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 deeplearning 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 the version incorporating population and gene-level information (DeepSAV+PG) has similar predictive power as some of the best available. We transformed DeepSAV scores of rare SAVs in the human population into a quantity termed "mutation severity measure" for each human protein-coding gene. It 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 disease-associated 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.

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

“…For variants available only in one data set we utilized Firth regression (MAC≥5) 25 . Recessive variants can have high mutation severity in comparison to e.g., autosomal dominant variants 27 . Thus, we further analyzed the genome with a recessive inheritance model by exploiting a similar scheme (total homozygote minor allele carriers ≥5; WES and WGS homozygote carriers ≥2).…”

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

“…To date, more than 6000 rare diseases have been reported worldwide, approximately 80% of which are caused by pathogenetic variants [53]. Missense variants are included among the variants in approximately 80% of the rare disease-associated genes [54]. Missense variants possibly cause misfolding or unfolding of the encoded proteins, which are then degraded by the ERAD pathway.…”

Genome interpretation using in silico predictors of variant impact

“…Methods citations (Adzhubei et al 2010 ; Alirezaie et al 2018 ; Baugh et al 2016 ; Bendl et al 2014 , 2016 ; Bromberg and Rost 2007 ; Calabrese et al 2009 ; Capriotti et al 2013 , 2006 ; Carter et al 2013 ; Chennen et al 2020 ; Choi et al 2012 ; Chun and Fay 2009 ; Dong et al 2015 ; Gonzalez-Perez and Lopez-Bigas 2011 ; Gray et al 2018 ; Gulko et al 2015 ; Hecht et al 2015 ; Ioannidis et al 2016 ; Ionita-Laza et al 2016 ; Jagadeesh et al 2016 ; Katsonis and Lichtarge 2014 ; Kircher et al 2014 ; Li et al 2009 , 2020 ; Munro and Singh 2020 ; Ng and Henikoff 2001 , 2003 ; Niroula et al 2015 ; Olatubosun et al 2012 ; Pei et al 2020 ; Pejaver et al 2020 ; Ponzoni et al 2020 ; Qi et al 2021 ; Quang et al 2015 ; Quinodoz et al 2022 ; Raimondi et al 2016 , 2017 ; Ramensky et al 2002 ; Reva et al 2011 ; Rogers et al 2018 ; Samocha et al 2017 ; Schwarz et al 2010 ; Shihab et al 2013 , 2014 , 2015 ; Stone and Sidow 2005 ; Sundaram et al 2018 ; Takeda et al 2020 ; Tavtigian et al 2006 ; Thomas et al 2003 ; Vaser et al 2016 ; Yue et al 2005 ...…”