scholarly journals Network analysis of genome-wide selective constraint reveals a gene network active in early fetal brain intolerant of mutation

2015 ◽  
Author(s):  
Jinmyung Choi ◽  
Parisa Shooshtari ◽  
Kaitlin E Samocha ◽  
Mark J Daly ◽  
Chris Cotsapas
Keyword(s):  
De Novo ◽  
Sequence Data ◽  
Fetal Brain ◽  
Selective Constraint ◽  
Adverse Outcomes ◽  
Integrated Analysis ◽  
Disease Genes ◽  
De Novo Mutations ◽  
Strong Constraint ◽  
Genome Wide

Using robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriched for genes mutated in neurological, but not other, Mendelian disorders. We thus conclude that carefully orchestrated developmental processes are under strong constraint in early brain development, and perturbations caused by mutation have adverse outcomes subject to strong purifying selection. Our findings demonstrate that selective forces can act on groups of genes involved in the same process, supporting the notion that adaptation can act coordinately on multiple genes. Our approach provides a statistically robust, interpretable way to identify the tissues and developmental times where groups of disease genes are active. Our findings highlight the importance of considering the interactions between genes when analyzing genome-wide sequence data.

scholarly journals Paternally inherited noncoding structural variants contribute to autism

2017 ◽  
Author(s):  
William M. Brandler ◽  
Danny Antaki ◽  
Madhusudan Gujral ◽  
Morgan L. Kleiber ◽  
Michelle S. Maile ◽  
...  
Keyword(s):  
De Novo ◽  
Fetal Brain ◽  
Wide Distribution ◽  
Autism Spectrum ◽  
Structural Variants ◽  
De Novo Mutations ◽  
Whole Genome Analysis ◽  
Protein Coding ◽  
Genome Wide ◽  
Exome Aggregation Consortium

AbstractThe genetic architecture of autism spectrum disorder (ASD) is known to consist of contributions from gene-disrupting de novo mutations and common variants of modest effect. We hypothesize that the unexplained heritability of ASD also includes rare inherited variants with intermediate effects. We investigated the genome-wide distribution and functional impact of structural variants (SVs) through whole genome analysis (≥30X coverage) of 3,169 subjects from 829 families affected by ASD. Genes that are intolerant to inactivating variants in the exome aggregation consortium (ExAC) were depleted for SVs in parents, specifically within fetal-brain promoters, UTRs and exons. Rare paternally-inherited SVs that disrupt promoters or UTRs were over-transmitted to probands (P = 0.0013) and not to their typically-developing siblings. Recurrent functional noncoding deletions implicate the gene LEO1 in ASD. Protein-coding SVs were also associated with ASD (P = 0.0025). Our results establish that rare inherited SVs predispose children to ASD, with differing contributions from each parent.

scholarly journals De novo mutations in regulatory elements cause neurodevelopmental disorders

2017 ◽  
Author(s):  
Patrick J. Short ◽  
Jeremy F. McRae ◽  
Giuseppe Gallone ◽  
Alejandro Sifrim ◽  
Hyejung Won ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Genetic Disorders ◽  
Fetal Brain ◽  
Regulatory Elements ◽  
De Novo Mutations ◽  
Active Elements ◽  
Diagnostic Coding ◽  
Genome Wide

SummaryDe novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetaLbrain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.

scholarly journals Contribution of retrotransposition to developmental disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Protein Coding ◽  
Genome Wide ◽  
De Novo Gene ◽  
The Impact ◽  
Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals HAPDeNovo: a haplotype-based approach for filtering and phasing de novo mutations in linked read sequencing data

2017 ◽  
Author(s):  
Xin Zhou ◽  
Serafim Batzoglou ◽  
Arend Sidow ◽  
Lu Zhang
Keyword(s):  
False Positive ◽  
De Novo ◽  
False Positives ◽  
Sequencing Data ◽  
De Novo Mutations ◽  
Congenital Diseases ◽  
Genome Wide ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Haplotype Information

AbstractBackgroundDe novo mutations (DNMs) are associated with neurodevelopmental and congenital diseases, and their detection can contribute to understanding disease pathogenicity. However, accurate detection is challenging because of their small number relative to the genome-wide false positives in next generation sequencing (NGS) data. Software such as DeNovoGear and TrioDeNovo have been developed to detect DNMs, but at good sensitivity they still produce many false positive calls.ResultsTo address this challenge, we develop HAPDeNovo, a program that leverages phasing information from linked read sequencing, to remove false positive DNMs from candidate lists generated by DNM-detection tools. Short reads from each phasing block are allocated to each of the two haplotypes followed by generating a haploid genotype for each putative DNM.HAPDeNovo removes variants that are called as heterozygous in one of the haplotypes because they are almost certainly false positives. Our experiments on 10X Chromium linked read sequencing trio data reveal that HAPDeNovo eliminates 80% to 99% of false positives regardless of how large the candidate DNM set is.ConclusionsHAPDeNovo leverages the haplotype information from linked read sequencing to remove spurious false positive DNMs effectively, and it increases accuracy of DNM detection dramatically without sacrificing sensitivity.

STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi22-vi22
Author(s):  
Chirayu R Chokshi ◽  
David Tieu ◽  
Kevin R Brown ◽  
Chitra Venugopal ◽  
Lina Liu ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
De Novo ◽  
Tyrosine Phosphatase ◽  
Treatment Resistance ◽  
Recurrent Glioblastoma ◽  
De Novo Mutations ◽  
Genome Wide ◽  
Molecule Inhibitor ◽  
Signaling Axis ◽  
Single Domain Antibodies

Abstract Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to resist chemoradiotherapy and drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel driver of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 repress axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and exploit a genetic dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and present a dependence on a PTP4A2-ROBO1 signaling axis at GBM recurrence.

scholarly journals De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

2021 ◽  
Vol 118 (52) ◽  
pp. e2115140118
Author(s):  
Matthew Halvorsen ◽  
Laura Gould ◽  
Xiaohan Wang ◽  
Gariel Grant ◽  
Raquel Moya ◽  
...  
Keyword(s):  
Sudden Death ◽  
Odds Ratio ◽  
Neuronal Excitability ◽  
De Novo ◽  
Sequence Data ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Sudden Unexplained Death ◽  
Unexplained Death

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 “trios” (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10−4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C. Both RYR2 mutations are pathogenic (P = 1.7 × 10−7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10−7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

scholarly journals Identification of de novo mutations in the Chinese ASD cohort via whole-exome sequencing unveils brain regions implicated in autism

2021 ◽  
Author(s):  
Bo Yuan ◽  
Mengdi Wang ◽  
Xinran Wu ◽  
Peipei Cheng ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Human Brain ◽  
De Novo ◽  
Brain Regions ◽  
Imaging Data ◽  
De Novo Mutations ◽  
Genetic Studies ◽  
Single Cell Sequencing ◽  
Genome Wide ◽  
Whole Exome ◽  
Brain Imaging Data

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts is still under-represented in the genome-wide genetic studies. Here we performed whole-exome sequencing on 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combining with single-cell sequencing data from the developing human brain, we found that expression of genes with de novo mutations were specifically enriched in pre-, post-central gyrus (PRC, PC) and banks of superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and health controls, we found that the gray volume of the right BST in ASD patients significantly decreased comparing to health controls, suggesting the potential structural deficits associated with ASD. Finally, we found that there was decrease in the seed-based functional connectivity (FC) between BST/PC/PRC and sensory areas, insula, as well as frontal lobes in ASD patients. This work indicated that the combinatorial analysis with genome-wide screening, single-cell sequencing and brain imaging data would reveal brain regions contributing to etiology of ASD.

scholarly journals Fetal Brain Infection Is Not a Unique Characteristic of Brazilian Zika Viruses

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 541 ◽  
Author(s):  
Yin Setoh ◽  
Nias Peng ◽  
Eri Nakayama ◽  
Alberto Amarilla ◽  
Natalie Prow ◽  
...  
Keyword(s):  
De Novo ◽  
Sequence Data ◽  
Fetal Brain ◽  
Vero Cells ◽  
Neurological Complications ◽  
Interferon Α ◽  
Brain Infection ◽  
Recent Emergence ◽  
Congenital Zika Syndrome

The recent emergence of Zika virus (ZIKV) in Brazil was associated with an increased number of fetal brain infections that resulted in a spectrum of congenital neurological complications known as congenital Zika syndrome (CZS). Herein, we generated de novo from sequence data an early Asian lineage ZIKV isolate (ZIKV-MY; Malaysia, 1966) not associated with microcephaly and compared the in vitro replication kinetics and fetal brain infection in interferon α/β receptor 1 knockout (IFNAR1−/−) dams of this isolate and of a Brazilian isolate (ZIKV-Natal; Natal, 2015) unequivocally associated with microcephaly. The replication efficiencies of ZIKV-MY and ZIKV-Natal in A549 and Vero cells were similar, while ZIKV-MY replicated more efficiently in wild-type (WT) and IFNAR−/− mouse embryonic fibroblasts. Viremias in IFNAR1−/− dams were similar after infection with ZIKV-MY or ZIKV-Natal, and importantly, infection of fetal brains was also not significantly different. Thus, fetal brain infection does not appear to be a unique feature of Brazilian ZIKV isolates.

scholarly journals Convergent evolution of conserved mitochondrial pathways underlies repeated adaptation to extreme environments

2020 ◽  
Vol 117 (28) ◽  
pp. 16424-16430 ◽  
Author(s):  
Ryan Greenway ◽  
Nick Barts ◽  
Chathurika Henpita ◽  
Anthony P. Brown ◽  
Lenin Arias Rodriguez ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Convergent Evolution ◽  
De Novo ◽  
Extreme Environments ◽  
De Novo Mutations ◽  
Poecilia Mexicana ◽  
Genome Wide ◽  
Different Populations ◽  
Mechanistic Basis ◽  
Harsh Conditions

Extreme environments test the limits of life; yet, some organisms thrive in harsh conditions. Extremophile lineages inspire questions about how organisms can tolerate physiochemical stressors and whether the repeated colonization of extreme environments is facilitated by predictable and repeatable evolutionary innovations. We identified the mechanistic basis underlying convergent evolution of tolerance to hydrogen sulfide (H2S)—a toxicant that impairs mitochondrial function—across evolutionarily independent lineages of a fish (Poecilia mexicana, Poeciliidae) from H2S-rich springs. Using comparative biochemical and physiological analyses, we found that mitochondrial function is maintained in the presence of H2S in sulfide springP. mexicanabut not ancestral lineages from nonsulfidic habitats due to convergent adaptations in the primary toxicity target and a major detoxification enzyme. Genome-wide local ancestry analyses indicated that convergent evolution of increased H2S tolerance in different populations is likely caused by a combination of selection on standing genetic variation and de novo mutations. On a macroevolutionary scale, H2S tolerance in 10 independent lineages of sulfide spring fishes across multiple genera of Poeciliidae is correlated with the convergent modification and expression changes in genes associated with H2S toxicity and detoxification. Our results demonstrate that the modification of highly conserved physiological pathways associated with essential mitochondrial processes mediates tolerance to physiochemical stress. In addition, the same pathways, genes, and—in some instances—codons are implicated in H2S adaptation in lineages that span 40 million years of evolution.

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