Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The revolution in human monogenic disease mapping.

ABSTRACT: The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such as skeletal dysplasias. In this review, we illustrate the challenges of mapping disease genes in such conditions through the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP) and we discuss the advances that are being made through current massively parallel ("next generation") sequencing (MPS) technologies.

SUBMITTER: Duncan E

PROVIDER: S-EPMC4198931 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The revolution in human monogenic disease mapping.

Duncan Emma E Brown Matthew M Shore Eileen M EM

Genes 20140905 3

The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such a ...[more]

PMID: 25198531

Similar Datasets

Human monogenic disease genes have frequently functionally redundant paralogs.

Project description:Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population; this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes.

| S-EPMC3656685 | biostudies-literature

Pharmacogenomics: mapping monogenic mutations to direct therapy.

Project description:The molecular mapping of mutations that underlie congenital disorders of monogenic origin can result in both a broader understanding of the molecular basis of the disorder and novel therapeutic insights. Indeed, genotyping patients and then replicating the behavior of the mutant gene products in well-defined biochemical or electrophysiological systems will allow tailoring of therapy to be mutation- and protein sequence-dependent. In this issue of the JCI, Shen and colleagues describe such an approach that identified novel mutations in the ? subunit of the nicotinic receptor linked to myasthenia gravis.

| S-EPMC3386840 | biostudies-literature

Human induced pluripotent stem cells for monogenic disease modelling and therapy.

Project description:Recent and advanced protocols are now available to derive human induced pluripotent stem cells (hiPSCs) from patients affected by genetic diseases. No curative treatments are available for many of these diseases; thus, hiPSCs represent a major impact on patient' health. hiPSCs represent a valid model for the in vitro study of monogenic diseases, together with a better comprehension of the pathogenic mechanisms of the pathology, for both cell and gene therapy protocol applications. Moreover, these pluripotent cells represent a good opportunity to test innovative pharmacological treatments focused on evaluating the efficacy and toxicity of novel drugs. Today, innovative gene therapy protocols, especially gene editing-based, are being developed, allowing the use of these cells not only as in vitro disease models but also as an unlimited source of cells useful for tissue regeneration and regenerative medicine, eluding ethical and immune rejection problems. In this review, we will provide an up-to-date of modelling monogenic disease by using hiPSCs and the ultimate applications of these in vitro models for cell therapy. We consider and summarize some peculiar aspects such as the type of parental cells used for reprogramming, the methods currently used to induce the transcription of the reprogramming factors, and the type of iPSC-derived differentiated cells, relating them to the genetic basis of diseases and to their inheritance model.

| S-EPMC4835672 | biostudies-literature

Lessons in human biology from a monogenic pancreatic β cell disease.

Project description:Deciphering the complexities of human β cell physiology is critical to our understanding of the pathophysiology behind both type 1 and type 2 diabetes. One way to do this is to study individuals with congenital hyperinsulinism (CHI), a rare genetic disease characterized by dysregulation of insulin secretion resulting in hypoglycemia. In this issue of the JCI, Henquin et al. report in vitro studies of pancreatic tissue obtained from CHI patients during therapeutic pancreatectomy that have yielded exciting new insights into human β cell physiology. The data validate and extend observations made in model organisms.

| S-EPMC3195485 | biostudies-literature

Mapping the NFT revolution: market trends, trade networks, and visual features.

Project description:Non Fungible Tokens (NFTs) are digital assets that represent objects like art, collectible, and in-game items. They are traded online, often with cryptocurrency, and are generally encoded within smart contracts on a blockchain. Public attention towards NFTs has exploded in 2021, when their market has experienced record sales, but little is known about the overall structure and evolution of its market. Here, we analyse data concerning 6.1 million trades of 4.7 million NFTs between June 23, 2017 and April 27, 2021, obtained primarily from Ethereum and WAX blockchains. First, we characterize statistical properties of the market. Second, we build the network of interactions, show that traders typically specialize on NFTs associated with similar objects and form tight clusters with other traders that exchange the same kind of objects. Third, we cluster objects associated to NFTs according to their visual features and show that collections contain visually homogeneous objects. Finally, we investigate the predictability of NFT sales using simple machine learning algorithms and find that sale history and, secondarily, visual features are good predictors for price. We anticipate that these findings will stimulate further research on NFT production, adoption, and trading in different contexts.

| S-EPMC8536724 | biostudies-literature

Knockout mice are an important tool for human monogenic heart disease studies.

Project description:Mouse models are relevant to studying the functionality of genes involved in human diseases; however, translation of phenotypes can be challenging. Here, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to International Mouse Phenotyping Consortium (IMPC) data. We found 153 genes associated with cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, of which 151 have one-to-one mouse orthologues. For 37.7% (57/151), viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice are available. In knockout mice, 75.4% (43/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20/57). Multisystem phenotypes are common, with 58.8% (20/34) of heterozygous (homozygous lethal) and 78.6% (11/14) of homozygous (viable) mice showing cardiovascular, metabolic/homeostasis, musculoskeletal, hematopoietic, nervous system and/or growth abnormalities mimicking the clinical manifestations observed in patients. These IMPC data are critical beyond cardiac diagnostics given their multisystemic nature, allowing detection of abnormalities across physiological systems and providing a valuable resource to understand pleiotropic effects.

| S-EPMC10073007 | biostudies-literature

Comparative genetic analysis: the utility of mouse genetic systems for studying human monogenic disease.

Project description:One of the long-term goals of mutagenesis programs in the mouse has been to generate mutant lines to facilitate the functional study of every mammalian gene. With a combination of complementary genetic approaches and advances in technology, this aim is slowly becoming a reality. One of the most important features of this strategy is the ability to identify and compare a number of mutations in the same gene, an allelic series. With the advent of gene-driven screening of mutant archives, the search for a specific series of interest is now a practical option. This review focuses on the analysis of multiple mutations from chemical mutagenesis projects in a wide variety of genes and the valuable functional information that has been obtained from these studies. Although gene knockouts and transgenics will continue to be an important resource to ascertain gene function, with a significant proportion of human diseases caused by point mutations, identifying an allelic series is becoming an equally efficient route to generating clinically relevant and functionally important mouse models.

| S-EPMC1998876 | biostudies-literature

Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth.

Project description: Not available

| S-EPMC10014100 | biostudies-literature

Monogenic Lupus: A Developing Paradigm of Disease.

Project description:Monogenic lupus is a form of systemic lupus erythematosus (SLE) that occurs in patients with a single gene defect. This rare variant of lupus generally presents with early onset severe disease, especially affecting the kidneys and central nervous system. To date, a significant number of genes have been implicated in monogenic lupus, providing valuable insights into a very complex disease process. Throughout this review, we will summarize the genes reported to be associated with monogenic lupus or lupus-like diseases, and the pathogenic mechanisms affected by the mutations involved upon inducing autoimmunity.

| S-EPMC6232876 | biostudies-literature

Preimplantation Genetic Testing for Monogenic Kidney Disease.

Project description:Background and objectivesA genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands.Design, setting, participants, & measurementsThis is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests.ResultsIn total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons.ConclusionsReferrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.

| S-EPMC7480540 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data