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A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect disruptions to splicing

ABSTRACT: A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect disruptions to splicing

PROVIDER: PRJNA494162 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7946370_1.fastq.gz	Fastqsanger.gz
	SRR7946370_2.fastq.gz	Fastqsanger.gz
	SRR7946380_1.fastq.gz	Fastqsanger.gz
	SRR7946380_2.fastq.gz	Fastqsanger.gz
	SRR7946371_1.fastq.gz	Fastqsanger.gz

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A Multiplexed Assay for Exon Recognition Reveals that an Unappreciated Fraction of Rare Genetic Variants Cause Large-Effect Splicing Disruptions.

Project description:Mutations that lead to splicing defects can have severe consequences on gene function and cause disease. Here, we explore how human genetic variation affects exon recognition by developing a multiplexed functional assay of splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs). Importantly, we find that 83% of SDVs are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate extant, rare genetic variants can have large functional effects on splicing at appreciable rates, even outside the context of disease, and MFASS enables their empirical assessment at scale.

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A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect disruptions to splicing

Project description:Mutations that cause exon skipping can have severe consequences on gene function and cause disease. Here we explore how human genetic variation affects exon recognition by developing a Multiplexed Functional Assay of Splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter, and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs). Importantly, we find that 83% of SDVs are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate extant, rare genetic variants, even outside the context of disease, can have large functional effects at appreciable rates, and that MFASS enables their empirical assessment for large-effect splicing defects at scale.

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Project description:Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Genes within the same folding domain demonstrate similar expression and histone-modification profiles1. Therefore, boundaries separating different domains have important roles in reinforcing the stability of these domain-wide features. Indeed, domain boundary disruptions in human genetic disorders2,3 or human cancers lead to misregulation of certain genes4,5, due to de novo enhancer exposure to promoters. However, the frequency of boundary disruptions in human cancers, and whether there are recurrently affected boundaries in specific cancer types, remains unclear. Here, to understand effects and distributions of somatic structural variations (SVs) across TADs, we utilized 288,457 high-confidence somatic structural variations from 2658 high-coverage whole genome sequencing datasets across various cancer types. We comprehensively profiled structural variations effects on the domain boundaries and the regulation of genes in human cancers. Notably, most of the TAD disruptions do not result in appreciable changes in nearby gene expression where more than 2-fold expression change was observed in only 14% of regions with the boundary deletions. In addition, we demonstrated that SV types affect TADs differently, specifically, complex rearrangements drastically change chromatin folding maps in the cancer genomes.

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