Mutation severity spectrum of rare alleles in the human genome is predictive of disease type

Abstract

The human genome harbors a variety of genetic variations. Single-nucleotide changes that alter amino acids in protein-coding regions are one of the major causes of human phenotypic variation and diseases. These single-amino acid variations (SAVs) are routinely found in whole genome and exome sequencing. Evaluating the functional impact of such genomic alterations is crucial for diagnosis of genetic disorders. We developed DeepSAV, a deep-learning convolutional neural network to differentiate disease-causing and benign SAVs based on a variety of protein sequence, structural and functional properties. Our method outperforms most stand-alone programs and has similar predictive power as some of the best available. We transformed DeepSAV scores of rare SAVs observed in the general population into a mutation severity measure of protein-coding genes. This measure reflects a gene's tolerance to deleterious missense mutations and serves as a useful tool to study gene-disease associations. Genes implicated in cancer, autism, and viral interaction are found by this measure as intolerant to mutations, while genes associated with a number of other diseases are scored as tolerant. Among known diseaseassociated genes, those that are mutation-intolerant are likely to function in development and signal transduction pathways, while those that are mutation-tolerant tend to encode metabolic and mitochondrial proteins.

Molecular and in vivo phenotyping of missense variants of the human glucagon receptor

“…A recent study showed that mutation-tolerant genes exemplified by olfactory receptors ( i.e. , those with fewer disease mutations) tend to function in metabolism, whereas more mutation-intolerant genes tended to function in development and signal transduction pathways ( 37 ). These findings imply a higher fitness cost for mutations in developmental than in metabolic genes ( 38 ).…”

“…The glucagon receptor ranked among the lowest on the list with only one known disease-associated mutation, rs1801483/G40ECDS associating with diabetes, recorded in DisGeNET (37). A recent study showed that mutation-tolerant genes exemplified by olfactory receptors, (i.e., those with fewer disease mutations), tend to function in metabolism, whereas more mutation-intolerant genes tended to function in development and signal transduction pathways (38).These findings imply a higher fitness cost for mutations in developmental than in metabolic genes (39).…”

Estimation of CYP3A4*1B Single Nucleotide Polymorphism Using Target-Assembled In-Situ Detection by Synthetic DNA-Mounted Excimers

“…Evidently, the different hydrogenbonding and stacking in G/T and G/A mismatches results in different thermodynamic trends and the energy and structural information are the compositions of the following variables, such as bond angle energies, bond energies, planarity energies, dihedral angle energies, Van der Waals energies or/and electrostatic energies. These results indicate that duplexes containing mismatches are considerably destabilized (Figure 5) compared with their correctly paired parent the extent being dependent on the base composition and sequence of the The mismatch of DNA leads to alterations of amino acid properties and can cause a change in protein structure [45,46]. Consequently, SNP may affect enzyme activity through the modification of protein structure and function [47].…”

Whole-genome sequencing identifies variants inANK1,LRRN1,HAS1,and other genes and regulatory regions for stroke in type 1 diabetes

“…Due to the rarity of the variant, we performed additional genotyping for replication, whereby the variant replicated for hemorrhagic stroke (p-value=0.02, N=3,263). Recessive variants can have high mutation severity in comparison to e.g., autosomal dominant variants 33 . Therefore, we further considered a recessive inheritance model and identified a genome-wide significant variant on DHX8 intron with the minimal adjustment (rs1728177, p-value=7.19×10 -9 , MAF=26%) (Extended Data Fig.…”