bluuebunny/crossref_metadata_2025 huggingface dataset:
Intellectually Disabled in Britain: Sexuality and Procreation
Authors: McCarthy Jane , Sinason Valerie , Hollins Sheila
Published: April 2013

Ethical and social issues surround the issue of sexuality and parenting for people with intellectual disabilities. The traumatic history of eugenics is encapsulated in Nazi Germany's description of those with intellectual disability as unworthy of life and the 250 000 children and adults who were gassed but conscious and unconscious wishes to deny sexual and procreative rights to those with an intellectual disability is world‐wide and contemporary despite legislative change. However, given the high levels of sexual abuse and exploitation that come from internal and external stigmatisation and trauma the movement towards greater human rights, sexual education and access to psychotherapy heralds new hope for children and adults with an intellectual disability and the wider community.

Key Concepts:

In working with people with intellectual disability on the themes of sexuality and procreation a multi‐disciplinary approach is needed.

Ethics, human rights, genetics and psychotherapy are all relevant in working with sexuality and procreation in people with intellectual disability.

A history of trauma and eugenics is a necessary prerequisite to understanding the controversial topic of disability, sexuality and procreation.

Co‐operation with geneticists is important in considering procreation and disability.

People with an intellectual disability have a right to their own sexuality.
Preimplantation Genetic Diagnosis: Ethical Aspects
Authors: Juth Niklas
Published: April 2013

Preimplantation genetic diagnosis is a procedure, which allows for the selection between embryos before the initiation of pregnancy. Although considered morally controversial, for example, depending on views regarding the moral status of embryos, this procedure seemingly reduces ethical problems in prenatal diagnosis by offering the possibility of selecting offspring without the need to consider abortion. However, counselling of patients becomes more complicated. Also, there are controversies regarding who should be the primary beneficiary, for instance when an embryo is chosen partly to be a suitable tissue donor to a sibling, as well as regarding when benefits outweighs downsides. Moreover, preimplantation genetic diagnosis raises concerns about the connection between the pre‐selection of children on genetic grounds and the discrimination of disabled people. It also raises the ethical problem of whether the selection of future children on the basis of less serious or even nonpathological traits is an acceptable practice.

Key Concepts:

Preimplantation genetic diagnosis (PGD), selecting embryos based on genetic analysis before pregnancy byin vitrofertilisation (IVF), gives rise to ethical issues on the basic, clinical and societal level.

The acceptability of PGD depends on how one views parental responsibilities towards future children and the moral status of embryos.

Prospective parents may consider PGD to be preferable to prenatal genetic diagnosis, since in PGD selection can be made without subsequent abortion.

Drawbacks of PGD may outweigh benefits if the procedure of IVF is considered too burdensome, if the pattern of heredity is considered too complex to yield unambiguous genetic information, or if the condition is not considered serious enough.

PGD may also be used to select embryos that can become suitable bone marrow donors to seriously ill siblings, which has aroused controversies regarding the instrumentalisation and future well‐being of these children.

PGD makes genetic counselling more complex and possibly harder to comply with the ideal of nondirectiveness.

The question of which uses of PGD should be allowed can only be answered against the background of the basic ethical issue of what goal PGD should be taken to serve.

The goal of promoting reproductive autonomy gives rise to ethical issues of using PGD for less serious conditions or nonpathological traits, which may lead to backdoor eugenics.

The goal of preventing (the birth of individuals with) certain serious diseases gives rise to ethical questions of which diseases should be considered serious enough, as well as concerns of a subsequent reinforcement of discrimination and stigmatisation of disabled people.

The idea of a list of pre‐defined conditions serious enough for PGD sends the message that people affected by these conditions are more undesirable than others, which may push the situation closer to morally problematic forms of eugenics.
Personality and Temperament
Authors: Gagne Jeffrey R
Published: April 2013

Temperament is an early developing set of characteristics related to later personality. Commonly studied dimensions of temperament include activity level, anger/frustration, behavioural inhibition/fear, effortful control and positive affect. Personality includes a range of traits, including major traits of extraversion, neuroticism and impulsivity/sensation‐seeking. Different aspects of personality and temperament are related to important developmental outcomes such as behavioural problems and psychopathology. Both behavioural genetic and molecular genetic research have contributed to the understanding of major traits of temperament and personality. Behavioural genetic approaches use twin and adoption study designs to estimate genetic and environmental contributions to individual differences in traits. Most behavioural genetic studies have found substantial heritability for personality and temperament. Molecular genetic investigations focus on the effects of specific genes (primarily dopamine‐ and serotonin‐related genes in studies of temperament and personality).

Key Concepts:

Rothbart's broad extraversion/surgency, negative affectivity and effortful control dimensions of temperament are related to three of the Big Five personality factors: extraversion, neuroticism and conscientiousness, respectively.

The results of twin and adoption studies have shown significant genetic and nonshared environmental variance in temperament and personality.

Contemporary researchers investigating personality and temperament from a molecular genetic standpoint typically use either candidate gene studies or genome‐wide association studies (GWAS).

Although behavioural and molecular genetics are separate fields, most behavioural genetic researchers have begun incorporating molecular techniques into their research programs.

Genotype–environment interactions, genotype–environment correlations and endophenotype approaches are utilised in genetic studies of temperament and personality.

Candidate gene studies of dopaminergic and serotonergic genes have informed ongoing molecular genetic research in temperament and personality.

Increasingly, studies of other candidate genes as well as GWAS approaches are also extant in the literature.
Structural Databases of Biological Macromolecules
Authors: Gabanyi Margaret J , Berman Helen M
Published: April 2013

A biological macromolecule's function is determined by the chemical and physical characteristics of its three‐dimensional (3D) shape, or ‘structure’. For this reason, knowing the structure of a biomolecule is very helpful if we want to be able to understand living systems and disease. The Protein Data Bank (PDB) began as an archive of the structural data available about biological macromolecules. The advances made in all technologies have been mirrored in further development of the PDB and in the structural speciality and structural characteristic databases that have also evolved. New resource portals such as the Protein Structure Initiative (PSI) Structural Biology Knowledgebase (SBKB) also collect all available genomic, structural, and functional information together to reduce the time needed to obtain the latest information on structurally determined proteins. This article will describe selected structural databases and resources available to the public today.

Key Concepts:

Structural information about proteins at the atomic‐level can lead to an explanation of its role in living systems.

The Protein Data Bank archive is the sole provider of primary structural data of biological macromolecules worldwide.

The four members of the worldwide protein data bank consortium, the RCSB PDB, PDBe, PDBj and BMRB, maintain the PDB archive and provide tools for exploring and understanding the structural entries.

Other value‐added databases further classify derived structural information by combining the structural and/or biological aspects of a biomolecule.

Meta‐portals such as the Structural Biology Knowledgebase integrate all available genetic, structural, functional, and experimental information for all structurally determined proteins to enable a better understanding of sequence–structure–function relationships.
Hidden Markov Models
Authors: Przytycka Teresa M , Zheng Jie
Published: April 2013

A hidden Markov model (HMM) is a statistical approach that is frequently used for modelling biological sequences. In applying it, a sequence is modelled as an output of a discrete stochastic process, which progresses through a series of states that are ‘hidden’ from the observer. Each such hidden state emits a symbol representing an elementary unit of the modelled data, for example, in case of a protein sequence – an amino acid. The parameters of a hidden Markov model can be estimated by learning from training data. Efficient algorithms are available to infer the most likely paths of states for given sequence data, which often lead to biological predictions and interpretations. Thanks to the well developed theories and algorithms, hidden Markov models have found wide applications in diverse areas of computational molecular biology.

Key Concepts:

Hidden Markov model is a statistical approach for modelling sequences with broad applications in computational biology.

In an HMM, a biological sequence is modelled as being generated by a stochastic process moving from one state to the next state, where each state emits one element of the sequence according to some emission probability distribution which, in general, is different in different states.

Training of an HMM is a process in which the parameters of the model are computed based on a training set of representative examples.

Overfitting/overtraining the model occurs when model parameters correctly represent the training set but the model cannot generalise the training data to a larger set.

Gene finding is a process of computational identification of genes, including exon/intron structure, in a genome.
Protein Homology Modelling
Authors: Peitsch Manuel C , Schwede Torsten
Published: April 2013

Protein structure prediction aims to model the three‐dimensional (3D) structure of so far structurally uncharacterised proteins from their amino acid sequence. Motivated by the observation that homologous proteins with related amino acid sequences have similar 3D structures, protein homology modelling uses comparative methods to generate models for a target protein based on one or more related proteins with known 3D structure. The coordinates of the model are generated based on alignments between the target's and template's amino acid sequences, which define the correspondence between residues in both proteins. Ultimately, the quality of a computational model determines its usefulness for specific biomedical applications. Therefore, model quality estimation methods are used to identify unreliable or erroneous regions in the resulting models, and to estimate the overall accuracy of a model. Homology modelling (or comparative modelling) is currently the most accurate computational method available to routinely generate models of sufficient quality for various applications in life science research. Comparative protein modelling methods have been completely automated in recent years, and several Internet servers offer protein modelling services which are reliable and easy to use – also for the nonexpert in computational biology.

Key Concepts:

Protein structure prediction aims to model the three‐dimensional structure of so far structurally uncharacterised proteins (‘target’) based on their amino acid sequence.

Homologous proteins with related amino acid sequences have similar three‐dimensional structures.

Protein homology modelling uses information from one or more related proteins with known three‐dimensional structure (‘template’) to generate models for the target protein.

Sensitive sequence searching methods are applied to identify template proteins with known structures in large databases.

An alignment between the target's and template's amino acid sequences describes the correspondence between residues in both proteins.

The coordinates of the model are constructed by extracting positional information from the corresponding structural template.

Segments of the target protein not covered by template information (e.g. insertions/deletion in the alignment) have to be constructed using
de novo
modelling methods.

Model quality estimation methods are used to identify unreliable or erroneous regions in the resulting models.

Ultimately, the quality of a structural model determines its usefulness for specific biomedical applications.
Genome Databases
Authors: Tramontano Anna
Published: April 2013

A genome comprises all the genetic material of an organism and contains all the instructions needed to direct its activities. Since a genome also provides a natural reference frame for mapping information about genes and proteins, genome databases, the official repositories of the data produced by the genomic initiatives, are rapidly becoming the primary entry point for accessing biological knowledge. They are continuously enriched with new information and with functional annotations about the genome products and are meant to serve many diverse communities, from biologists to geneticists, from clinical researchers to pharmacologists and more. This implies that a major effort is required for solving the complex issue of visualising the genomic and functional data in an integrated fashion whereas at the same time providing different views of the data, tailored to the many diverse user needs.

Key Concepts:

Genome databases are the official repositories of the ever growing amount of genomic sequences.

The genome represents a natural framework for mapping the biological data of an organism.

Genome browsers provide integrated and customizable views of the information.

Genome databases and their associated tools are becoming the primary entry points for accessing biological information.

As more data on individual genomes becomes available, genome databases are also the repositories of variation data and of their associated phenotype.

Future challenges are not only related to the sheer size of the data, but also to the need of protecting sensitive information without hampering the exploitation of the data for new discoveries.
Neanderthal Mitochondrial
DNA
Authors: Goodwin William , Ovchinnikov Igor
Published: April 2013

Mitochondrial deoxyribonucleic acid
(mtDNA) has been important in understanding the evolutionary histories of both modern humans and archaic hominins, especially the Neanderthals. mtDNA to date (2012) has been successfully extracted from 13 specimens recovered from the geographical range of the Neanderthals. Primer extension capture along with next generation sequencing has been used along with standard shotgun sequencing to determine the entire mtDNA genome of six specimens: two from Kleine Feldhofer Grotte in Germany, one from El Sidron cave in Spain, two from Vindija Cave in Croatia and one from Mezmaiskaya Cave in Russia. New mtDNA sequences have enhanced the data available from earlier studies that analysed the hypervariable regions of several specimens. The Neanderthal mtDNA pool is distinct from modern human mtDNA and forms a separate phylogenetic clade; genetic diversity of Neanderthals is estimated to be approximately one‐third of extant modern human populations. In addition to analysis of the mtDNA, next generation sequencing has allowed the first insights into the Neanderthal nuclear genome.

Key Concepts:

The mtDNA genomes of six Neanderthals from four countries have been fully sequenced. The hypervariable regions of several other specimens have also been analysed.

The Neanderthals form a distinct genetic clade from modern humans; the two lineages diverged approximately 500 000 years before the present.

Genetic diversity in the Neanderthal population appears to be considerably reduced in comparison to the modern human populations.

Based on the mtDNA analysis, the Eurasian Neanderthal population appeared to be fragmented into subpopulations with separate demographic histories.

The likelihood of admixture between Neanderthals and modern humans is so low that either behavioural or biological barriers to interbreeding may have existed.
Uniparental Disomy
Authors: Schinzel Albert , Baumer Alessandra
Published: April 2013

Uniparental disomy (UPD) is defined as the inheritance of both homologues of a given genome region from only one parent. In the majority of cases, a UPD concerns an entire chromosome; it may also be limited to part of a chromosome (segmental UPD) or may involve the entire genome (genome‐wide UPD: androgenetic or gynogenetic, if the two haplotypes derive from the father or the mother, respectively). The types of UPD are defined as ‘isodisomy’ (two identical copies of one of the parental alleles) or ‘heterodisomy’ (two distinct alleles derived from the same parent). A further issue relevant to uniparental disomies is mosaicism: certain uniparental disomies, for example, genome‐wide uniparental disomies, are viable only in the presence of normal biparental cells (mosaic state).

A UPD may cause abnormal development if it leads to abnormal expression of imprinted genes or to reduction to homozygosity of recessive mutations.

Key Concepts:

Uniparental disomy explains pedigrees in conflict with mendelian inheritance.

Uniparental disomy carries a risk for recessive diseases.

Segmental uniparental disomy is an excellent model to explain fundamental genetic rules.

Recombination errors around meiosis and early thereafter are very frequent as, among others, seen from (segmental) uniparental disomy cases.
Retrotransposons and Human Disease
Authors: Roy‐Engel Astrid M , Belancio Victoria P
Published: April 2013

Retrotransposition is a ‘copy‐and‐paste’ mechanism whereby a retrotransposable element is copied from one genomic location and inserted into another genomic location, using a ribonucleic acid intermediate. The consequences of the retrotransposon‐associated alterations of the genomic landscape range from silent events to changes contributing to species‐specific and individual differences as well as a broad spectrum of diseases. Retrotransposon‐induced genetic variation can lead to inactivation or alteration of expression of critical genes

via

insertional mutagenesis, loss of genomic sequences through nonallelic homologous recombination or in association with

de novo

integration. In addition to these well‐recognised mutagenic events, some retroelements such as LINE‐1 can induce deoxyribonucleic acid double‐strand breaks that, if repaired unfaithfully, may lead to mutations. Moreover, retroelements have also contributed to generation of novel genes or functions through pseudogene formation, exonisation or shuffling of genetic material during retrotransposition. Thus, a complete understanding of their cumulative effect on any given genome or on genome evolution remains elusive.

Key Concepts:

Retroelements are currently active in the human genome, but only a limited number of functional loci are retrotranspositionally competent.

Retrotransposition is a multistep process that requires LINE‐1 proteins and cellular factors.

Human retrotransposons (LINE‐1, Alu and SVA) contribute to disease through several mechanisms.

LINE‐1 ORF2 protein induces DNA double‐strand breaks, but their contribution to human disease is not yet characterised.

LINE‐1 expression varies among germ line, normal somatic tissues and cancer.

Retrotransposition can occur in the germ line, normal somatic tissues and cancer.

There is variation in the rate of LINE‐1, Alu and SVA retrotransposition.

The estimated frequency of LINE‐1‐, Alu‐ and SVA‐associated diseases is likely an underestimation of their contribution to human disease.
RNA
Editing and Human Disorders
Authors: Gott Jonatha M
Published: April 2013

Ribonucleic acid (RNA)
editing can be broadly defined as any process that changes the sequence of an RNA molecule in a way that could be encoded within the genome. These small, targeted changes at the RNA level can have profound effects on gene expression. Such programmed alterations can be controlled in a tissue‐specific or developmentally regulated fashion, providing an alternative means of augmenting the information encoded within the genome. In mammalian cells, cytidine to uridine (C to U) and adenosine to inosine (A to I) changes have been observed in both coding and noncoding sequences, including microRNAs, and dysregulation has been linked to disease states. Editing enzymes are often essential, and can act on viral, as well as cellular RNAs. Some human pathogens utilise additional forms of RNA editing for gene expression; these forms of editing provide potential therapeutic targets.

Key Concepts:

RNA editing is a means of generating genetic diversity that is far more flexible than simply encoding information at the genomic level.

Editing is regulated both developmentally and spatially, and dysregulation can have serious consequences.

Most editing events in humans fall outside of coding regions; the functional consequences of many of these changes are still being elucidated, but will likely be far‐reaching.

Editing can impact the function of noncoding RNAs, including those involved in RNA silencing.

RNA editing can have both antiviral and proviral effects.
Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease
Authors: Passarge Eberhard
Published: April 2013

Hirschsprung disease is a complex, heterogeneous disorder, resulting from absence of the intramural intestinal ganglion cells (congenital intestinal aganglionosis) owing to failure of migration from the neural crest during embryonic development. Therefore, Hirschsprung disease is considered a neural crest disorder (neurocristopathy). Nine genes and three signal pathways have been identified in relation to the aetiology of this group of disorders. In addition, disease‐related noncoding regions in theRETgene contribute to the causes by interacting with at least one of the other predisposing genes. The disease susceptibility between males and females differs by a factor of 5 (5:1 higher disease frequency in males than in females).

Key Concepts:

Hirschsprung disease is currently the best understood multifactorial, nonMendelian genetic disorder.

Mutations in the receptor tyrosine kinase geneRETlocated at human chromosome 10q11.1 play a pivotal role in the etiology, in combination with other genes.

A common noncoding variant in intron 1 of theRETgene within a conserved enhancer‐like DNA sequence markedly influences the susceptibility to congenital intestinal aganglionosis.

This variant reduces enhancer activityin vitroand contributes to the disease risk 20‐fold more than other rare alleles, in spite of its low penetrance.

The eight other known genes involved in the genetic aetiology account for less than 30% of patients.

Three different signal pathways related to ganglion cell migration and intramural intestinal function are involved in the genetic pathogenesis of congenital intestinal aganglionosis: (1) the RET receptor kinase pathway with theRETgene and its ligand GDNF (glial cell line‐derived neurotrophic factor), (2) the endothelin type B receptor pathway with the EDNRB receptor and its ligand EDN3 (endothelin‐3) and (3) the transcription factor SOX10.

A single genetic change in any of the known genes and chromosomal regions predisposing to congenital intestinal aganglionosis is neither sufficient nor necessary to cause the disease.

The genetic effects differ in males and females. The frequency of transmission of predisposing factors differs between males and females, resulting in a 5.7‐fold and 2.1‐fold increase in susceptibility in males and females, respectively.

The predisposingRETsusceptibility allele differs in world‐like frequency. It is virtually absent in Africa (less than 5%) in contrast to Asia (40% in China and Japan) and Europe (25%).

In about 12% of patients, congenital intestinal aganglionosis occurs in syndromic form associated with other clinical manifestations outside the GI tract, usually in a monogenetic inheritance pattern.
Paroxysmal Nocturnal Hemoglobinuria
Authors: Kinoshita Taroh
Published: April 2013

Paroxysmal nocturnal hemoglobinuria is a peculiar acquired clonal genetic disease caused by somatic mutation of the X‐linkedPIGAgene in a hematopoietic stem cell. Loss‐of‐function mutation inPIGAgene causes a lack or a decreased biosynthesis of glycosylphosphatidylinositol (GPI), which in turn results in a complete or a partial deficiency in the cell surface expression of GPI‐anchored proteins, such as CD59 and CD55. ThePIGA‐mutant stem cell clone becomes dominant in hematopoiesis due to an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics after additional genetic change(s) such that it causes ectopic expression ofHMGA2gene known to cause benign tumours. Mutant red blood cells lacking CD59 and CD55 are highly sensitive to complement and are lysed upon activation of complement during infection and other events, resulting in haemolytic anemia and hemoglobinuria. A humanised monoclonal antibody against fifth component of complement C5 that inhibits activation of C5 is now in clinical use to prevent intravascular haemolysis.

Key Concepts:

Paroxysmal nocturnal hemoglobinuria is an acquired genetic disease due to somatic mutation in the X‐linkedPIGAgene that occurs in the hematopoietic stem cell.

Loss‐of‐function somaticPIGAmutation causes a defective biosynthesis of glycosylphosphatidylinositol (GPI).

The defective biosynthesis in GPI that anchors many proteins onto the plasma membrane, leads to defective cell surface expression of GPI‐anchored proteins.

ThePIGA‐defective mutant clone expands and dominates hematopoietic cells in bone marrow and the peripheral blood.

The clonal expansion is mediated by an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics.

A lack of GPI‐anchored proteins makes red blood cells sensitive to homologous complement due to a loss of complement regulators, CD59 and CD55.

Complement‐mediated haemolysis of GPI‐deficient red blood cells results in haemolytic anemia and hemoglobinuria.

A humanised anti‐C5 monoclonal antibody is in clinical use to prevent intravascular haemolysis.
Microdeletion Syndromes
Authors: Slavotinek Anne
Published: April 2013

A microdeletion syndrome is the clinical consequence of a submicroscopic chromosome deletion leading to monosomy for a small chromosomal segment. The clinical pictures of well‐known microdeletion syndromes are relatively specific and the phenotypic characteristics were often recognised before the causal microdeletions were identified. In recent years, the widespread use of array comparative genomic hybridisation (array CGH) has lead to the discovery of numerous novel microdeletion and microduplication syndromes that were clinically delineated only after the chromosome aberration was ascertained by array. The newer microdeletion syndromes are more likely to be rare and to have milder, less specific clinical features, such as developmental delays and behavioural differences. Many of the phenotypes are still evolving. It is also becoming clear for some of the smaller deletions that the same microdeletions can be present in normal individuals and that they thus can be considered to be susceptibility factors for the development of neurocognitive differences.

Key Concepts:

There are numerous novel microdeletion and microduplication syndromes that have been identified and characterised after the use of array comparative genomic hybridisation (array CGH) became widespread.

Many microdeletion syndromes have a corresponding microduplication syndrome that is generally rarer and associated with a milder phenotype; the phenotypes of many of the newer microdeletion and microduplication syndromes are still evolving.

Low copy repeats (LCRs) predispose to chromosome deletions and duplications through nonallelic homologous recombination (NAHR), and many of the copy number variable regions that result in microdeletion or microduplication syndromes are situated between blocks of LCRs.

Most of the smaller microdeletions that were identified by array CGH have milder dysmorphic features that are less likely to be recognisable as a distinct phenotype; these microdeletions are also more likely to have been inherited from a normal or mildly affected parent.

Individuals with small microdeletions can still have a ‘chromosomal’ presentation that is developmental differences and intellectual disability, growth differences, behavioural problems, feeding difficulties, low muscle tone, seizures, dysmorphic features and a pattern of varying malformations.
Multiple Sclerosis (
MS
): Genetics
Authors: Dyment DA , Ebers GC
Published: April 2013

Multiple sclerosis (MS) is a complex trait and highlights the interplay between nature, nurture and the stochastic events of development. Genetic‐epidemiological studies have shown the importance of the genetic contribution to the marked familial clustering of MS. Environmental factors also increase MS risk and act at a population‐based level. Climate and the subsequent effect on vitamin D levels are thought to play an important role. There is a clear association with MS and human leukocyte antigen (HLA) polymorphisms located at chromosome 6p21. Individuals who carry the at‐risk genotypes (DRB1
*
15/15) have a five‐ to sixfold increased chance of MS. Genome‐wide searches for other non‐HLA susceptibility genes by association have been successful in identifying many disease genes of mild effects. The genes implicated have an immune‐related function. There are likely additional genes contributing to MS risk and new technologies may prove fruitful for their identification.

Key Concepts:

Genetic‐epidemiological studies have shown the importance of genes to MS risk and studies such as twin, adoptive and half‐siblings are useful tools in the study of complex traits.

The search for genes in complex traits is difficult and often requires hundreds to thousands of cases and unaffected controls. This is due to the small effect of any given risk gene.

A risk‐related gene may be modified by its interaction with other genes and the environment and may be further modified by chance developmental processes.
Rheumatoid Arthritis: Genetics
Authors: Steel Kathryn , Barton Anne
Published: April 2013

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

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

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

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

Chromosome 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

180 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

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

Utilitarianism 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

Geneticisation 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.