Noncoding deletions reveal a gene that is critical for intestinal function

Oz-Levi, Danit; Olender, Tsviya; Bar-Joseph, Ifat; Zhu, Yiwen; Marek‐Yagel, Dina; Barozzi, Iros; Osterwalder, Marco; Alkelai, Anna; Ruzzo, Elizabeth K.; Han, Yujun; Vos, Erica S.M.; Reznik‐Wolf, Haike; Hartman, Corina; Shamir, Raanan; Weiss, Batia; Shapiro, Rivka; Pode‐Shakked, Ben; Tatarskyy, Pavel; Milgrom, Roni; Schvimer, Michael; Barshack, Iris; Imai, Denise M.; Coleman‐Derr, Devin; Dickel, Diane E.; Nord, Alexander; Afzal, Veena; Bueren, Kelly Lammerts van; Barnes, Ralston M.; Black, Brian L.; Mayhew, Christopher N.; Kuhar, Matthew; Pitstick, Amy; Tekman, Mehmet; Stanescu, Horia; Wells, James M.; Kleta, Robert; Laat, Wouter de; Goldstein, David B.; Pras, Elon; Visel, Axel; Lancet, Doron; Anikster, Yair; Pennacchio, Len A.

doi:10.1038/s41586-019-1312-2

Cited by 28 publications

(24 citation statements)

References 33 publications

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“…The first is a TATA box mutation in UGT1A1 (NM_000463.2:c.-41_-40dupTA) [36]. The second is a deletion (chr16:1480850_1483950del) in a patient with unexplained diarrhea, and this deletion was reported very recently to be the cause of chronic diarrhea secondary to its regulatory effect on PERCC1 [37].…”

Section: Quantifying the Contribution Of Transcript-deleterious Variantsmentioning

confidence: 99%

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics

et al. 2020

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Background: At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which noncoding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results: Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all "solved" cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received "negative" clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions: Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.

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Section: Quantifying the Contribution Of Transcript-deleterious Variantsmentioning

confidence: 99%

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics

et al. 2020

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“…In contrast to the well-established effects of coding variation, the impact of noncoding SVs on regulatory elements is mostly unknown. Examples of SVs with strong noncoding effects are scarce in humans and model organisms, [39][40][41] though recent studies have shown that noncoding SVs are relevant for gene regulation and disease. 42,43 We explored noncoding dosage sensitivity across a spectrum of 14 regulatory element classes, ranging from high-confidence experimentally validated enhancers to large databases of computationally predicted elements.…”

Section: Figure 3 | Genome-wide Mutational Patterns Of Svsmentioning

confidence: 99%

An open resource of structural variation for medical and population genetics

Team¹

2019

Preprint

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Structural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation.To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute. org) and will have broad utility for population genetics, disease association, and diagnostic screening.

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“…These studies may lead one to the interpretation that loss of an individual enhancer is not likely to produce strong phenotypic effects. However, it has been shown that alterations at single enhancers are linked to rare Mendelian diseases [23][24][25][26]. Thus, based on our current understanding, the phenotypic effects of enhancer LoF likely fall into a spectrum where deletion of LoF-tolerant enhancers would not elicit substantial phenotypic impact, while some enhancers are likely to cause fitness defects even when single enhancers exhibit LoF.…”

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confidence: 99%

Loss-of-function tolerance of enhancers in the human genome

Gökçümen

Khurana

2020

PLoS Genet

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Previous studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that individual human genomes possess at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers tend to be more tissue-specific and regulate fewer and more dispensable genes relative to other enhancers. They are enriched in immune-related cells while enhancers with low LoF-tolerance are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoFtolerance of all enhancers, which achieved an area under the receiver operating characteristics curve (AUROC) of 98%. We predict 3,519 more enhancers would be likely tolerant to LoF and 129 enhancers that would have low LoF-tolerance. Our predictions are supported by a known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies. Author summaryEnhancers are elements where transcription factors bind and regulate the expression of protein-coding genes. Although multiple previous studies have focused on which genes can tolerate loss-of-function (LoF), none has systematically evaluated the tolerance of all enhancers in the human genome to LoF. Individual studies have shown a broad range of phenotypic effects of enhancer LoF. The phenotypic effects of enhancer LoF likely fall into a spectrum where deletion of LoF-tolerant enhancers would not elicit substantial phenotypic impact, while some enhancers are likely to cause fitness defects when deleted. Here PLOS GENETICSPLOS Genetics | https://doi.

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Noncoding deletions reveal a gene that is critical for intestinal function

Cited by 28 publications

References 33 publications

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics

An open resource of structural variation for medical and population genetics

Loss-of-function tolerance of enhancers in the human genome

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