bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rheumatoid Arthritis: Genetics
Authors: Steel Kathryn , Barton Anne 
Published: April 2013

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease, affecting up to 1% of the UK population. It is thought that RA is the result of several genetic and environmental susceptibility factors, which in combination can result in disease manifestation. Overall it is estimated that genetic factors contribute 50% of disease risk, indicating a greater understanding of this component is essential.
Although genetic studies have been performed for several years, a greater understanding of human genetics, combined with advances in molecular technology has revolutionised the identification of RA‐associated genes. To date 34 susceptibility loci have been identified, including many immune genes indicating that immune disparity may have a great role to play in RA pathogenesis.
With several potential associations in the pipeline, future challenges focus on the identification of biological functions of susceptibility genes. These discoveries will provide crucial information for unravelling the pathogenic disease networks and elucidating potential targets for novel RA therapies.

Key Concepts:

Rheumatoid arthritis has a significant genetic contribution to risk.

Recent advances have identified a number of genes or genomic regions associated with disease risk.
Sex Selection
Authors: Davis Dena S 
Published: April 2013

Abstract

People have always attempted to influence the sex of their children. Until recently, amniocentesis or chorionic villus sampling followed by abortion of the undesired fetus was the only effective method. Today, a simple maternal blood test can discover the sex of the fetus at an earlier stage of pregnancy. It is also possible to use

in vitro

fertilisation and pre‐natal genetic diagnosis to determine the sex of embryos before choosing which embryos to implant in the uterus. Even before conception, one can influence the sex of the embryo through sperm sorting. In some countries, sex selection is used almost exclusively to have boys, but in the West people are more likely to want to ‘balance’ their families than to avoid girls. These developments raise new questions about the ethics of sex selection.

Key Concepts:

Interest in sex selection varies across time and culture.

Currently available methods of sex selection are all quite burdensome, and include sperm sorting; termination of pregnancy after determination of fetal sex;
in vitro
fertilisation and preimplantation genetic diagnosis.

Sperm sorting enables couples to influence their future child's gender before conception and without embryo destruction.
Population Carrier Screening: Psychological Impact
Authors: Archibald Alison D , Wilfond Benjamin S 
Published: April 2013

Abstract

The psychological consequences of carrier screening for genetic conditions can include impacts on self‐efficacy, self‐concept, anxiety and understanding. Studies suggest that individuals’ willingness to undergo screening and their psychological responses to screening are variable, influenced by factors relating to programme design, presentation of information and the awareness and understanding of the condition/s for which screening is being offered. The integration of education and genetic counselling into screening programmes can facilitate informed decision‐making and positive adjustment to carrier status thus minimising the potential for negative psychosocial impacts. This will become increasingly important as advances in genetic testing technology broaden the scope of population‐based screening.

Key Concepts:

Limited public knowledge and awareness of genetic conditions poses challenges for individuals’ decision‐making regarding population‐based carrier screening.

The design of a screening programme can have an important influence on uptake of the genetic test.

Genetic counselling can play an integral role in facilitating informed decision‐making about screening and empowering individuals to adjust and adapt to a carrier result.

It is necessary to incorporate creative modes of educating individuals who are considering screening regarding the conditions for which testing is being offered.
Down Syndrome
Authors: Patterson David , Lott Ira T 
Published: April 2013

Abstract

Down syndrome, first described by Langdon Down in 1866, is caused by an extra copy of all or part of chromosome 21. It is the most commonly recognised genetic cause of intellectual disability and is characterised by a number of dysmorphic features and congenital malformations. The features of Down syndrome vary greatly from individual to individual, although some level of intellectual disability is always present as is hypotonia. The life expectancy of individuals with Down syndrome now approaches 60 years. The sequencing of the long arm of chromosome 21 was a milestone in research about Down syndrome but the complete understanding of the genetic information on the chromosome is still in progress. Several different mouse models with features reminiscent of aspects of Down syndrome have been produced. Although it is difficult to extrapolate from mice to humans, several studies using these mouse models suggest that it will be possible to develop therapies for aspects of Down syndrome, perhaps including intellectual disability.

Key Concepts:

The incidence of Down syndrome in the newborn population is in the vicinity of 1 per 700 live births in the United States and about 1 in 1000 in Europe. There is considerable variability in reported incidence in other parts of the world.

The condition of overriding critical importance in Down syndrome is intellectual disability.

The memory profile in Down syndrome is distinct from that seen in other phenotypic disorders associated with developmental disability such as Williams syndrome and Fragile x syndrome.

Pathological, metabolic and neurochemical changes of Alzheimer disease are present after the third decade in the brain of all individuals with Down syndrome.

With the changing patterns of institutionalisation and of the utilisation and methods of medical and surgical therapy, the mean life expectancy for persons with Down syndrome has improved dramatically in the last 50 years.

No pharmacological or dietary therapy as yet has been shown to have a beneficial effect on the intellectual disability associated with Down syndrome.

As one of the first triumphs of the Human Genome Project, the sequence of the long arm of chromosome 21 has been completed.

The successful amelioration of some of the learning and memory deficits and alterations in brain abnormalities in mouse models are encouraging since they support the hypothesis that successful post‐natal treatment of Down syndrome may be possible.
Chromatin in the Cell Nucleus: Higher‐order Organisation
Authors: Cremer Marion , Markaki Yolanda , Zunhammer Andreas , Cremer Christoph , Cremer Thomas 
Published: April 2013

AbstractChromosome territories (CTs) constitute a major feature of nuclear architecture. Recent progress in three‐dimensional (3D) super‐resolution microscopy further supports the following functional model of chromatin organisation: CTs consist of interconnected assemblies of approximately 1 Mb chromatin domains (CDs). These domains are permeated by a 3D channel system, the so‐called interchromatin compartment (IC), which may serve as a preferential compartment forribonucleic acid(RNA) transport. Wider parts of the IC are nearlydeoxyribonucleic acid(DNA) free, expand between CTs and accommodate splicing speckles and nuclear bodies. The interior of CDs contains transcriptionally silent chromatin, whereas their periphery represents a zone of decondensed, transcriptionally competent chromatin. This perichromatin region borders on the network of IC channels and is the site of RNA transcription and DNA replication. During interphase large‐scale movements of CTs are typically absent, although exceptions may exist. In contrast, chromosome neighbourhood arrangements change profoundly during prometaphase resulting in variable CT neighbourhoods arrangements in cycling cells.Key Concepts:Each individual chromosome occupies a distinct region (territory) of the nuclear space.Chromosome territories (CTs) do not occupy fixed positions in the nucleus but show a polarised radial orientation: gene‐dense chromatin is typically located towards the nuclear interior and gene‐poor chromatin at the nuclear periphery.During interphase large‐scale movement of chromatin is not typically observed. Nuclear rotational movements are likely essential for chromatin reorganisation during post‐mitotic differentiation.In cycling cells profound repositioning of chromatin occurs during prometaphase, resulting in new CT neighbourhoods in subsequent daughter nuclei.Recently developed 3D super‐resolution light microscopy provides detailed insight into chromatin ultrastructure and increasing evidence for a highly compartmentalised functional organisation of CTs.We postulate that CTs are built up from interconnected approximately 1 Mb chromatin domains (CD). CDs are permeated by a network of channels, which constitute the interchromatin compartment (IC). The IC is connected to nuclear pores. It accommodates splicing speckles and nuclear bodies and provides a compartment for RNA transport. A zone of decondensed chromatin, called the perichromatin region (PR), is located at the periphery of CDs and lines the IC. It constitutes the site of transcription, splicing, DNA‐replication and possibly also DNA‐repair.
Chromosome Numbers in Mammals
Authors: Scherthan Harry 
Published: April 2013

Abstract180 million years of mammalian radiation have shaped the genomes of approximately 4600 extant species and are witnessed by karyotypic diversity in extant species. Knowledge of chromosome numbers and morphology among mammalian species arrived during the period of classical cytogenetics in the 1960s and provided a first glimpse of the extent of karyotype reorganisation among various mammalian species. Further technical advances like banding techniques and the subsequent arrival of molecular tools like chromosome sorting, painting anddeoxyribonucleic acid(DNA) probes of different complexity led to improved molecular tools that allowed the visualisation of homology at the DNA level directly on chromosomes leading to modern phylogenomics. This article will provide an overview of what is known about mammalian karyotypic diversity and the research in mechanisms of chromosome rearrangements that shaped the present‐day karyotypes, with a special emphasis on muntjac chromosome evolution.Key Concepts:The chromosome number and morphology is a species‐specific feature.Most diploid chromosome numbers of mammals lie within the range of 36–60.Comparative cytogenomics suggests a 2n=44 karyotype for the mammalian ancestor.Comparative cytogenetic comparisons are only informative among species that display a similarly low rates of karyotypic change.Despite a wide range of chromosome numbers and morphologies there is remarkable conservation of the coding part of mammalian genomes.Chromosome rearrangements fixed during mammalian evolution are witness of benign karyotypic change.Polymorphisms in heterochromatin and copy number variation of repetitive DNA sequences are the source of significant karyotype and genome size variations in mammals and beyond.Cervidae evolution is associated with a rapid karyotypic turnover leading to chromosome numbers from 2n=6 to 2n=80.The extant muntjac karyotype displays the remnants of numerous chromosomal tandem fusions, an evolutionary rare aberration type.Illegitimate recombination events among telomeric and centromeric repetitive sequences in combination with a prevalence of inbreeding can be considered as driving force of muntjac karyotype evolution.
Complex Genetic Systems and Diseases
Authors: Sarkar Sahotra 
Published: April 2013

Abstract

Most traits of interest in medical (including psychiatric) contexts are complex traits, generally of multifactorial aetiology including genetic factors. These genetic factors may include coding and noncoding sequences (with the variation in the latter being the dominant mode of human genetic variation). Epigenetic factors may also be involved in the aetiology of diseases. The study of genetic aspects of complex traits presents a level of conceptual and technical difficulties not seen elsewhere in genetics. New molecular techniques, especially those that have emerged in the post‐genomic era, provide promise for a solution to these problems. Genome‐wide association studies have provided evidence for the common disease–common variant hypothesis. However, other studies have noted the importance of rare variants including some with severe effects. The importance of epigenetic factors has recently come to be recognised. Over all, the advances of genomics and the post‐genomic era have underscored the complexity of disease aetiology in most cases.

Key Concepts:

Disease traits are a result of complex developmental interactions between genomic and environmental factors.

Complex genetic traits are those that fall between simple Mendelising traits and the quantitative (continuously varying) traits traditionally studied by the methods of quantitative genetics.

Many disease traits are complex genetic systems of this sort.

The contribution of classical genetics (including quantitative genetics) to the study of most disease traits has been modest.

In contrast, recent molecular methods including allele sharing, quantitative trait locus mapping and allelic association studies show more promise.

Genome‐wide allelic association studies have provided a wealth of new insight and considerable support for the ‘common disease–common variant’ model of disease aetiology.

However, rare genetic variants may also be important for the aetiology of some diseases including psychiatric ones.

Because of the social and political ramifications of genetic explanations, care must be taken in imputing genetic etiologies to diseases.
Bioethics: Utilitarianism
Authors: Savulescu Julian , Birks David 
Published: April 2013

AbstractUtilitarianism is a moral theory that defines the right action as the action that maximises the total well‐being. It is one of the dominant moral theories, and it has a significant influence in bioethical debates. According to utilitarianism, what matters most is the promotion of well‐being, not merely the treatment or prevention of disease. In many cases, utilitarianism departs from traditional moral views on bioethical problems. Applied to genetics, utilitarianism broadly supports genetic testing, genetic selection of offspring with the opportunity to enjoy the best lives, gene therapy and genetic enhancement. This article considers some of the central issues related to utilitarianism and these bioethical questions.Key Concepts:According to utilitarianism, an action is right if, and only if it maximises well‐being.When we assess a person's well‐being, we are assessing how well or badly that person's life is going.Utilitarianism entails that it is morally required to kill an innocent person if it promotes overall well‐being.For utilitarians, allowing a person to die or suffer when that could have been avoided is just as bad as directly inflicting suffering or killing.For utilitarians, a couple (or a single reproducer) has a significant moral reason to select the best child, one with the lowest chance of disease and the best prospects for the best life.Because utilitarians have a broad understanding of what makes a life go well, which goes beyond prevention or treatment of disease, they have no objections to genetic enhancement, if it promotes overall well‐being.
Geneticisation: Concept
Authors: ten Have Henk AMJ 
Published: April 2013

AbstractGeneticisation is the sociocultural process of interpreting and explaining human beings using the terminology and concepts of genetics, so that not only health and disease but also all human behaviour and social interactions are viewed through the prism of biomolecular technology. Introduced in the 1990s, it has developed into a heuristic tool to study and critically analyse the impact of the new genetics at the levels of the individual as well as society and culture, but also within healthcare by influencing and transforming notions of health and disease, diagnosis and prevention. Clarification of the concept is provided in this contribution. Lessons can be learned from the earlier concept of medicalisation. Using the concept of geneticisation in bioethics requires a critical analysis of the current ethical discourse in genetics, particularly the dominating principle of respect for autonomy. It also requires examination of common notions of responsibility and human identity that are undergoing significant transformation under the influence of the new genetics. Geneticisation draws attention back to social–ethical issues as well as the relevancy of social and cultural context, which tend to be neglected or disregarded because of the current fascination with genetics.Key Concepts:The advances of the new genetics have transformed society and (popular) culture, attributing an impact to genetics that goes beyond its scientific significance; this is called ‘geneticisation’.Bioethical analysis should not only focus on the individual level but also on the social and cultural level.
Microsatellites
Authors: Epplen Jörg T , Akkad Amer D 
Published: April 2013

Abstract

Microsatellites are short, in‐tandem arranged repetitive
deoxyribonucleic acid
(DNA) elements which are widespread in eukaryotic and prokaryotic genomes. The basic unit lengths of microsatellites (or simple DNA sequence repeats) comprise up to six (or eight) nucleotides, and these motifs are perfectly reiterated from 5 to more than 100 times. Longer and more imperfectly reiterated periodicities border on the definitions of the so‐called minisatellites. Microsatellites have been utilised as markers for population genetic studies, forensic and relatedness testing, investigations on genetic diversity and the identification of genetic traits. Albeit constituting elusive model disorders, microsatellite expansion diseases are rather rare entities characterised by differential pathogenetic pathways. Hence microsatellites exhibit a broad spectrum of biological relevance ranging from selfish or neutral to pathogenic elements.

Key Concepts:

Microsatellites exhibit perfect tandem repetition of short nucleotide motifs.

Microsatellites represent most variable components throughout most genomes.

The biological significance of microsatellites ranges from selfishness and molecular marker for a small genome region to disease causing mutation when expanded, respectively.
Tuberous Sclerosis: Genetics
Authors: Tee Andrew R , Sampson Julian R , Davies D Mark 
Published: April 2013

Abstract

Tuberous sclerosis is an autosomal‐dominant disorder characterised by seizures, intellectual disability, autistic spectrum disorder and the growth of benign tumours in multiple organs including the brain, skin, heart and kidneys. It is caused by mutations in either the
TSC1
gene on 9q34 or the
TSC2
gene on 16p13.3. The gene products, TSC1 and TSC2, interact and as a heterodimer act to integrate multiple of stimuli such as mitogenic stimulation, oxygen and energy levels into the control of diverse cell processes. One of the best characterised downstream targets of TSC1/TSC2 is mammalian target of rapamycin complex 1 (mTORC1), which regulates proteins synthesis, metabolism, autophagy and cell division amongst other cellular processes. Clinical trials in patients with tuberous sclerosis using mTOR inhibitors have shown promising results.

Key Concepts:

Tuberous sclerosis is an autosomal‐dominant multisystem disorder.

Tuberous sclerosis is caused by mutations in either of two genes
TSC1
or
TSC2
.

One of the key functions of the TSC1/TSC2 protein complex is to integrate signals from multiple stimuli to regulate cellular processes such as growth and division via the mammalian target of rapamycin (mTOR) pathway.

Knowledge of the molecular pathology of tuberous sclerosis has been translated into clinical trials using mTOR inhibitors to treat manifestations of the condition.
Monogenic Hypercholesterolemia: Genetics
Authors: Day Ian N M 
Published: April 2013

AbstractSeveral specific genes, when mutated, cause high blood cholesterol levels, with consequent early atherosclerosis and coronary events. The classical example and commonest defects involves the low‐density lipoprotein receptor (LDLR) gene, haploinsufficiency of which leads to slow LDL‐cholesterol clearance and homozygous mutation of which leads to extreme hypercholesterolaemia and coronary disease during childhood. Familial defective apolipoprotein B (FDB) involvingAPOBtransmits as an autosomal dominant trait with incomplete penetrance and affects ApoB, the ligand within LDL particles for the receptor.PCSK9also transmits as an autosomal dominant trait, with high penetrance. PCSK9, proprotein convertase subtilisin kexin type‐9, is secreted and by binding to the LDL receptor promotes receptor degradation, gain‐of‐function mutations increasing binding and reducing receptor availability. LDLRAP1, a clathrin adaptor protein, if defective on both alleles, causes autosomal recessive hypercholesterolaemia in which there is failure to internalise the receptor. Knowledge of these new genes has identified new targets for pharmaceutical developments and mutation analysis has contributed diagnostically to cascade screening now in use to identify and offer preventive treatment.Key Concepts:Single gene mutations can cause inherited familial patterns of hypercholesterolaemia.The monogenic hypercholesterolaemias all involve genes encoding products participating in the pathway of LDL particle clearance by the LDL receptor.LDLR defects represent a genocopy for the phenotype of dietary hypercholesterolaemia and offer inference about the causal role of population hypercholesterolaemia in coronary risk.Four genes are known which can cause an inherited hypercholesterolaemia, these areLDLR,APOB,PCSK9andLDLRAP1.The patterns of inheritance differ,LDLR,APOBandPCSK9causing autosomal dominant hypercholesterolaemia,LDLRAP1causing autosomal recessive hypercholesterolaemia.Mutations inPCSK9mutations involve gain‐of‐function, whereasLDLR,APOBandLDLRAP1mutations involve loss of function.PCSK9 in particular represents a potential novel target for new pharmaceutical development of cholesterol lowering drugs.Mutation knowledge and mutation identification now support cascade screening to identify and offer treatment to individuals at high risk of early coronary disease.