Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

2017 ◽  
Vol 21 (1) ◽  
pp. 54-67 ◽  
Author(s):  
Jane E Armes ◽  
Mark Williams ◽  
Gareth Price ◽  
Tristan Wallis ◽  
Renee Gallagher ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Early Death ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Rare Disorders ◽  
Infant Deaths ◽  
Genetic Causes ◽  
Early Infant ◽  
Genetic Aberration

Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype–genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death.

scholarly journals One substance to rule them all and in the darkness bind them: whole-genome sequencing illuminates multifaceted targets of humic adaptation in Eurasian perch

2021 ◽  
Author(s):  
Mikhail Ozerov ◽  
Kristina Noreikiene ◽  
Siim Kahar ◽  
Magnus Huss ◽  
Ari Huusko ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Extreme Environments ◽  
Gene Families ◽  
Regulatory Elements ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Humic Lakes ◽  
Whole Genome Analysis ◽  
Eurasian Perch

Extreme environments are inhospitable to the majority of species, but some organisms are able to survive in such hostile conditions due to evolutionary adaptations. For example, modern bony fishes have colonized various aquatic environments, including perpetually dark, hypoxic, hypersaline and toxic habitats. Eurasian perch (Perca fluviatilis) is among the few fish species of northern latitudes that is able to live in extremely acidic humic lakes. Such lakes represent almost “nocturnal” environments; they contain high levels of dissolved organic matter, which in addition to creating a challenging visual environment, also affects a large number of other habitat parameters and biotic interactions. To reveal the genomic targets of humic-associated selection, we performed whole-genome sequencing of perch originating from 16 humic and 16 clear-water lakes in northern Europe. We identified over 800,000 SNPs, of which >10,000 were identified as potential candidates under selection (associated with >3,000 genes) using multiple outlier approaches. Our findings suggest that adaptation to the humic environment involves hundreds of regions scattered across the genome. Putative signals of adaptation were detected in genes and gene families with diverse functions, including organism development and ion transportation. The observed excess of variants under selection in regulatory regions highlights the importance of adaptive evolution via regulatory elements, rather than via protein sequence modification. Our study demonstrates the power of whole-genome analysis to illuminate multifaceted nature of humic adaptation and highlights the next challenge moving from high-throughput outlier identification towards functional validation of causal mutations underlying phenotypic traits of ecological and evolutionary importance.

scholarly journals Molecular Epidemiological Analysis of ST11-K64 Extensively Drug-Resistant Klebsiella pneumoniae Infections Outbreak in Intensive Care and Neurosurgery Units Based on Whole-Genome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Liuxin Xiong ◽  
Lebin Su ◽  
Hanqing Tan ◽  
Wansha Zhao ◽  
Shuying Li ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Relatedness ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Drug Resistant ◽  
Extensively Drug Resistant

Klebsiella pneumoniae (Kp) is the primary causative bacteria for nosocomial infections and hospital outbreaks. In particular, extensively drug-resistant K. pneumoniae (XDRKp) causes severe clinical infections in hospitalized patients. Here, we used pulsed-field gel electrophoresis (PFGE), drug susceptibility tests, and the whole-genome sequencing (WGS) technology to examine genetic relatedness and phenotypic traits of the strains isolated during an outbreak period. Based on PFGE, a distinct clones cluster comprised of eight XDRKp was observed. These strains were confirmed as ST11-K64 via multiple-locus sequence typing database of Kp. The strains also had genes related to the regulation of biofilm biosynthesis (type 1 & 3 fimbriae, type IV pili biosynthesis, RcsAB, and type VI secretion system) and multiple drug resistance (β-lactamase and aminoglycoside antibiotic resistance). WGS data based on core-single nucleotide polymorphisms and epidemiological investigation showed that the neurosurgery unit was likely the source of the outbreak, the strain was likely to have been transmitted to the ICU through patients. In addition, the two highly probable transmission routes were in the ICU (exposure through shared hospital beds) and the neurosurgery units (all cases were treated by the same rehabilitation physician and were most likely infected during the physical therapy). Notably, the bed mattress had played a crucial transmission role of this outbreak, served as a pathogen reservoir.

scholarly journals Homozygous duplication identified by whole genome sequencing causes LRBA deficiency

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Daniele Merico ◽  
Yehonatan Pasternak ◽  
Mehdi Zarrei ◽  
Edward J. Higginbotham ◽  
Bhooma Thiruvahindrapuram ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cytotoxic T Lymphocyte ◽  
Genetic Defect ◽  
Digital Pcr ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Reading Frame ◽  
Inherited Immunodeficiency ◽  
Genetic Aberration

AbstractIn more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.

scholarly journals Multi-OMICS and Molecular Biology Perspective in Buffalo Genome

2021 ◽  
pp. 21-31
Author(s):  
Suranjana Sikdar ◽  
◽  
Tuhin Das ◽  
Emran Hossain Sajib ◽  
Kazi Mahbub Ur Rahman Rahman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Expression Profiling ◽  
Phenotypic Diversity ◽  
Genomic Research ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Single Nucleotide ◽  
Geographical Regions

The bovine species buffalo was domesticated from its wild strain Bubalus arnee and is widely used livestock in southern Asia. There are two distinct types of Buffalo- the swamp buffalo (B. bubalis kerebau) and the river buffalo (B. bubalis bubalis), which diverged from the wild Asian water buffalo and then evolved in separate geographical regions. Several research studies performed on buffalo, like- characterization of trait-specific Single Nucleotide Polymorphism (SNP), genetic and phenotypic diversity, gene prediction and function annotation, mapping of the draft genome, have helped our understanding of the buffalo genome. Some advanced discovery as identification of Single Nucleotide Variant (SNVs), Simple Sequence Repeats (SSR) marker and their association with various phenotypic traits, MicroRNA's expression profiling, whole-genome sequencing, etc. have also enabled us to track the chromosomal evolution, physiological processes, and gene expression of buffalo. Proper enhancement of these traits can lead us to apply multi-omics-based tools for better animal health and production. Recent advancement in genomic research on buffalo is being accelerated with the association of modern tools like- Genome-Wide Association Study (GWAS), genotyping by sequencing, epigenomic screening, microRNA's expression profiling, microarray technology, and whole-genome sequencing. All these tools bear great significance in breed up-gradation, identification of the phylogenetic relationship between species in proteome and genomic level, study gene expression level, diagnose diseases or developmental stages, phenotypic diversity, etc. All this knowledge paved the way for better optimization of production efficiency, product quality, and resistance to certain health hazards.

scholarly journals Crowdfunded whole-genome sequencing of the celebrity cat Lil BUB identifies causal mutations for her osteopetrosis and polydactyly

2019 ◽  
Author(s):  
Mike Bridavsky ◽  
Heiner Kuhl ◽  
Arthur Woodruff ◽  
Uwe Kornak ◽  
Bernd Timmermann ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genomic Analysis ◽  
Heterozygous Mutation ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Genetic Literacy ◽  
Alternative Funding ◽  
Diagnosis And Prognosis ◽  
Frameshift Deletion

AbstractRare diseases and their underlying molecular causes are often poorly studied, posing challenges for patient diagnosis and prognosis. The development of next-generation sequencing and its decreasing costs promises to alleviate such issues by supplying personal genomic information at a moderate price. Here, we used crowdfunding as an alternative funding source to sequence the genome of Lil BUB, a celebrity cat affected by rare disease phenotypes characterized by supernumerary digits, osteopetrosis and dwarfism, all phenotypic traits that also occur in human patients. We discovered that Lil BUB is affected by two distinct mutations: a heterozygous mutation in the limb enhancer of the Sonic hedgehog gene, previously associated with polydactyly in Hemingway cats; and a novel homozygous frameshift deletion affecting the TNFRSF11A (RANK) gene, which has been linked to osteopetrosis in humans. We communicated the progress of this project to a large online audience, detailing the ‘inner workings’ of personalized whole genome sequencing with the aim of improving genetic literacy. Our results highlight the importance of genomic analysis in the identification of disease-causing mutations and support crowdfunding as a means to fund low-budget projects and as a platform for scientific communication.

scholarly journals Analysis of Structural Variants Reveal Novel Selective Regions in the Genome of Meishan Pigs by Whole Genome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Heng Du ◽  
Xianrui Zheng ◽  
Qiqi Zhao ◽  
Zhengzheng Hu ◽  
Haifei Wang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome Sequencing Data ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Structural Variants ◽  
Domestic Pig ◽  
Pig Breeds ◽  
Wide Range ◽  
Meishan Pig

Structural variants (SVs) represent essential forms of genetic variation, and they are associated with various phenotypic traits in a wide range of important livestock species. However, the distribution of SVs in the pig genome has not been fully characterized, and the function of SVs in the economic traits of pig has rarely been studied, especially for most domestic pig breeds. Meishan pig is one of the most famous Chinese domestic pig breeds, with excellent reproductive performance. Here, to explore the genome characters of Meishan pig, we construct an SV map of porcine using whole-genome sequencing data and report 33,698 SVs in 305 individuals of 55 globally distributed pig breeds. We perform selective signature analysis using these SVs, and a number of candidate variants are successfully identified. Especially for the Meishan pig, 64 novel significant selection regions are detected in its genome. A 140-bp deletion in the Indoleamine 2,3-Dioxygenase 2 (IDO2) gene, is shown to be associated with reproduction traits in Meishan pig. In addition, we detect two duplications only existing in Meishan pig. Moreover, the two duplications are separately located in cytochrome P450 family 2 subfamily J member 2 (CYP2J2) gene and phospholipase A2 group IVA (PLA2G4A) gene, which are related to the reproduction trait. Our study provides new insights into the role of selection in SVs' evolution and how SVs contribute to phenotypic variation in pigs.

Utility of Whole Genome Sequencing in diagnosing complex disorders: lesson from renal tubular disorders

2018 ◽  
Author(s):  
Mark Stevenson ◽  
Alistair T Pagnamenta ◽  
Heather G Mack ◽  
Judith A Savige ◽  
Kate E Lines ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Complex Disorders ◽  
Tubular Disorders ◽  
Renal Tubular Disorders ◽  
Renal Tubular
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