Human functional genetic studies are biased against the medically most relevant primate-specific genes

Abstract

BackgroundMany functional, structural and evolutionary features of human genes have been observed to correlate with expression breadth and/or gene age. Here, we systematically explore these correlations.ResultsGene age and expression breadth are strongly correlated, but contribute independently to the variation of functional, structural and evolutionary features, even when we take account of variation in mRNA expression level. Human genes without orthologs in distant species ('young' genes) tend to be tissue-specific in their expression. As computational inference of gene function often relies on the existence of homologs in other species, and experimental characterization is facilitated by broad and high expression, young, tissue-specific human genes are often the least characterized. At the same time, young genes are most likely to be medically relevant.ConclusionsOur results indicate that functional characterization of human genes is biased against young, tissue-specific genes that are mostly medically relevant. The biases should not be taken lightly because they may pose serious obstacles to our understanding of the molecular basis of human diseases. Future studies should thus be designed to specifically explore the properties of primate-specific genes.

Human Monogenic Disease Genes Have Frequently Functionally Redundant Paralogs

“…GO annotations are known to be biased towards highly expressed and more conserved genes [25]; the same would also apply to the PPI data. Additionally, current GO annotation and human PPI network only cover limited numbers of genes; consequently, only ∼37% duplication pairs were annotated by GO, and ∼36% by PPIs.…”

Pharmacology and Signaling of MAS-Related G Protein–Coupled Receptors

“…From an evolutionary point of view, the strong positive selection pressure indicates that novel MRGPRX proteins are crucial for primatespecific physiology and represent important differences between primates and rodents. Indeed, primate-specific genes are clearly over represented in the fraction of human disease-causing genes (Hao et al, 2010). Interestingly, a continuing positive selection pressure on MRGPRX genes may account for frequent polymorphisms of MRGPRX genes in the human population and, thus, account for differences in published MRGPRX/SNSR subtypes.…”

Younger Genes Are Less Likely to Be Essential than Older Genes, and Duplicates Are Less Likely to Be Essential than Singletons of the Same Age

“…Genes that originated early tend to be conserved across species, highly and broadly expressed, and broadly useful (Hao et al 2010). Thus, we hypothesized that knocking out phyletically old genes is more likely to have severe phenotypic effects: old genes should be more often essential.…”