Abstract
PLOS Computational Biology recently published an article by Chen, Zhao, van Noort, and Bork [1] reporting that, in contrast to duplicated nondisease genes, human monogenic disease (MD) genes are (1) enriched in duplicates (in agreement with earlier reports [2]–[5]) and (2) more functionally similar to their closest paralogs based on sequence conservation and expression profile similarity. Chen et al. then proposed that human MD genes frequently have functionally redundant paralogs that can mask the phenotypic effects of deleterious mutations.
Highlights
PLOS Computational Biology recently published an article by Chen, Zhao, van Noort, and Bork [1] reporting that, in contrast to duplicated nondisease genes, human monogenic disease (MD) genes are (1) enriched in duplicates and (2) more functionally similar to their closest paralogs based on sequence conservation and expression profile similarity
The first line of evidence indicates that human gene duplicates should be distinguished depending on whether they originate from smallscale duplication (SSD) or from the two rounds of whole genome duplication (WGD) that occurred in early vertebrates some 500 million years ago
The second line of evidence concerns the mode of inheritance of human MDs, which provides a more stringent criterion than sequence conservation or coexpression profile to assess the likelihood of functional compensation by paralogs of MD genes
Summary
Human Dominant Disease Genes Are Enriched in Paralogs Originating from Whole Genome Duplication. These observations clearly show that the maintenance of recessive MD genes is largely independent of their WGD, SSD, or singleton status, suggesting limited effects of functional compensation by paralogs on the retention of gene duplicates associated to recessive MDs in human. Only dominant MD genes exhibit a clear enrichment in WGD duplicates, while the retention of duplicates of recessive MDs or essential genes, which might in principle experience functional compensation from paralogs, is largely independent of their WGD, SSD, or singleton status These results cannot be explained by the functional compensation hypothesis proposed in Chen et al [1]. They are, consistent with a population genetics model taking into account the initial fixation of ohnologs through WGD-induced speciation and the ensuing purifying selection in post-WGD populations [5,9]
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