bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Imprinting at the Transcriptional Level
Authors: da Rocha Simão Teixeira , Heard Edith 
Published: April 2013

AbstractGenomic imprinting is an epigenetic mechanism of gene regulation that causes genes to be expressed from only one of the two parentally inherited chromosomes in mammals. This form of regulation affects less than 1% of genes and has crucial roles in embryonic growth, development and brain function. Imprinted genes are often clustered in large chromosomal domains and their expression is regulated bycis‐acting imprinting control regions (ICRs). ICRs carry a methylation imprint that is laid down in one of the two parental germlines, when the two genomes are separated, to distinguish the paternal and the maternal alleles. To date, regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers orcis‐regulation induced by long noncoding RNAs (ncRNAs). Aberrant expression of imprinted genes leads to human pathologies and is frequent in cancer. Genomic imprinting provides a unique model for studying the epigenetic influence on transcriptional activity and repression.Key Concepts:A subset of genes in the mammalian genome (less than 1%) known as imprinted genes are expressed exclusively from one of the two parental alelles.The existence of genomic imprinting highlights the nonequivalence of parental genomes and precludes the viability of mammalian embryos with exclusive contribution of genetic material from one of the parents.Imprinted genes are involved in fetal growth and placental development in the uterus, as well as brain function and metabolism in adults.Genomic imprinting has been reported in placental mammals and marsupials but not in montremes.Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are co‐ordinatively regulated.Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alelles during gametogenesis.DNA methylation is the bona fide imprint mark that distinguishes the two parental alleles at the ICRs, resisting the wave of DNA demethylation after fertilisation and being erased and reset in the germline.Insulation of common enhancers by the methylated sensitive protein CTCF explains the imprinting regulation at theIgf2/H19region.Silencing of genes incisby long non‐coding RNAs explains the imprinting regulation for at least three imprinted clusters by yet unknown mechanisms.Deregulation of genomic imprinting can cause imprinted disorders in humans which exhibit parent of origin effects in their pattern of inheritance.
Darwin and the Idea of Natural Selection
Authors: Dover Gabriel 
Published: April 2013

AbstractNatural selection is a consequence of differences in reproductive success among distinctly unique individual phenotypes living at a given generation and resulting in a biased representation of genes at the next generation. Reproducing, transient phenotypes, not ‘eternally selfish’ genes, form the arena in which selection takes place in a given biotic and abiotic environment. The evolved, complex relationship between genotype and phenotype is largely unknown and perhaps unknowable given the promiscuity of genes to participate in different functional networks at one and the same time, and given the vagaries of the external environment on individual ontogeny and life cycle. Accordingly, there is a many‐on‐many discourse between genes and traits, making the complex evolutionary role of natural selection difficult to fathom. Hopes for, or fears of, genetic determinism of human behaviour are premature.Key Concepts:Natural selection is a simple idea widely misunderstood: ‘Adaptation’ has come to mean both the mechanism of natural selection and its product.The ephemeral, reproducing individual phenotype is at the heart of natural selection, not the ‘eternally selfish’ gene.The unique pathway of individual development is not predictable given the ‘degeneracy’ of network interactions among genes, proteins, neurons, etc. within an ever shifting environmental milieu.There is a many‐on‐many, not a one‐to‐one, relationship between genes and traits.Natural selection is a means of changing the average genotype/phenotype of a population with the passing of the generations. There are two other means (‘neutral drift’ and ‘molecular drive’) for achieving the same effect.Natural selection is not a process as such as the internal and external factors that influence differences in reproductive success differ at each generation.It is not logically possible, without recourse to ‘just‐so’ stories, to determine which of two or more co‐extensive traits in a species was naturally selected and which a ‘free‐rider’.The pattern of a given set of genetic interactions (network topology) may differ between individuals yet have the same trait outcome (‘degeneracy’).
Distributive Justice and Genetics
Authors: Farrelly Colin 
Published: April 2013

AbstractWhat will the demands of distributive justice be in the post‐genetic revolutionary world? Will genetic inheritance be regarded as socially distributed goods? This may seem a more reasonable position to assert as biotechnology progresses further toward human genetic manipulation. Advances in human genetics raise a number of unique considerations for theories of justice, ranging from the realisation of egalitarian ideals and the therapy/enhancement distinction to the scope and limits of reproductive freedom. As new empirical discoveries are made concerning the environmental and natural determinants of human welfare, theories of justice must re‐conceptualise what the demands of justice are and how society can fairly distribute the natural and social goods which influence the life prospects of humans.Key Concepts:Aging is the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age.Distributive justice is concerned with what constitutes a fair distribution of the benefits and burdens of social cooperation.Luck egalitarianism is the view which maintains that inequalities that are the result of factors beyond a person's control, such as inequalities in natural endowments, are unjust.The Priority View maintains that it is morally more important to benefit the people who are worse off.Procreative liberty is freedom in activities and choices related to procreation.The Sufficiency View maintains that what is morally important is for everyone to have enough.
Tooth Agenesis
Authors: Luder Hans Ulrich , Mitsiadis Thimios A 
Published: April 2013

Abstract

Tooth agenesis denotes a condition where teeth are missing due to a developmental failure. According to severity, this malformation can be subdivided into hypodontia, oligodontia and anodontia. With a frequency of 20–30%, tooth agenesis is the most prevalent dental dysplasia, but not all teeth are equally affected. Familial occurrence and concordance in twins indicate potential genetic causes. Thus far, mutations could be identified for the genes
MSX1
,
PAX9
and
AXIN2
. All result in oligodontia. It is assumed that the defects cause haploinsufficiency, reducing the functional gene products below a critical level, which is required for normal odontogenesis. Both hypodontia and oligodontia can occur as an isolated dental malformation or in combination with defects in other organs, for example the skin and its appendages. Such syndromes can result from genetic defects affecting
MSX1
and the EDA signalling pathway. In the case of isolated hypodontia, associations have been found with sequence variants of several genes.

Key Concepts:

Tooth agenesis is a dental malformation in which teeth are missing, because they fail to develop.

Tooth agenesis in humans allows inferences to be drawn regarding the control of odontogenesis, when phenotypes and genotypes are related to experimental findings obtained from mice.

Mutations in human genes regulating early stages of tooth formation cause agenesis of multiple teeth, that is, oligodontia.

Defects of genes important for early odontogenesis probably result in haploinsufficiency and lead to a disruption of dental development, because the quantity of functional gene products is reduced below a critical level required for normal tooth formation.

Not all teeth are equally susceptible to a reduction in odontogenic potential.

Tooth agenesis can occur in a syndromic form, that is, in combination with defects in other organs and tissue, for example the skin and its appendages.

DNA sequence variants, which have less severe consequences for gene products are also likely to contribute to mild forms of tooth agenesis, where only a few teeth are congenitally absent.
Molecular Genetics of Attention Deficit–Hyperactivity Disorder (
ADHD
)
Authors: Coghill David R , Hogg Kirsty M 
Published: April 2013

Abstract

Attention deficit–hyperactivity disorder (ADHD) comprises a common and highly heritable group of syndromes with childhood onset that are characterised by impairments in attention span, impulse control and/or activity level. Neurobehavioral, imaging, treatment and genetic studies are consistent with the clinical symptoms of ADHD being caused by abnormalities of the ventral projections of catecholamine pathways in the brain. Twin and adoption studies suggest that there is a strong genetic influence on ADHD with a heritability of approximately 0.76. Linkage studies have identified chromosome areas 5p13, 11q22–25, 17p11 and bin16.4 as being associated with ADHD. Candidate gene studies have focused on the genes influencing catecholaminergic and serotoninergic pathways. Whilst no one gene has yet been unequivocally demonstrated to be causally associated with ADHD, systematic review and meta‐analysis supports the involvement of several genes (DRD4 and DRD5, DAT1, SNAP25 and the 5‐HTT gene). Genome wide association scans have not yet found any genome‐wide significant associations. Preliminary findings suggest increased numbers of copy number variants (CNVs) in ADHD.

Key Concepts:

ADHD is characterised by pervasive and impairing inattention, impulsivity and hyperactivity.

ADHD is a neurodevelopmental disorder with a prevalence of approximately 5% worldwide.

ADHD is thought to be associated with abnormalities in dopaminergic and noradrenergic functioning.

Twin and adoption studies have established that ADHD is highly heritable with a heritability of approximately 0.76.

Linkage studies have identified chromosome areas 5p13, 11q22–25, 17p11 and bin16.4 as being associated with ADHD.

Candidate gene studies have thus far tended to focus on genes located within the dopaminergic, noradrenergic and serotonergic pathways.

Converging lines of evidence and meta analyses of candidate gene studies have identified that polymorphisms within the dopamine receptor genes 4 and 5 (DRD4 and DRD5), the dopamine transporter gene (DAT1), the synaptosome‐associated protein gene (SNAP25) and the serotonin receptor gene (5‐HTT) are associated with an increased the risk of ADHD.

None of these genes have yet be unequivocally associated with ADHD as p values do not yet meet the strict criteria required to demonstrate causality (p<10
−8
).

Whilst signals of interest have been identified using GWAS, none have yet reached the required levels of statistical significance.

Recent studies have suggested that those with ADHD have increased numbers of CNVs. However, further study is required to investigate the specificity of these findings to ADHD.
Malignant Hyperthermia and Central Core Disease
Authors: McCarthy Tommie V 
Published: April 2013

Abstract

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder triggered by certain types of anaesthetic agents. Genetic and biochemical evidence show that defects in the skeletal muscle ryanodine receptor calcium release channel account for most cases of MH and the related myopathy central core disease (CCD). Analysis of mutant receptors shows that these disorders are largely explained by abnormalities in ryanodine receptor‐mediated calcium release and have identified three distinct classes of channel defects. Most MH and mild CCD mutations make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat. A second class of mutations, which are rarer make the channel significantly deficient in calcium release in response to depolarisation in muscle and are essentially excitation–contraction uncoupling type mutations. The third class of mutation which are also rare have been associated with recessive multimini core disease (MmD) and core myopathy and lead to a decrease in the stability of the RyR1 complex causing partial depletion of RyR1 channels expressed in skeletal muscle.

Key Concepts:

Malignant hyperthermia is a pharmacogenetic disorder triggered by anaesthetics and manifests as a rapid increase in body temperature and metabolism accompanied by contracture of skeletal muscles.

Central core disease is closely associated with malignant hyperthermia and presents as muscle weakness at infancy and the presence of cores in muscle fibres.

The ryanodine receptor is the central channel in skeletal muscle responsible for release of calcium from the sarcoplasmic reticulum into the myoplasm.

The ryanodine receptor is physically coupled to the dihydropyridine receptor. The latter is located in the t‐tubules and is a voltage‐gated calcium release channel.

Depolarisation of the t‐tubular membrane causes a conformational change in the dihydropyridine receptor which interlocks with the ryanodine receptor to open its calcium release channel. The released calcium cause muscle contraction.

Human and animal genetics have shown that mutations in the ryanodine receptor account for most cases of malignant hyperthermia and central core disease whereas mutations in the alpha channel of the dihydropyridine receptor account for a small number of malignant hyperthermia cases.

The ryanodine receptor mutations causing malignant hyperthermia and central core disease fall into three classes.

The first class of mutations are most common and make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat.

The second class of mutations make the channel significantly deficient in calcium release in response to depolarisation.

The third class of mutation lead to a decrease in the stability of the RyR1 complex.
Multiple Endocrine Neoplasias
Authors: Kunstman John W , Carling Tobias 
Published: April 2013

Abstract

Multiple endocrine neoplasia (MEN), types 1 and 2 (MEN1, MEN2) are autosomal dominant hereditary syndromes that predispose to wide variety of both hormone‐secreting and nonsecreting tumours throughout the body. MEN1 most classically demonstrates neoplasia of the parathyroid glands, anterior pituitary and neuroendocrine tumours of the pancreas and foregut. MEN2 has several variants, but medullary carcinoma of the thyroid is the dominant feature in all. Understanding of the molecular genetics of each disease has greatly affected treatment, especially for MEN2, which generally carries a worse prognosis. Therapy has evolved from symptomatic management of clinically detected tumours to resection of susceptible tissues even prior to tumour development based on genetic testing. This has vastly improved the outcomes for patients with these disorders.

Key Concepts:

The multiple endocrine neoplasia (MEN) syndromes are hereditary cancer syndromes that drive selected tissues in the body to develop both benign and malignant tumours.

Like most other hereditary cancer syndromes, MEN syndromes cause tumour growth by causing unregulated cell growth in susceptible tissues.

Unlike most hereditary cancer syndromes, MEN syndromes predominantly cause tumour growth in endocrine tissues, which can produce manifestations of hormone excess in affected patients.

Although MEN syndromes are relatively rare, patients with suspicious clinical presentations should undergo genetic testing, as the consequences of a missed MEN diagnosis can be catastrophic in certain variants of the disease.

Treatment of MEN syndromes is primarily via surgery, although medical therapy plays an important role for certain manifestations of the disease.

The evolution of MEN therapy is a prototype for demonstrating how molecular genetics can improve disease management.
Dental Anomalies: Genetics
Authors: Nieminen Pekka 
Published: April 2013

Abstract

Development of teeth is under strict genetic control, which ensures the formation and renewal of a certain number of teeth with specific shapes and positions in a reproducible timetable. Gene mutations can disturb normal dental development and affect tooth number, shape, eruption or formation of the hard tissues, enamel, dentin or cementum. These anomalies are often observed as isolated, that is, only dentition is affected, and especially failure to develop all teeth, tooth agenesis or hypodontia is extremely common. Different dental anomalies are also observed in numerous rare developmental syndromes because the genes and genetic networks that regulate tooth morphogenesis and differentiation are also active in the development of other organs and tissues. Tooth anomalies are especially associated with other ectodermal defects and orofacial clefts. Many examples indicate that teeth are often most sensitive to a reduced activity of a specific genetic pathway which is related to the complexity and self‐organising features of dental development.

Key Concepts:

Teeth are specialised ectodermal organs.

Development of dentition is regulated by cell interactions by same signalling pathways that are active in other organs and requires modulation of signalling by antagonist factors.

Tooth agenesis (failure to develop all teeth) is one of the most common developmental anomalies.

Most cases of tooth agenesis and supernumerary teeth are caused by reduced rather than complete inactivation of gene activity.

Dental anomalies are often diagnostic indications of a heritable syndrome or systemic disease.

Dental hard tissues do not regenerate after an injury and their development involve unique mechanisms.

Studies into congenital enamel defects are revealing functions for novel proteins that are involved in cellular regulation in ameloblasts and other cells.
Chronic Myeloproliferative Neoplasms: Clinical and Molecular Genetics
Authors: Albitar Maher 
Published: April 2013

AbstractChronic myeloproliferative neoplasms (previously called myeloproliferative diseases) are group of haematopoietic neoplasms characterised by clonal proliferation of differentiated cells from the myeloid lineage. This includes granulocytes, erythrocytes and megakaryocytes. In general, the course of these neoplasms is chronic and some patients may live more than 20 years and die from other causes, however, in some patients, they may manifest aggressively and kill patients in short time. Significant progress have been made in understanding the molecular basis of these diseases and recently new pharmaceutical agents have been developed that specifically target these molecular abnormalities and converted these neoplasms to chronic diseases to live with as any other chronic disease. We find in this group of diseases chronic myeloid leukaemia and polycythaemia vera, which are perhaps the most molecularly defined two neoplasms. TheBCR‐ABL1fused gene is the cause of the first neoplasm and the mutated JAK2 gene cause the second disease, both of which are targeted in the current treatment of these two diseases.Key ConceptsMutations cause the uncontrolled growth of cells, but these cells are capable of differentiation.The ability of these leukaemic cells to differentiate leads to their death at some point making these diseases less aggressive than acute leukaemias.Chromosomal translocations and mutations in specific genes are implicated in these groups of diseases.Most of the genomic abnormalities in these diseases lead to activating specific kinases and this leads to uncontrolled cell proliferation.By targeting these kinases, cell growth can be controlled and these diseases can be managed successfully.Translocations may lead to fusing two genes and the expression of a fused protein or may lead to a change in the regulation of the gene and its deregulation.Activation of a geneviatranslocation is usually into other genomic locus and a specific partner gene, but occasionally can be promiscuous and accept other partners.Historically the Philadelphia chromosome is considered the first hint for the fact cancer is genomic disease was discovered in CML, which is one of the cMPNs discussed here.
Complement System: Evolution
Authors: Nonaka Masaru , Sekiguchi Reo 
Published: April 2013

Abstract

The human complement system is one of the principal effector systems of innate immunity and consists of more than 30 serum and cell surface proteins. Most complement components show a striking modular structure, which makes evolutionary studies feasible. The evolutionary origin of the complement system can be traced back to the common ancestor of eumetazoa, predating by far the origin of the canonical adaptive immunity unique to the jawed vertebrates. Although the complement system has been conserved by all deuterostomes analysed thus far, it has been lost multiple times independently in the protostome lineage. Sophistication of the complement system from a simpler system by gene duplications and exon shuffling occurred in the vertebrate lineage.

Key Concepts:

The complement system is one of the most ancient body defence mechanisms of eumetazoa.

Most complement components have a characteristic modular structure.

The modern complement system was established in a common ancestor of jawed vertebrates by gene duplication and exon shuffling of the primitive complement genes.

The complement system has been lost multiple times independently in protostome lineages, whereas it has been retained by all deuterostomes analysed so far.

The thioester‐containing protein family is subdivided into two subfamilies, the C3 and A2M subfamilies.