Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology

Abstract

Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease.

Human and mouse essentiality screens as a resource for disease gene discovery

“…Here we demonstrate that the FUSIL categorisation of gene essentiality, combined with intolerance to variation scores, patient phenotypes and their overlap with those observed in mouse lines with null alleles can assist in the prioritisation of disease-causal variant candidates. We show an enrichment for disease genes among developmental essential genes, which is consistent with the proposed model where disease associated genes occupy an intermediate position between highly essential and non-essential genes 29,43,44 . In this model, highly essential genes will not be associated with human diseases because any function-altering mutation will likely lead to miscarriage or early embryonic death.…”

“…For certain gene features, we replicate previously observed trends where genetic features are most differentiated between the two ends of the FUSIL spectrum e.g. genes with paralogues, gene expression, number of protein-protein interactions or the likelihood of being part of a protein complex 16,29,45 . The CL bin shows the lowest rates of recombination, and both the CL and DL fractions exhibit significantly lower rates than the viable categories.…”

“…Quantitative definitions of "low" and "high" gene essentiality have been proposed to account for the degree of dependency on external factors as well as the likelihood of a compensatory mutation rescuing necessary function 28 . Essential genes have also been classified by whether they are known to be associated with human disease, with functional mutations in non-disease-associated genes and with a mouse orthologue that is LoF embryonic lethal suggested as likely to prevent pregnancy, lead to miscarriage or to early death 29 . Other research has reported that orthologues of embryonic lethal LoF mouse genes are shown to have an increased association to diseases with high mortality and neurodevelopmental disorders 23,30,31 .…”

Selective pressures on human cancer genes along the evolution of mammals

“…Therefore, it is expected that genes under relaxed purifying selection are more likely associated with hereditary than with sporadic cancer. In addition, since cancer is a complex and late-onset disease, where each allele contributes to a small fraction of cancer risk and with small effects on fitness, it is plausible that genes directly associated with cancer susceptibility are under weak purifying selection [38,41,42]. In addition, genes associated with complex diseases typically are under widespread purifying selection but also show signatures of positive selection [38], in concordance with our results.…”

A map of constrained coding regions in the human genome

“…We hypothesize that this is likely owing to the fact that these regions are under extreme purifying selection which prevents the observation of a pathogenic variant among patients studied to date. There is support for this hypothesis; genes predicted to be essential, despite not having a known disease association, 22 are significantly enriched relative to nonessential genes in the set of 1,415 genes with at least one 99th percentile CCR (one-tailed Fisher's exact test, p=8.6e-67, OR=3.73). Furthermore, genes lying in loci with low haplotype diversity are enriched for essential function 23,24 and are similarly prevalent in genes having a 99th percentile CCR.…”