The human gene connectome as a map of short cuts for morbid allele discovery

Itan, Yuval; Zhang, Shen-Ying; Vogt, Guillaume; Abhyankar, Avinash; Herman, Melina; Nitschké, Patrick; Fried, Dror; Quintana-Murci, Lluı́s; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1073/pnas.1218167110

Cited by 76 publications

(99 citation statements)

References 41 publications

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“…We found that biological proximity, as predicted by the human gene connectome, was greater among high-GDI genes and among low-GDI genes than for randomly selected human genes (P < 1.0 × 10 −5 for both sets) (15)(16)(17). This biological proximity suggests that high-GDI genes are functionally related to each other, as are low-GDI genes.…”

Section: Genes Found To Be Highly Mutated In Patients With Monogenicmentioning

confidence: 69%

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The human gene damage index as a gene-level approach to prioritizing exome variants

Itan

Shang

Boisson

et al. 2015

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

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The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.

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Section: Genes Found To Be Highly Mutated In Patients With Monogenicmentioning

confidence: 69%

“…Finally, a consideration of copy number variation would also refine the calculation of the GDI (49). The rigorous study of mutational damage across human genes, at the genome-wide and population levels, together with other genome-wide approaches (11,15,50,51), should facilitate studies of human genetics, particularly for monogenic disorders.…”

Section: Discussionmentioning

confidence: 99%

The human gene damage index as a gene-level approach to prioritizing exome variants

Itan

Shang

Boisson

et al. 2015

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

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221

239

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“…bwh.harvard.edu/pph2/), which predicts the effect of an amino acid substitution on the structure and function of human proteins. BCL10 ranked very highly in the human gene connectomes of MALT1, CARD11, and CARD9 (17). A homozygous splice site Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

Torres¹,

Martı́nez-Barricarte²,

García-Gómez³

et al. 2014

J. Clin. Invest.

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Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.

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“…A number of gene-and variant-level methods have been proposed for the analysis of WES data to select candidate variants in rare Mendelian disorders and more common traits (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These analyses benefit from the use of additional information, such as familial linkage, homozygosity rate, and ethnic background, which are commonly used in the study of inherited diseases (14)(15)(16)(17).…”

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confidence: 99%

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Belkadi

Pedergnana

Cobat

et al. 2016

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

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Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions.exome sequencing | genotyping array | population structure | homozygosity mapping | linkage analysis W hole-exome sequencing (WES) has become the leading strategy for uncovering germ-line exome variants in humans. A number of gene-and variant-level methods have been proposed for the analysis of WES data to select candidate variants in rare Mendelian disorders and more common traits (1-13). These analyses benefit from the use of additional information, such as familial linkage, homozygosity rate, and ethnic background, which are commonly used in the study of inherited diseases (14-17). Genomewide single-nucleotide variant array (GWSAs) are the gold standard method for linkage analysis, because they provide maximal linkage information for the whole genome (18). GWSAs are also classically used to estimate homozygosity rate in patients, confirming or sometimes, revealing parental consanguinity through the inbreeding coefficient parameter F in particular (19,20). Population stratification can be an issue in the analysis of population-based genetic data, including WES, particularly for association studies (21-24). Population structures have been widely determined by GWSA (25, 26) in European (27), African (28, 29), Asian (30), Jewish (31), Mexican (32), and other populations (33). These analyses are mostly based on principal component analysis (PCA) (34), which can also be used to confirm or reveal the ethnicity of an individual patient (or his or her parents).U...

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The human gene connectome as a map of short cuts for morbid allele discovery

Cited by 76 publications

References 41 publications

The human gene damage index as a gene-level approach to prioritizing exome variants

The human gene damage index as a gene-level approach to prioritizing exome variants

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

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