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Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

ABSTRACT: Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.

SUBMITTER: Coban-Akdemir Z

PROVIDER: S-EPMC6081281 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

Coban-Akdemir Zeynep Z White Janson J JJ Song Xiaofei X Jhangiani Shalini N SN Fatih Jawid M JM Gambin Tomasz T Bayram Yavuz Y Chinn Ivan K IK Karaca Ender E Punetha Jaya J Poli Cecilia C Boerwinkle Eric E Shaw Chad A CA Orange Jordan S JS Gibbs Richard A RA Lappalainen Tuuli T Lupski James R JR Carvalho Claudia M B CMB

American journal of human genetics 20180719 2

Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within ...[more]

PMID: 30032986

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Project description:BackgroundGossypium hirsutum L. is grown worldwide and is the largest source of natural fiber crop. We focus on exploring the favorable alleles (FAs) for upland cotton varieties improvement, and further understanding the history of accessions selection and acumination of favorable allele during breeding.ResultsThe genetic basis of phenotypic variation has been studied. But the accumulation of favorable alleles in cotton breeding history in unknown, and potential favorable alleles to enhance key agronomic traits in the future cotton varieties have not yet been identified. Therefore, 419 upland cotton accessions were screened, representing a diversity of phenotypic variations of 7362 G. hirsutum, and 15 major traits were investigated in 6 environments. These accessions were categorized into 3 periods (early, medium, and modern) according to breeding history. All accessions were divided into two major groups using 299 polymorphic microsatellite markers: G1 (high fiber yield and quality, late maturity) and G2 (low fiber yield and quality, early maturity). The proportion of G1 genotype gradually increased from early to modern breeding periods. Furthermore, 21 markers (71 alleles) were significantly associated (-log P > 4) with 15 agronomic traits in multiple environments. Seventeen alleles were identified as FAs; these alleles accumulated more in the modern period than in other periods, consistent with their phenotypic variation trends in breeding history. Our results demonstrate that the favorable alleles accumulated through breeding effects, especially for common favorable alleles. However, the potential elite accessions could be rapidly screened by rare favorable alleles.ConclusionIn our study, genetic variation and genome-wide associations for 419 upland cotton accessions were analyzed. Two favorable allele types were identified during three breeding periods, providing important information for yield/quality improvement of upland cotton germplasm.

Dataset Information

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

Publications

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

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