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

2015 ◽  
Vol 112 (44) ◽  
pp. 13615-13620 ◽  
Author(s):  
Yuval Itan ◽  
Lei Shang ◽  
Bertrand Boisson ◽  
Etienne Patin ◽  
Alexandre Bolze ◽  
...  
Keyword(s):  
General Population ◽  
De Novo ◽  
Damage Index ◽  
Monogenic Disease ◽  
Sequence Length ◽  
De Novo Mutations ◽  
Protein Coding ◽  
A Genome ◽  
Gene Level ◽  
Gene Damage

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.

scholarly journals Haplotyping by linked-read sequencing (HLRS) of the genetic disease carriers for preimplantation genetic testing without a proband or relatives

2020 ◽  
Author(s):  
Qing Li ◽  
Yan Mao ◽  
Shaoying Li ◽  
Hongzi Du ◽  
Wenzhi He ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Disease ◽  
De Novo ◽  
Monogenic Disease ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Preimplantation Genetic Testing ◽  
Linkage Analyses ◽  
Alpha Thalassemia ◽  
Polar Bodies

Abstract Background: In order to mitigate the risk of allele dropout (ADO) and ensure the accuracy of preimplantation genetic testing for monogenic disease (PGT-M), it is necessary to construct parental haplotypes.. Typically, haplotype resolution is obtained by genotyping multiple polymorphic markers in both parents and a proband or a relative. Sometimes, single sperm typing, or tests on the polar bodies may also be useful. Nevertheless, this process is time-consuming. At present, there was no simple linkage analysis strategy for patients without affected relatives.Method: To solve this problem, we established a haplotyping by linked-read sequencing (HLRS) method without the requirement for additional relatives. First, the haplotype of the genetic disease carriers in the family was constructed by linked-read sequencing, and then the informative single nucleotide polymorphisms (SNPs) in upstream and downstream mutation region were selected to construct the embryo haplotype and to determine whether the embryo was carrying the mutation. Two families were selected to validate this method; one with alpha thalassemia and the other with NDP gene disorder.Results: The haplotyping by linked-read sequencing (HLRS) method was successfully applied to construct parental haplotypes without recruiting additional family members; the method was also validated for PGT-M. The mutation carriers in these families were sequenced by linked-read sequencing, and their haplotypes were successfully phased. Adjacent SNPs of the mutation gene were identified. The informative SNPs were chosen for linkage analyses to identify the carrier embryos. For the alpha thalassemia family, a normal blastocyst was transferred to the uterus and the accuracy of PGT-M was confirmed by amniocentesis at 16 weeks of gestation. Conclusions: Our results suggest that HLRS can be applied for PGT-M of monogenic disorders or de novo mutations where the mutations haplotype cannot be determined due to absence of affected relatives. Keywords: Preimplantation Genetic Testing for monogenic disease, Linked-read sequencing, Linkage analyses, Haplotype

scholarly journals Draft Genome Assembly and Annotation of Red Raspberry Rubus Idaeus

2019 ◽  
Author(s):  
Haley Wight ◽  
Junhui Zhou ◽  
Muzi Li ◽  
Sridhar Hannenhalli ◽  
Stephen M. Mount ◽  
...  
Keyword(s):  
De Novo ◽  
Draft Genome ◽  
Rubus Idaeus ◽  
Slow Process ◽  
Red Raspberry ◽  
Protein Coding ◽  
Draft Genome Assembly ◽  
Protein Coding Genes ◽  
A Genome ◽  
Exceptional Value

AbstractThe red raspberry, Rubus idaeus, is widely distributed in all temperate regions of Europe, Asia, and North America and is a major commercial fruit valued for its taste, high antioxidant and vitamin content. However, Rubus breeding is a long and slow process hampered by limited genomic and molecular resources. Genomic resources such as a complete genome sequencing and transcriptome will be of exceptional value to improve research and breeding of this high value crop. Using a hybrid sequence assembly approach including data from both long and short sequence reads, we present the first assembly of the Rubus idaeus genome (Joan J. variety). The de novo assembled genome consists of 2,145 scaffolds with a genome completeness of 95.3% and an N50 score of 638 KB. Leveraging a linkage map, we anchored 80.1% of the genome onto seven chromosomes. Using over 1 billion paired-end RNAseq reads, we annotated 35,566 protein coding genes with a transcriptome completeness score of 97.2%. The Rubus idaeus genome provides an important new resource for researchers and breeders.

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 A sporadic case of congenital aniridia caused by pericentric inversion inv(11)(p13q14) associated with a 977 kb deletion in the 11p13 region

2020 ◽  
Vol 13 (S8) ◽  
Author(s):  
Tatyana A. Vasilyeva ◽  
Andrey V. Marakhonov ◽  
Marina E. Minzhenkova ◽  
Zhanna G. Markova ◽  
Nika V. Petrova ◽  
...  
Keyword(s):  
General Population ◽  
Pericentric Inversion ◽  
De Novo ◽  
Wilms Tumor ◽  
Normal Karyotype ◽  
Paternal Allele ◽  
De Novo Mutations ◽  
Chromosome 11 ◽  
Dna Diagnosis ◽  
Congenital Aniridia

Abstract Background Because of the significant occurrence of “WAGR-region” deletions among de novo mutations detected in congenital aniridia, DNA diagnosis is critical for all sporadic cases of aniridia due to its help in making an early diagnosis of WAGR syndrome. Standard cytogenetic karyotype study is a necessary step of molecular diagnostics in patients with deletions and in the patients’ parents as it reveals complex chromosomal rearrangements and the risk of having another affected child, as well as to provide prenatal and/or preimplantation diagnostics. Case presentation DNA samples were obtained from the proband (a 2-year-old boy) and his two healthy parents. Molecular analysis revealed a 977.065 kb deletion that removed loci of the ELP4, PAX6, and RCN1 genes but did not affect the coding sequence of the WT1 gene. The deletion occurred de novo on the paternal allele. The patient had normal karyotype 46,XY and a de novo pericentric inversion of chromosome 11, inv(11)(p13q14). Conclusions We confirmed the diagnosis of congenital aniridia at the molecular level. For the patient, the risk of developing Wilms’ tumor is similar to that in the general population. The recurrence risk for sibs in the family is low, but considering the possibility of gonadal mosaicism, it is higher than in the general population.

scholarly journals De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome

2020 ◽  
Vol 139 (11) ◽  
pp. 1363-1379
Author(s):  
Roser Ufartes ◽  
Hanna Berger ◽  
Katharina Till ◽  
Gabriela Salinas ◽  
Marc Sturm ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Xenopus Laevis ◽  
Cellular Localization ◽  
De Novo ◽  
Postnatal Growth ◽  
Global Developmental Delay ◽  
De Novo Mutations ◽  
Protein Coding ◽  
Aberrant Phenotype ◽  
Craniofacial Defects

Abstract We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome.

scholarly journals Transcriptomic and Epigenomic Landscape in Rett Syndrome

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 967
Author(s):  
Domenico Marano ◽  
Salvatore Fioriniello ◽  
Maurizio D'Esposito ◽  
Floriana Della Ragione
Keyword(s):  
Rett Syndrome ◽  
Transcriptional Activation ◽  
Large Scale ◽  
Developmental Disorder ◽  
De Novo ◽  
Current Knowledge ◽  
Biological Processes ◽  
De Novo Mutations ◽  
Protein Coding ◽  
Methylated Dna

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.

scholarly journals De novo assembly and characterization of the first draft genome of quince (Cydonia oblonga Mill.)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aysenur Soyturk ◽  
Fatima Sen ◽  
Ali Tevfik Uncu ◽  
Ibrahim Celik ◽  
Ayse Ozgur Uncu
Keyword(s):  
Ab Initio ◽  
De Novo ◽  
Draft Genome ◽  
Mirna Precursor ◽  
Machine Learning Algorithms ◽  
Genomic Research ◽  
Support Vector ◽  
Cydonia Oblonga ◽  
Protein Coding ◽  
A Genome

AbstractQuince (Cydonia oblonga Mill.) is the sole member of the genus Cydonia in the Rosacea family and closely related to the major pome fruits, apple (Malus domestica Borkh.) and pear (Pyrus communis L.). In the present work, whole genome shotgun paired-end sequencing was employed in order to assemble the first draft genome of quince. A genome assembly that spans 488.4 Mb of sequence corresponding to 71.2% of the estimated genome size (686 Mb) was produced in the study. Gene predictions via ab initio and homology-based sequence annotation strategies resulted in the identification of 25,428 and 30,684 unique putative protein coding genes, respectively. 97.4 and 95.6% of putative homologs of Arabidopsis and rice transcription factors were identified in the ab initio predicted genic sequences. Different machine learning algorithms were tested for classifying pre-miRNA (precursor microRNA) coding sequences, identifying Support Vector Machine (SVM) as the best performing classifier. SVM classification predicted 600 putative pre-miRNA coding loci. Repetitive DNA content of the assembly was also characterized. The first draft assembly of the quince genome produced in this work would constitute a foundation for functional genomic research in quince toward dissecting the genetic basis of important traits and performing genomics-assisted breeding.

scholarly journals De novo phased assembly of the Vitis riparia grape genome

2019 ◽  
Author(s):  
Nabil Girollet ◽  
Bernadette Rubio ◽  
Pierre-François Bert
Keyword(s):  
Genome Assembly ◽  
De Novo ◽  
Genomic Analysis ◽  
Comparative Genomic ◽  
Protein Coding ◽  
Important Species ◽  
Vitis Riparia ◽  
Fruit Species ◽  
Long Reads ◽  
A Genome

AbstractGrapevine is one of the most important fruit species in the world. In order to better understand genetic basis of traits variation and facilitate the breeding of new genotypes, we sequenced, assembled, and annotated the genome of the American native Vitis riparia, one of the main species used worldwide for rootstock and scion breeding. A total of 164 Gb raw DNA reads were obtained from Vitis riparia resulting in a 225X depth of coverage. We generated a genome assembly of the V. riparia grape de novo using the PacBio long-reads that was phased with the 10x Genomics Chromium linked-reads. At the chromosome level, a 500 Mb genome was generated with a scaffold N50 size of 1 Mb. More than 34% of the whole genome were identified as repeat sequences, and 37,207 protein-coding genes were predicted. This genome assembly sets the stage for comparative genomic analysis of the diversification and adaptation of grapevine and will provide a solid resource for further genetic analysis and breeding of this economically important species.

scholarly journals Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype–phenotype correlations in the Chinese population

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Yuduo Wu ◽  
Hairui Sun ◽  
Jianbin Wang ◽  
Xin Wang ◽  
Ming Gong ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Marfan Syndrome ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
De Novo ◽  
Low Frequency ◽  
Monogenic Disease ◽  
De Novo Mutations ◽  
Fbn1 Gene ◽  
Whole Exome

Abstract Marfan syndrome (MFS) is a dominant monogenic disease caused by mutations in fibrillin 1 (FBN1). Cardiovascular complications are the leading causes of mortality among MFS. In the present study, a whole-exome sequencing of MFS in the Chinese population was conducted to investigate the correlation between FBNI gene mutation and MFS. Forty-four low-frequency harmful loci were identified for the FBN1 gene in HGMD database. In addition, 38 loci were identified in the same database that have not been related to MFS before. A strict filtering and screening protocol revealed two patients of the studied group have double mutations in the FBN1 gene. The two patients harboring the double mutations expressed a prominent, highly pathological phenotype in the affected family. In addition to the FBN1 gene, we also found that 27 patients had mutations in the PKD1 gene, however these patients did not have kidney disease, and 16 of the 27 patients expressed aortic related complications. Genotype-phenotype analysis showed that patients with aortic complications are older in the family, aged between 20 and 40 years.

scholarly journals Draft Genome of the Rice Coral Montipora capitata Obtained from Linked-Read Sequencing

2019 ◽  
Vol 11 (7) ◽  
pp. 2045-2054 ◽  
Author(s):  
Martin Helmkampf ◽  
M Renee Bellinger ◽  
Scott M Geib ◽  
Sheina B Sim ◽  
Misaki Takabayashi
Keyword(s):  
Tandem Repeats ◽  
De Novo ◽  
Draft Genome ◽  
Cost Effective ◽  
Sequence Length ◽  
High Molecular Weight Dna ◽  
Protein Coding ◽  
Montipora Capitata ◽  
Considerable Uncertainty ◽  
Repeat Content

Abstract The rice coral, Montipora capitata, is widely distributed throughout the Indo-Pacific and comprises one of the most important reef-building species in the Hawaiian Islands. Here, we describe a de novo assembly of its genome based on a linked-read sequencing approach developed by 10x Genomics. The final draft assembly consisted of 27,870 scaffolds with a N50 size of 186 kb and contained a fairly complete set (81%) of metazoan benchmarking (BUSCO) genes. Based on haploid assembly size (615 Mb) and read k-mer profiles, we estimated the genome size to fall between 600 and 700 Mb, although the high fraction of repetitive sequence introduced considerable uncertainty. Repeat analysis indicated that 42% of the assembly consisted of interspersed, mostly unclassified repeats, and almost 3% tandem repeats. We also identified 36,691 protein-coding genes with a median coding sequence length of 807 bp, together spanning 7% of the assembly. The high repeat content and heterozygosity of the genome proved a challenging scenario for assembly, requiring additional steps to merge haplotypes and resulting in a higher than expected fragmentation at the scaffold level. Despite these challenges, the assembly turned out to be comparable in most quality measures to that of other available coral genomes while being considerably more cost-effective, especially with respect to long-read sequencing methods. Provided high-molecular-weight DNA is available, linked-read technology may thus serve as a valuable alternative capable of providing quality genome assemblies of nonmodel organisms.

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