explaining the observed enrichment of disease genes in duplicates, and the contribution of additional factors should be explored and taken into consideration

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Conclusion