Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information

Capriotti, Emidio; Calabrese, Remo; Casadio, Rita

doi:10.1093/bioinformatics/btl423

Cited by 778 publications

(598 citation statements)

References 24 publications

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“…homolog 1 (Mlh1), Structural maintenance of chromosomes protein 1B (Smc1b), and Testis-expressed gene 15 (Tex15) (Fig. 1B), were then evaluated with six additional tools that predict functional consequences of SNPs: Mutation Assessor, PANTHER, PhD-SNP, SNPs&GO, SNAP, and CADD (20)(21)(22)(23)(24)(25). Overall, each of these four nsSNPs was predicted to be deleterious by at least five of the eight computational algorithms used (Table 1).…”

Section: Significancementioning

confidence: 99%

The genetics of human infertility by functional interrogation of SNPs in mice

Singh

Schimenti

2015

Proc. Natl. Acad. Sci. U.S.A.

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Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association-and linkagefree approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.CRISPR/Cas9 | meiosis | spermatogenesis | cyclin | genome editing

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Section: Significancementioning

confidence: 99%

The genetics of human infertility by functional interrogation of SNPs in mice

Singh

Schimenti

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Variant tolerance prediction methods included Mutation Taster [Schwarz et al, 2010], MutPred [Li et al, 2009], nsSNPAnalyzer [Bao et al, 2005], PhD-SNP [Capriotti et al, 2006], PMut [Ferrer-Costa et al, 2005], PolyPhen2 [Adzhubei et al, 2010], SIFT [Ng and Henikoff, 2003], SNAP [Bromberg and Rost, 2007], and SNPs&GO [Calabrese et al, 2009]. Sequence-based stability effect predictions were performed with SCPRED [Dosztányi et al, 1997], MUPRO [Cheng et al, 2006], and I-Mutant 3.0 [Capriotti et al, 2005], and structurebased predictions with SCide (stabilization centers) [Dosztanyi et al, 2003] and SRide (stabilizing residues) [Magyar et al, 2005] for MSH2 and MSH6 variants.…”

Section: Prediction Of Pathogenicitymentioning

confidence: 99%

Classification of mismatch repair gene missense variants with PON-MMR

Ali¹,

Olatubosun²,

Vihinen

2012

Hum. Mutat.

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“…The new method has an overall accuracy of 84% and area under the curve (AUC) of 0.91. When compared to a previously developed sequence-based method [Capriotti et al, 2006], an increase of 5% in the accuracy and AUC was observed.…”

Section: Prediction Of Variant Functionalitymentioning

confidence: 76%