Systems Biology Analysis of Human Genomes Points to Key Pathways Conferring Spina Bifida Risk

Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance and environmental influences that hamper GWAS approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases vs. controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation and essential transcriptional regulation, indicating their impact on the pathogenesis of human SB. Additionally, interrogation of conserved non-coding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to interrogation of coding and non-coding sequence variant contributions to rare complex genetic disorders.

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Systems biology analysis of human genomes points to key pathways conferring spina bifida risk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106844118 ◽

2021 ◽

Vol 118 (51) ◽

pp. e2106844118

Author(s):

Vanessa Aguiar-Pulido ◽

Paul Wolujewicz ◽

Alexander Martinez-Fundichely ◽

Eran Elhaik ◽

Gaurav Thareja ◽

...

Keyword(s):

Systems Biology ◽

Spina Bifida ◽

Association Studies ◽

Mendelian Inheritance ◽

Population Substructure ◽

Whole Genome Sequence ◽

Incomplete Penetrance ◽

Sequence Variant ◽

Genome Wide Association Studies ◽

Genome Wide

Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.

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A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽

10.3390/genes12050643 ◽

2021 ◽

Vol 12 (5) ◽

pp. 643

Author(s):

Thibaud Kuca ◽

Brandy M. Marron ◽

Joana G. P. Jacinto ◽

Julia M. Paris ◽

Christian Gerspach ◽

...

Keyword(s):

Genome Wide Association Study ◽

Homozygosity Mapping ◽

Mendelian Inheritance ◽

Large Animal Model ◽

Large Animal ◽

Loss Of Function ◽

Protein Coding ◽

Positional Candidate ◽

Genome Wide ◽

A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

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The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

Endocrine Reviews ◽

10.1210/er.2017-00232 ◽

2018 ◽

Vol 39 (5) ◽

pp. 676-700 ◽

Cited By ~ 38

Author(s):

Mylène Tajan ◽

Romain Paccoud ◽

Sophie Branka ◽

Thomas Edouard ◽

Armelle Yart

Keyword(s):

Noonan Syndrome ◽

Mapk Pathway ◽

Genetic Disorders ◽

Mapk Signaling ◽

Mendelian Inheritance ◽

Disease Genes ◽

Type I ◽

Future Directions ◽

Legius Syndrome ◽

Anagen Hair

Abstract Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.

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Genomic Analysis of Sarcomyxa edulis Reveals the Basis of Its Medicinal Properties and Evolutionary Relationships

Frontiers in Microbiology ◽

10.3389/fmicb.2021.652324 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fenghua Tian ◽

Changtian Li ◽

Yu Li

Keyword(s):

Single Molecule ◽

De Novo ◽

Genomic Analysis ◽

Single Copy ◽

Whole Genome Sequence ◽

Type I ◽

Whole Genome ◽

Uridine Diphosphate ◽

Protein Coding ◽

Medicinal Value

Yuanmo [Sarcomyxa edulis (Y.C. Dai, Niemelä & G.F. Qin) T. Saito, Tonouchi & T. Harada] is an important edible and medicinal mushroom endemic to Northeastern China. Here we report the de novo sequencing and assembly of the S. edulis genome using single-molecule real-time sequencing technology. The whole genome was approximately 35.65 Mb, with a G + C content of 48.31%. Genome assembly generated 41 contigs with an N50 length of 1,772,559 bp. The genome comprised 9,364 annotated protein-coding genes, many of which encoded enzymes involved in the modification, biosynthesis, and degradation of glycoconjugates and carbohydrates or enzymes predicted to be involved in the biosynthesis of secondary metabolites such as terpene, type I polyketide, siderophore, and fatty acids, which are responsible for the pharmacodynamic activities of S. edulis. We also identified genes encoding 1,3-β-glucan synthase and endo-1,3(4)-β-glucanase, which are involved in polysaccharide and uridine diphosphate glucose biosynthesis. Phylogenetic and comparative analyses of Basidiomycota fungi based on a single-copy orthologous protein indicated that the Sarcomyxa genus is an independent group that evolved from the Pleurotaceae family. The annotated whole-genome sequence of S. edulis can serve as a reference for investigations of bioactive compounds with medicinal value and the development and commercial production of superior S. edulis varieties.

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Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Disorders

Journal of Ophthalmology ◽

10.1155/2021/6691291 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Jasmine Y. Serpen ◽

Stephen T. Armenti ◽

Lev Prasov

Keyword(s):

Immune System ◽

Lupus Erythematosus ◽

Genetic Disorders ◽

Anterior Segment ◽

Adaptive Immune System ◽

Mendelian Inheritance ◽

Ocular Involvement ◽

Inherited Disorders ◽

Molecular Features ◽

Organ Systems

Autoimmune and autoinflammatory diseases cause morbidity in multiple organ systems including the ocular anterior segment. Genetic disorders of the innate and adaptive immune system present an avenue to study more common inflammatory disorders and host-pathogen interactions. Many of these Mendelian disorders have ophthalmic manifestations. In this review, we highlight the ophthalmic and molecular features of disorders of the innate immune system. A comprehensive literature review was performed using PubMed and the Online Mendelian Inheritance in Man databases spanning 1973–2020 with a focus on three specific categories of genetic disorders: RIG-I-like receptors and downstream signaling, inflammasomes, and RNA processing disorders. Tissue expression, clinical associations, and animal and functional studies were reviewed for each of these genes. These genes have broad roles in cellular physiology and may be implicated in more common conditions with interferon upregulation including systemic lupus erythematosus and type 1 diabetes. This review contributes to our understanding of rare inherited conditions with ocular involvement and has implications for further characterizing the effect of perturbations in integral molecular pathways.

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The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health

Frontiers in Pediatrics ◽

10.3389/fped.2021.663752 ◽

2021 ◽

Vol 9 ◽

Author(s):

Audrey C. Woerner ◽

Renata C. Gallagher ◽

Jerry Vockley ◽

Aashish N. Adhikari

Keyword(s):

Newborn Screening ◽

Exome Sequencing ◽

Genetic Disorders ◽

Population Based ◽

Lessons Learned ◽

Screening Tests ◽

Whole Genome ◽

Whole Exome ◽

Challenges And Opportunities ◽

History Of

Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

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Diseases of the teeth and supporting structures

Soames' & Southam's Oral Pathology ◽

10.1093/oso/9780199697786.003.0010 ◽

2018 ◽

Author(s):

Max Robinson ◽

Keith Hunter ◽

Michael Pemberton ◽

Philip Sloan

Keyword(s):

Dental Health ◽

Genetic Disorders ◽

Adult Life ◽

Mendelian Inheritance ◽

Structural Basis ◽

Pathological Examination ◽

Dental Arch ◽

Supernumerary Teeth ◽

Tooth Germs ◽

Genetically Determined

A wide variety of processes can affect the formation of teeth during development. The number, size, shape, and quality of dental hard tissue may be abnormal and teeth may erupt early or be prematurely shed or resorbed. When a child presents with a tooth abnormality, the clinical and radiographic features are often distinctive and management depends on diagnosis (Box 5.1). Broadly, developmental abnormalities of the teeth can be either genetically determined or acquired as a result of injurious processes affecting the developing teeth. It can be problematic to make a diagnosis, particularly when teeth initially erupt. Sometimes pathological examination of a shed or extracted tooth by ground sectioning (for enamel) or conventional sectioning of a decalcified tooth can provide a diagnosis. Research has provided insights into the genetic and structural basis of dental anomalies, and has resulted in a complex and extensive classification of subtypes. Minor abnormalities, such as failure of development of a few teeth or enamel erosion in adult life, may be dealt with in general dental practice, but it is advisable to refer younger patients with more complex or extensive dental abnormalities to a specialist in child dental health, with links to expert diagnostic facilities and input from orthodontic and restorative colleagues. The publically available Online Mendelian Inheritance in Man (OMIM) database provides an invaluable resource for genetic disorders, including dental abnormalities. Supernumerary teeth are common and may be rudimentary in form or of normal morphology, when they are referred to as supplemental teeth. The most common supernumerary tooth occurs in the mid- line of the maxillary alveolus and is referred to as a mesiodens, which usually has a conical shape. Eruption of adjacent normal successor teeth may be impeded by a mesiodens, which is an indication for its removal. Most supernumerary teeth occur as a sporadic event in development, but multiple extra teeth can be found in certain developmental disorders. Failure of development of tooth germs results in teeth missing from the dental arch and is referred to as hypodontia. Most often the missing teeth are third molars, second premolars, and upper lateral incisors. Hypodontia is more common in the permanent dentition than in the primary teeth.

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Establishment and evaluation of a core genome multilocus sequence typing scheme for whole-genome sequence-based typing of Pseudomonas aeruginosa

Journal of Clinical Microbiology ◽

10.1128/jcm.01987-20 ◽

2020 ◽

pp. JCM.01987-20

Author(s):

Hauke Tönnies ◽

Karola Prior ◽

Dag Harmsen ◽

Alexander Mellmann

Keyword(s):

Pseudomonas Aeruginosa ◽

Multilocus Sequence Typing ◽

Core Genome ◽

Target Genes ◽

Multidrug Resistant ◽

Population Based ◽

Whole Genome Sequence ◽

Nucleotide Polymorphisms ◽

Environmental Bacterium ◽

Random Dataset

The environmental bacterium Pseudomonas aeruginosa, in particular multidrug resistant clones, is often associated with nosocomial infections and outbreaks. Today, core genome multilocus sequence typing (cgMLST) is frequently applied to delineate sporadic cases from nosocomial transmissions. However, until recently, no cgMLST scheme for a standardized typing of P. aeruginosa was available.To establish a novel cgMLST scheme for P. aeruginosa, we initially determined the breadth of the P. aeruginosa population based on MLST data with a Bayesian approach (BAPS). Using genomic data of representative isolates for the whole population and for all 12 serogroups, we extracted target genes and further refined them using a random dataset of 1,000 P. aeruginosa genomes. Subsequently, we investigated reproducibility and discriminatory ability with repeatedly sequenced isolates and isolates from well-defined outbreak scenarios, respectively, and compared clustering applying two recently published cgMLST schemes.BAPS generated seven P. aeruginosa groups. To cover these and all serogroups, 15 reference strains were used to determine genes common in all strains. After refinement with the dataset of 1,000 genomes, the cgMLST scheme consisted of 3,867 target genes, which are representative for the P. aeruginosa population and highly reproducible using biological replicates. We finally evaluated the scheme by reanalyzing two published outbreaks, where the authors used single nucleotide polymorphisms (SNPs) typing. In both cases cgMLST was concordant to the previous SNP results and to the results of the two other cgMLST schemes.In conclusion, the highly-reproducible novel P. aeruginosa cgMLST scheme facilitates outbreak investigations due to the publicly available cgMLST nomenclature.

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Construction of Pseudomolecules for the Chinese Chestnut (Castanea mollissima) Genome

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401532 ◽

2020 ◽

Vol 10 (10) ◽

pp. 3565-3574

Author(s):

Jinping Wang ◽

Shoule Tian ◽

Xiaoli Sun ◽

Xinchao Cheng ◽

Naibin Duan ◽

...

Keyword(s):

Agronomic Traits ◽

Whole Genome Sequence ◽

Comparative Genomic ◽

Ecological Value ◽

Chromosome Conformation ◽

Protein Coding ◽

Chinese Chestnut ◽

Castanea Mollissima ◽

Long Read ◽

Improvement Programs

The Chinese chestnut (Castanea mollissima Bl.) is a woody nut crop with a high ecological value. Although many cultivars have been selected from natural seedlings, elite lines with comprehensive agronomic traits and characters remain rare. To explore genetic resources with aid of whole genome sequence will play important roles in modern breeding programs for chestnut. In this study, we generated a high-quality C. mollissima genome assembly by combining 90× Pacific Biosciences long read and 170× high-throughput chromosome conformation capture data. The assembly was 688.93 Mb in total, with a contig N50 of 2.83 Mb. Most of the assembled sequences (99.75%) were anchored onto 12 chromosomes, and 97.07% of the assemblies were accurately anchored and oriented. A total of 33,638 protein-coding genes were predicted in the C. mollissima genome. Comparative genomic and transcriptomic analyses provided insights into the genes expressed in specific tissues, as well as those associated with burr development in the Chinese chestnut. This highly contiguous assembly of the C. mollissima genome provides a valuable resource for studies aiming at identifying and characterizing agronomical-important traits, and will aid the design of breeding strategies to develop more focused, faster, and predictable improvement programs.

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The Role of MIR9-2 in Shared Susceptibility of Psychiatric Disorders during Childhood: A Population-Based Birth Cohort Study

Genes ◽

10.3390/genes10080626 ◽

2019 ◽

Vol 10 (8) ◽

pp. 626

Author(s):

Luciana Tovo-Rodrigues ◽

Gabriela Quinte ◽

Clarice Brum ◽

Gabriele Ghisleni ◽

Clarissa Bastos ◽

...

Keyword(s):

Psychiatric Disorders ◽

Birth Cohort ◽

Well Being ◽

Externalizing Disorders ◽

Population Based ◽

Current Data ◽

Birth Cohort Study ◽

Structured Interviews ◽

Protein Coding

Background: It has been suggested that microRNAs (miRNAs; short non-protein-coding RNA molecules that mediate post-transcriptional regulation), including mir-9 and mir-34 families, are important for brain development. Current data suggest that mir-9 and mir-34 may have shared effects across psychiatric disorders. This study aims to explore the role of genetic polymorphisms in the MIR9-2 (rs4916723) and MIR34B/C (rs4938723) genes on the susceptibility of psychiatric disorders in children from the 2004 Pelotas Birth Cohort. Methods: Psychiatric disorders were assessed in 3585 individuals using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria through the application of standard semi-structured interviews (using the Development and Well-Being Assessment, DAWBA) at the six-years-of-age follow-up. The outcome was defined as the presence of any mental disorder. We also considered two broad groups of internalizing and externalizing disorders to further investigate the role of these variants in mental health. Results: We observed an association between rs4916723 (MIR9-2) and the presence of any psychiatric disorder (odds ratios (OR) = 0.820; 95% CI = 0.7130–0.944; p = 0.006) and a suggestive effect on internalizing disorders (OR = 0.830; 95% CI = 0.698–0.987; p = 0.035). rs4938723 (MIR34B/C) was not associated with any evaluated outcome. Conclusion: The study suggests that MIR9-2 may have an important role on a broad susceptibility for psychiatric disorders and may be important mainly for internalization problems.

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