bluuebunny/crossref_metadata_2025 huggingface dataset:
History and Ethics of Stem Cell Research
Authors: Blasimme Alessandro , Dröscher Ariane
Published: April 2013

The history of stem cell research is considered a recent one, yet, it began as early as the middle of the nineteenth century and is rich in questions, approaches, concepts, tools, methodologies and lines of thought. There are at least nine disciplines or research fields which have made major contributions: botany and horticulture; cell theory; evolutionary biology; embryology and developmental biology; haematology; cell and tissue culture; regeneration biology; teratology and teratogeny and cancer research. Moreover, as soon as efforts aimed at extracting and culturing pluripotent cells from human embryos proved successful in 1998, stem cells became objects of bioethical controversy. The moral status of the embryo will be discussed, together with proposed technical means to avoid its destruction, such as altered nuclear transfer, single blastomere biopsy, cytoplasmic hybrids and induced pluripotent stem cells, and the possible ethical problems associated with future medical uses of stem cells.

Key Concepts:

Far from being a simple technology or a commodity, the study of stem cells concerns a broad spectrum of issues lying at the heart of the phenomenon of life itself, and thus touches on questions that have been on the agenda of biological inquiry for a long time.

Like most biological research fields, the history of stem cell research shows a constant weaving and unweaving of many concepts and tools, coming from different experimental settings, lines of thought and at least nine different biomedical areas.

At some moments of its history, the ‘stem cell’ has become a more concrete and even manageable object, at other moments it was found difficult to localise the phenomenon of self‐renewal in one or in a few cells.

Recently, stem cell research is characterised by harsh bioethical controversy, mainly revolving around the issue of the moral status of human embryos.

Scientists have proposed some technical ways for circumventing ethical problems, but other morally relevant issues still lie before stem cell research.

In the future, medical innovation through stem cell‐based regenerative medicine is likely to give rise to issues regarding safety, ethical oversight and distributive justice.
Role of Natural Selection in Chromosomal Speciation
Authors: Faria Rui , Neto Sandra , Noor Mohamed AF , Navarro Arcadi
Published: April 2013

Speciation can occur in the face of gene flow if there are mechanisms that are able to neutralise it. Two such mechanisms or forces are divergent selection and the suppression of recombination. New data and theory suggest that chromosomal rearrangements (CRs) facilitate speciation with gene flow mainly by suppressing recombination. However, the role of natural selection in chromosomal speciation is less clear. According to recent models, natural selection can play a role in speciation by facilitating the fixation of CRs; and later, acting synergistically with CRs, by allowing the accumulation of incompatibilities along large regions of the genome. Interestingly, instead of resulting exclusively from disruptive selection among populations, a potential signal of selection within CRs may also result from the inability of favourable mutations to migrate between populations. However, empirical evidence for natural selection in suppressed‐recombination chromosomal speciation is scarce, reinforcing the need for further multidisciplinary studies.

Key Concepts:

For evolutionary biologists, speciation has always been a controversial topic, both in terms of mechanisms and geographical context.

Although allopatry has been the most consensual geographic context of speciation, the divergence of taxa in the face of gene flow is not a rare observation.

In purely genetic terms, speciation can be viewed as the evolution of restrictions on the freedom of genetic recombination.

Recombination originates new genetic combinations upon which natural selection can act, transforming the genomes of lineages connected by gene flow into a mosaic of genetic information.

The molecular characterisation of genes involved in reproductive isolation between someDrosophilaspecies suggests that natural selection has shaped their evolution.

The functional characterisation of genes involved in reproductive isolation suggests that genetic conflicts may have a more important role in speciation than what it was initially thought.

The formalisation of suppressed‐recombination models of speciation was highly influenced by research performed in fruit flies and sunflowers (DrosophilaandHelianthus).

CRs may play an important role in the origin and accumulation of incompatibilities between parapatric populations but also by avoiding species fusion after a secondary contact.

Signatures of selection within CRs may result from divergent environmental conditions but also from universally advantageous alleles.

Although, in theory, natural selection facilitates the role of CRs in speciation, signatures of natural selection within CRs have not been universally found in the species so far investigated.
Experimental Evolution in Viruses
Authors: Sanjuán Rafael , Domingo‐Calap Pilar
Published: April 2013

Experiments in which evolution takes place in real time can help us establish cause–effect relationships that are difficult to infer from the analysis of natural populations. The simplicity, rapid evolution and biomedical relevance of viruses make them a particularly interesting model system for experimental evolution. Bacterial, animal and plant viruses can be passaged under a variety of conditions, either in simple cell culture systems orin vivoto test population biology hypotheses, study the genetic basis of evolution, or predict evolutionary change in nature. Experimental evolution is a conceptually simple and flexible tool which allows us to address issues ranging from the molecular to the ecosystem level. In addition to studying basic processes such as mutation, adaptation, or random genetic drift, viruses can be experimentally evolved to better understand the emergence of drug resistance, explore new antiviral strategies such as lethal mutagenesis, create better attenuated vaccines, or target cancerous cells.

Key Concepts:

Experimental evolution can be done with many different model organisms, but microorganisms and viruses offer a series of advantages including their easy manipulation, storability and biomedical relevance.

The setup of an evolutionary experiment is conceptually simple and essentially consists of serially transferring viruses from flask to flask or,in vivo, from host to host. However, a careful experimental design is needed to be able to demonstrate which factors are responsible for the evolutionary changes observed in the laboratory.

Molecular biology is a powerful tool in virus experimental evolution because it allows us to manipulate viral genomes and to study the molecular basis of evolution.

Viruses can adapt to many different laboratory environments, but these adaptations often come at the cost of decreased performance in alternative environments, demonstrating the existence of certain limits to adaptation, or fitness tradeoffs.

Viral experimental evolution has both stochastic and deterministic components. Therefore, although viral evolution is not easy to predict, it shows some regular patterns.

The role played by population–genetic factors such as the population size or the mutation rate have been extensively studied in viruses, and several important generalisations have been established.

Experimental evolution has inspired new strategies to combat viral disease, including the use of selective mutagens to damage viral genomes or the use of less evolvable strains to create more effective and safer vaccines.
Geographical Origin of the Domestic Dog
Authors: Klütsch Cornelya FC , Savolainen Peter
Published: April 2013

The domestic dog (

Canis familiaris

) is considered to be the oldest domestic animal in the world. World‐wide mitochondrial
deoxyribonucleic acid
(mtDNA) studies clearly indicate a single origin in time and place in Southeast Asia less than 16 000 years ago including a high number of female foundation wolves resulting in 10 subhaplogroups within three haplogroups. Later hybridisation events in East Asia, the Middle East, Scandinavia and possibly North America formed 3–4 small haplogroups. In contrast, the archaeological record, favours other, sometimes multiple, regions for dog domestication (mainly Europe and Middle East), but suffers from a lack of samples from Southeast Asia and is problematic, because of the difficulty of distinguishing between wolf and dog in fossil remains. Future studies including, for example, paternal markers such as the Y‐chromosome, autosomal markers like SNPs, and ancient DNA samples of both wolves and dogs may give new insights into early domestication history and the dog's migration routes.

Key Concepts:

The dog is considered to be the oldest domestic animal species and it is widely accepted that its only ancestor is the wolf (
Canis lupus
).

Archaeological records of early potential dog remains are fragmentary and controversial as well as biased in their geographical coverage, focusing mainly on fossils found in Europe and the Middle East.

Recent genetic studies based on mtDNA suggest a single origin in Southeast Asia from numerous wolves less than 16 000 years ago as well as later hybridisation events in East Asia, the Middle East, Scandinavia and possibly North America.

New World dogs are likely to be descendants of Eurasian domesticated dogs, thereby ruling out North America as a centre of domestication.

The dingo is an ancient, originally domesticated, but now feral, dog which arrived to Australia about 5000 years before present (YBP).

Future studies may include ancient DNA approaches and additional markers such as Y‐chromosome and genome‐wide markers like SNPs to give additional insight into domestication history and migrations of early domestic dogs.
Adaptive Evolution of Centromeric Proteins
Authors: Roach Kevin C , Ross Benjamin D , Malik Harmit S
Published: April 2013

Kinetochore proteins assemble at centromeres and mediate chromosome segregation during eukaryotic cell division. This conserved function conceals a paradox; essential inner kinetochore proteins, CenH3 and CENP‐C, evolve rapidly under positive selection in primates, plants and insects. This paradox may be explained by a genetic conflict between selfish DNA sequences at the centromere and the kinetochore proteins that bind them. The centromere drive hypothesis provides a framework for understanding this conflict and makes predictions for patterns of evolution in the composition of the kinetochore. In contrast with the rapidly evolving inner kinetochore, the components of the outer kinetochore do not make contacts with centromeric DNA and evolve more slowly. Furthermore, genetic conflict at the centromere may underlie observed taxonomic differences in the rate of evolution of kinetochore proteins among species with different meiotic programs.

Key Concepts:

Despite an essential and conserved function, some centromere‐binding proteins evolve rapidly.

In contrast to canonical histone H3, the centromeric variant of histone H3 displays striking patterns of positive selection in functionally critical domains.

CENP‐C displays rapid evolution across a diverse taxa; the functional consequences of this rapid evolution have not yet been studied.

Asymmetric female meiosis provides an opportunity for competition among centromeres for evolutionary success but has deleterious consequences in male meiosis leading to genetic conflict.

Genetic conflict between centromeres and centromere‐binding proteins can explain the divergent patterns of evolution between inner and outer kinetochore proteins, as well as taxonomic differences in rapid evolution of centromeric proteins.
Magnetic Tweezers
Authors: Carrasco Pulido Carolina , Moreno‐Herrero Fernando
Published: April 2013

Magnetic tweezers is a technique that allows applying a constant pulling force and torque on a nucleic acid molecule while measuring its elongation in real time. By means of two magnets, the polymer is stretched and twisted between a magnetic bead and the surface of a glass cover slide. In the course of an experiment, the position of the magnetic bead is followed in real time while a buffer containing proteins, adenosine triphosphate (ATP), etc. is introduced in the experiment chamber. This approach has been used to study
deoxyribonucleic acid
(DNA) condensation, mechanical properties of nucleic acids and dynamics of protein–DNA interactions. In this article an introduction to the Magnetic Tweezers technique is given and some examples of application presented.

Key Concepts:

Magnetic Tweezers allow stretching and twisting nucleic acids (NA) using magnetic microspheres and a magnetic field.

An NA is attached at one end to a magnetic bead and at the other end to a transparent glass surface.

The position of the bead is determined from the optical image given by a video camera.

The force acting on the NA is calculated from the movements of the tethered magnetic bead.

Magnetic Tweezers are used to study mechanical properties of NA and real‐time dynamics of protein–DNA interactions.
Computational Methods for Interpretation of
EM
Maps at Subnanometer Resolution
Authors: Baker Matthew L , Baker Mariah R , Cong Yao
Published: April 2013

Driven by a remarkable number of technological advances in recent years, electron cryo‐microscopy (cryo‐EM) has played an increasingly important role in deciphering macromolecular structure and function. Today, cryo‐EM routinely achieves subnanometer resolutions, with current state‐of‐the‐art reconstructions approaching atomic resolutions. Though achieving high‐resolution density maps is still a challenging aspect of cryo‐EM, it is possible to isolate individual subunits, identify secondary structures elements and accurately fit atomic models in reconstructions of large macromolecular assemblies. Additionally, computational modelling and feature recognition tools are routinely employed to construct backbone and atomic models of entire assemblies directly from a density map. Together, these tools provide researchers with unprecedented insight into structure and function, revealing everything from subunit arrangements to complex sets of interactions in macromolecular assemblies.

Key Concepts:

Cryo‐EM is capable of imaging large macromolecular assemblies in order to understand their structure and function.

Analysing macromolecular assemblies requires a variety of complex computational tools.

In subnanometer resolution cryo‐EM density maps, it is possible to see individual protein subunits, as well as higher‐resolution structural features.

It is now possible to construct backbone and atomic models directly from cryo‐EM density maps at near‐atomic resolutions.
Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches
Authors: Koo Seok Hwee , Ku Chee Seng , Chui Paul , Lee Edmund Jon Deoon
Published: April 2013

The sudden unexplained death syndrome is a tragic and distressing event, which may arise due to an underlying fatal cardiac arrhythmia, which may be associated with a defective ion channel. These electrical abnormalities of the heart do not present with gross structural changes, rendering it a challenging task to the forensic pathologist in ascertaining the cause of death during autopsies. The attempts to identify genetic variations in the key ion channels known to cause arrhythmias have only been able to reveal the presence of putative mutations in a small percentage of the cases. It is thus imperative to look beyond the discovery of single‐nucleotide polymorphisms to other forms of genetic variations (such as copy number variations and structural rearrangements), as well as alternative mechanisms that may underlie the molecular pathogenesis of arrhythmias and electrocardiographic abnormalities causing sudden death. Additionally, the various technological platforms for genetic analysis are also described in this article.

Key Concepts:

Sudden unexplained death syndrome is an important clinical problem.

Sudden death may be the result of a fatal cardiac arrhythmia.

Arrhythmias are associated with genetic mutations in ion channel genes.

Genetic mutations often exhibit incomplete penetrance.

Genetic mutations may have functional impact on the ion channel.

Single‐nucleotide polymorphisms only account for a fraction of the cases.

Copy number variations and chromosomal aberrations may play a role in sudden death pathology.

The role of alternative mechanisms such as epigenetics in arrhythmias/sudden death remains to be ascertained.

The technology for identifying genetic variations is advancing rapidly.

Genome‐wide sequencing is expected to become increasingly feasible.
Genetics of Atrial Fibrillation
Authors: Koo Seok Hwee , Ku Chee Seng , Chen Lin Yee , Lee Edmund Jon Deoon
Published: April 2013

Atrial fibrillation (AF) is the most common sustained arrhythmia with poor prognosis, reaching epidemic proportions in the ageing population. The condition affects more than five million people worldwide and is a significant clinical problem. Of particular interest is a subset of younger patients (<60 years of age) who develop AF in the absence of known risk factors (such as advancing age, hypertension, structural heart disease and congestive heart failure), a condition classified as lone AF. Genetic variations in ion channel genes only account for a small percentage of the cases. Genome‐wide association studies (GWAS) look beyond the targeted genes and are capable of identifying novel mutations and genes, and biological pathways for AF. This review summarises the candidate gene and GWAS on AF, and discusses the application of exome sequencing approach in revisiting familial AF, as well as the potential clinical applications of the genetic data in the management of AF. A better understanding of the molecular mechanism of AF will aid the cardiologist in strategising the optimal therapeutic regimen for the patient.

Key Concepts:

Atrial fibrillation is an important clinical problem.

Atrial fibrillation is associated with genetic mutations in ion channel genes.

Genetic mutations often exhibit incomplete penetrance.

Genetic mutations may have functional impact on the ion channel.

Single‐nucleotide polymorphisms in ion channel genes only account for a small percentage of the cases.

The technology for identifying genetic variations is advancing rapidly.

Next‐generation sequencing is expected to become increasingly feasible.

The genetic data garnered from candidate gene and genome‐wide association studies have important clinical implications in management and treatment strategies of atrial fibrillation.
Sexual Selection and Female Competition
Authors: Bro‐Jørgensen Jakob
Published: April 2013

Sexual selection studies have traditionally focused on reproductive competition as a typical male characteristic, and regarded females as largely passive. However, empirical evidence now shows female competition to be widespread in nature. Sometimes the same conventional logic can be used to explain competitiveness in males and females: that the sex in surplus in the mating pool has to compete for the other sex as a limited resource. Still, female competition often does not follow this pattern. This is partly related to the fact that whereas the obvious target of male competition is usually access to mates, in females, competition for mating opportunities is often intertwined with competition for breeding resources. Rather than assuming a rigid dichotomous view of sex roles focusing on which sex is more competitive, the topic may be more rewardingly approached by identifying how ecology affects costs and benefits of competitiveness in the two sexes separately.

Key Concepts:

Larger mating skew in males than females often leads to stronger sexual selection on male competitive (and attractive) traits.

A switch from a male‐biased to a female‐biased operational sex ratio may often, but not always, explain reversal of competitive roles.

Female competition is widespread in species with otherwise conventional sex roles.

Female may compete for mates to increase conception probability, to secure the best providers, or to prevent others from reproducing and thereby reduce future resource competition.

Access to resources is more likely to be the ultimate cause of competitive traits in females compared to males.
Clinical Chemistry in Pregnancy
Authors: Taylor Anthony H , Melford Sarah E , Konje Justin C
Published: April 2013

During pregnancy, a woman undergoes a multitude of normal physiochemical changes that are specific to pregnancy and with increasing frequency, challenged with pregnancy‐related conditions. Additionally, there are a number of problems affecting the unborn fetus that, in turn, affect normal maternal biochemistry, endocrinology and physiology. Furthermore, normal biochemical, hormonal and clinically relevant measurements for the nonpregnant state often no longer apply to the pregnant woman. This makes clinical laboratory measurement difficult and normal clinical diagnosis using nonpregnant values potentially dangerous, with inappropriate treatment (when it is not required) and no treatment (when it is required) being offered. Problems within early pregnancy, for example, spontaneous and recurrent miscarriage, thus become very complicated to predict or treat. Therefore, reexamining what clinical chemical tests are available and what is just emerging from the experimental laboratory (and thus becoming available in the standard clinical laboratory), should inform the unwary clinician.

Key Concepts:

‘Normal’ pregnancy biochemical marker (Biomarker) concentrations fluctuate throughout pregnancy.

No single maternal biomarker can be used to predict gestational disease.

Both the concentrations of urinary, serum, plasma, salivary and amniotic fluid biomarkers and the timing of clinical sampling are critical in disease diagnosis.

Many new biomarkers are emerging, which may help aid the prediction/diagnosis of pregnancy‐related conditions.
Endocannabinoid System
Authors: Di Marzo Vincenzo
Published: April 2013

The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G‐protein‐coupled receptors known as cannabinoid receptors of type‐1 and ‐2 (CB
1
and CB
2
); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide (
N
‐arachidonoyl‐ethanolamine) and 2‐AG (2‐arachidonoyl‐glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors. A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate. The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed.

Key Concepts:

Endocannabinoids are local mediators with autocrine or paracrine function.

Endocannabinoids are usually produced

de novo

and ‘on demand’ following elevation of intracellular Ca
2+
concentrations.

Endocannabinoids often act in the central nervous system as ‘retrograde neuromodulators’, that is, they are released from post‐synaptic neurons and act at cannabinoid CB
1
receptors on pre‐synaptic axon terminals.

Endocannabinoids possess immune‐modulatory functions and usually inhibit cytokine release from immune cells and regulate the migration of the latter.

Endocannabinoids are key regulators of food intake, gastrointestinal function, energy storage in the adipose tissue and energy processing by the liver and the skeletal muscle.

Endocannabinoids are deeply involved in pain processing at peripheral, spinal and
supra
‐spinal sites.

Endocannabinoids regulate both male and female reproduction.

Endocannabinoid can differentially affect cell fate in healthy and cancer cells by regulating differentiation, proliferation and apoptosis.

Endocannabinoids, and anandamide in particular, also directly interact with non‐CB
1
, non‐CB
2
receptors, the most studied of which is the transient receptor potential vanilloid type‐1 (TRPV1) channel.

Dysregulation of the ECS underlies several neurological, immune and metabolic disorders, and therapeutic strategies manipulating the ECS are being developed.
Protein Association with Membrane Rafts
Authors: Veit Michael , Thaa Bastian
Published: April 2013

Membrane rafts are very small and highly dynamic assemblies in cellular membranes enriched in cholesterol and sphingolipids. Some proteins can functionally associate with rafts: peripheral membrane proteins are incorporated into rafts depending on cues such as the presence of a glycosyl‐phosphatidylinositol (GPI) anchor or S‐acylation (palmitoylation); transmembrane proteins can partition into raft domains depending on specific features within their transmembrane domain. Raft association of membrane proteins was originally defined by their resistance to cold Triton X‐100 extraction, which is however insufficient as the sole criterion – more sophisticated methodology such as fluorescence resonance energy transfer (FRET) has to be employed to determine whether and how a given protein interacts with raft structures.

Key Concepts:

Membrane rafts are small, dynamic clusters within biological membranes enriched in cholesterol and sphingolipids.

Rafts can be coalesced and stabilised to fulfil a biological function, for example, signal transduction or virus budding.

Some proteins are capable of partitioning into raft domains.

Raft‐targeting features in proteins are glycosyl‐phosphatidylinositol (GPI) anchors, S‐acylation (palmitoylation) and structural motifs in the transmembrane domain.

Assessment of detergent‐resistant membranes (DRM), the original biochemical method to analyse raft association of a protein, is artefact‐prone and therefore not suitable to prove raft involvement in a biological process.

More sophisticated methodology such as fluorescence resonance energy transfer (FRET) is needed to decipher raft association of a protein.
Oxidative Protein Folding
Authors: Gennaris Alexandra , Collet Jean‐François
Published: April 2013

Oxidative protein folding is the process by which a protein recovers both its native structure and its native disulphide bonds. Disulphide bonds are vital for the correct folding of many secreted proteins, such as insulin, albumin, tissue plasminogen activator and antibodies. The formation of a disulphide bond between two cysteine residues is a rate‐limiting step of the folding process. Therefore, living cells contain proteins that catalyse this reaction (DsbA, protein disulphide isomerase (PDI), Mia40). Pathways that form disulphide bonds have now been unraveled in the bacterial periplasm, the endoplasmic reticulum and the mitochondrial intermembrane space. These pathways have in common to form a relay that channels the electrons released upon cysteine oxidation to a final electron acceptor.

Key Concepts:

Disulphide bond formation is required for the correct folding of many secreted proteins.

Disulphide bond formation is a catalysed process
in vivo
.

Pathways of disulphide bond formation are found both in prokaryotes and in eukaryotes.

Pathways of disulphide bond formation form a relay that channels the electrons away from the substrate protein to a final electron acceptor.

Pathways of disulphide bond formation involve a direct disulphide donor and a disulphide generator.

Formation of native disulphides in proteins with multiple cysteine residues involves a disulphide isomerase.

A disulphide formation pathway and a disulphide isomerisation pathway co‐exist in bacteria such as
Escherichia coli
.

Protein disulphide isomerase (PDI) catalyses both disulphide bond formation and disulphide bond isomerisation in the endoplasmic reticulum.
Molecular Genetics of Medulloblastoma
Authors: Nadi Mustafa , Rutka James
Published: April 2013

Medulloblastoma (MB), the most common malignant paediatric brain tumour, arises in the cerebellum. Recent high‐throughput technology that includes ribonucleic acid‐based expression analysis and deoxyribonucleic acid (DNA)‐based copy number analysis, as well as whole‐genome sequencing studies have unravelled the mysteries of this embryonic tumour from clinical, histological and molecular standpoints. Studies of hereditary syndromes associated with MB have led to an increased understanding of the genomics of this tumour. Signalling pathways and growth factors, which are crucial in normal cerebellum development, are also involved in MB formation. The molecular discoveries in the last decade have led to advances in two major areas: (1) The clinical and molecular subgrouping of patients and their stratification; and (2) research being performed to individualise treatments according to the genetics of the patient's tumour. The use of extensive cancer genetic databases will ensure that future discoveries in MB pathogenesis will be made.

Key Concepts:

There is more than one cell of origin for MB.

MBs are genetically and histologically heterogeneous.

MB growth is similar to the normal growth of the cerebellum but it is growth gone awry.

Signalling pathways play significant roles in cerebellar growth. Mutations in these pathways lead to tumour formation.

Growth factor and DNA repair pathway mutations may drive MB formation.

MB in adults is different from that in children.

Metastatic MB has specific genomics that are different from the primary tumour in the same patient.

The new molecular discoveries have important prognostication impact.

The next era is to individualise novel therapies against each patient's MB.
Role of Bioinformatics in Genome‐wide Association Studies
Authors: Gilbert‐Diamond Diane , Asselbergs Folkert W , Williams Scott M , Moore Jason H
Published: April 2013

A central goal of human genetics is to identify genetic variants that are associated with disease. Better understanding the role of genetic and environmental factors in disease risk will likely improve diagnosis, prevention and treatment. It is now technically and economically feasible to conduct genome‐wide association studies (GWAS) with over a million single‐nucleotide polymorphisms (SNPs) distributed across the genome. Although GWAS have led to many discoveries, the genetic underpinnings of most common diseases remain largely unexplained. One likely explanation for this “missing hereditability” is that traditional GWAS approaches have focused on one SNP at a time and have failed to account for the complexity of many genotype–phenotype relationships that are characterised by substantial heterogeneity, and gene–gene and gene–environment interactions. Such underlying genetic complexity creates bioinformatics challenges related to modelling, attribute selection and biological interpretation that must be addressed in order to realise the full potential of GWAS. The benefits of meeting these bioinformatics challenges will also extend to whole‐genome and whole‐exome sequence analysis.

Key Concepts:

Genetic complexity is likely to underlie many common diseases.

Bioinformatics tools will be necessary to uncover nonlinear genetic predictors of common diseases.

Data mining and machine learning methods can increase power to discover nonlinear genetic predictors of common disease.

Filter and wrapper algorithms are necessary to limit the number of attributes examined so modelling strategies are powerful and computationally practical.

Prior biological knowledge can improve the analysis and interpretation of GWAS data.

Powerful and intuitive software packages are necessary to enable collaboration between biologists, biostatisticians and bioinformaticists.
Genetics of Taste Perception
Authors: Bachmanov Alexander A , Boughter John D
Published: April 2013

There is considerable genetic variation in taste perception within and among species. Some taste perception phenotypes have simple monogenic inheritance, whereas others have complex genetic architecture. Recent advances with genomic resources have made genetics a powerful approach to identify taste‐related genes. Chromosomal mapping and positional cloning studies facilitated discovery of taste receptors. The genetic mapping and candidate gene association studies show that taste perception phenotypes are influenced by allelic variation of genes involved in both peripheral and central taste processing. Sequence variation of taste receptor genes explains some species differences in taste perception and sheds light on evolution of ingestive behaviour. Genetic variation in taste perception impacts human nutrition and health and may be useful as a biomarker of predisposition to some diseases. Identification of genes responsible for within‐ and between‐species variation in taste can provide tools to better control food choice and intake in humans and other animals.

Key Concepts:

Genes contribute to individual variation in perception of each of the five primary taste qualities: bitter, sweet, umami, salty and sour.

Genetic variation in taste perception involves polymorphisms of taste receptors, genes involved in peripheral taste transduction and central taste processing.

Genetic variation in taste perception impacts human nutrition and health and could be used as a biomarker of predisposition to some diseases.
Stress‐induced Mutagenesis in Bacteria
Authors: Foster Patricia L
Published: April 2013

Bacteria spend their lives experiencing repeated rounds of feast and famine. In addition, they are buffeted by a variety of environmental insults such as fluctuations in temperature, pH, osmotic pressure, as well as exposure to DNA damaging agents and antibiotics. To cope with these changing conditions, bacteria have a variety of stress‐responses that result in profound but temporary cell‐wide changes in gene expression and protein activities. Keyed into these responses are a variety of ways in which the potential for genetic change is enhanced. Research has provided a number of examples of stress‐induced mutagenesis. Such transient mutator states may be important for adaptive evolution.

Key Concepts:

Bacteria respond to stress by inducing temporary cell‐wide changes in gene expression and protein activities. Some of these changes can increase the cell's potential for genetic change.

Adaptive evolution can be accelerated when mutation rates are high, but persistent high mutation rates are also deleterious. Thus, transient increases in mutation rates are potentially of greater evolutionary advantage than permanent increases.

Stress‐induced mutagenesis appears to be widespread among bacteria.

There are many mechanisms that contribute to stress‐induced mutagenesis.
HTLV‐1
Authors: Bangham Charles RM
Published: April 2013

Human T lymphotropic virus Type 1 (HTLV‐1) was the first human retrovirus discovered. Like the related virus human immunodeficiency virus Type‐1 (HIV‐1), HTLV‐1 persists lifelong in the host. HIV‐1 causes disease in over 99% of untreated infected people, whereas HTLV‐1 causes disease in only 2–8%: either a fatal leukaemia or lymphoma, or a disabling chronic inflammatory disease of the nervous system that causes paralysis of the legs. There is no satisfactory treatment for the malignant or inflammatory diseases, and no vaccine. HTLV‐1 is thought to have existed in the human population for over 50 thousand years; it is widely but unevenly distributed in the tropics and in some subtropical areas. A highly dynamic equilibrium is established in each infected person between persistent HTLV‐1 replication and the host immune response. The increasing understanding of this equilibrium has led to discoveries and conclusions of wide significance for virology, immunology and persistent infections.

Key Concepts:

Viral load and risk of HTLV‐1‐associated diseases are determined by the efficiency of the host's cell‐mediated immune response.

Immunological efficiency is determined by host genetic polymorphisms – chiefly HLA – and by targeting critical weak points in the pathogen's life cycle.

An immunodominant antigen is not necessarily the antigen recognised by the protective host immune response.

Attributes of T cells such as phenotype, frequency and function do not correlate with their efficiency in protecting against a pathogen in a persistent infection at equilibrium.

Viruses that target mobile cells such as leukocytes can use the mobility of the host cell to spread within and between hosts: they do not need to release large numbers of cell‐free virus particles.

Some viruses, such as HTLV‐1, can spread from one cell to another by an active, triggered process that involves formation of a specialised cell‐to‐cell contact called a virological synapse.
Polyomavirus Infections of Humans
Authors: Java Anuja , Cheng Xingxing , Brennan Daniel C
Published: April 2013

Research on polyomaviruses began in 1953 when Ludwik Gross isolated a filterable agent that induced tumours in newborn mice. This agent became the archetypal member of the
Polyomaviridae
family. In 1971, JC virus and BK virus were reported and named after the patients’ initials. More than 30 years passed before the Karolinska Institute virus and Washington University virus were identified from respiratory samples in paediatric patients. The Merkel cell polyomavirus was identified in 2008 for its association with the aggressive Merkel cell carcinoma skin cancer. Recently, polyomaviruses 6, 7, 9 and the trichodysplasia spinulosa‐associated polyomavirus have been discovered. Along with simian virus 40, which has been associated with human disease, there are now 10 polyomaviruses relevant to humans. The range of diseases associated with these human polyomaviruses shows that they are significant causes of human infections. The accumulated knowledge gained from the study of each individual virus helps to understand each in their particular niche.

Key Concepts:

Polyomaviruses are DNA viruses.

Polyomaviruses cause significant human infections, especially in the immunocompromised population.

Human infection most likely occurs during childhood.

Haemorrhagic cystitis and polyomavirus‐associated nephropathy are significant clinical entities caused by the BK virus in solid organ transplant recipients.

Progressive multifocal encephalopathy is a fatal demyelinating disease caused by the JC virus.

Merkel cell virus and SV40 are potential oncogenic agents.

Treatment is supportive and an effective antiviral agent has not been identified so far.
Blastocladiomycota
Authors: Longcore Joyce E , Simmons D Rabern
Published: April 2013

The Blastocladiomycota, a phylum of fungi that produce motile spores and gametes, live in water or in soils, where they are active when water is present and survive with thick‐walled resting sporangia when soils are dry. Some genera are saprobic, but the phylum also contains pathogens of invertebrates and plants. Life cycles can include alternation of haploid and diploid generations and different generations may have different hosts. Sexual reproduction begins by fusion of gametes and meiosis takes place during germination of resistant sporangia. Saprobic members have been used as model organisms and genome sequencing of
Allomyces
and
Blastocladiella
continues this trend.
Coelomomyces
species parasitise mosquito larvae and are capable of causing death of up to 90% of their hosts. Obligate parasitism, narrow host ranges, need for an alternate host and unpredictable rate of control have deterred development of
Coelomomyces
species for mosquito control.

Key Concepts:

Members of the Blastocladiomycota produce spores and gametes that are motile by means of a posteriorly directed whiplash flagellum.

Motile spores, which are recognisable by their centrally located nucleus that is apically surrounded by a nuclear cap consisting of ribosomes, are recognisable at the ultrastructural level by microtubules in groups of three that extend from the apex of the kinetosome and surround the nucleus.

Some saprobic species have an alternation of morphologically similar haploid and diploid generations and some pathogens have alternation of haploid and diploid generations with different morphologies and sometimes on different hosts.

Sexual reproduction is by fusion of motile gametes and meiosis takes place during the germination of resting sporangia.

The phylum contains pathogens of crustaceans, nematodes, algae and aquatic and semi‐aquatic plants.

Saprobic species, especially
Allomyces macrogynus
and
Blastocladiella emersonii
, are used for physiological and genetic studies and the genome of
A. macrogynus
has been sequenced.
Cave Evolution
Authors: Gross Joshua B
Published: April 2013

Cave‐dwelling animals are fascinating because of the phenotypic extremes they frequently exhibit, such as a reduced or complete loss of vision and pigmentation. Equally interesting is the fact that irrespective of taxonomic position, organisms colonising the subterranean environment converge on highly similar phenotypic deficits and improvements. Thus, a predictable suite of morphological, physiological and behavioural changes evolve in response to low nutrient conditions of the subterranean environment. Despite several decades of enquiry, the precise genetic and molecular underpinnings of cave‐associated changes are only beginning to be elucidated through the use of high‐resolution contemporary molecular and genetic techniques. Regressive phenotypic changes, those traits that are lost in derived lineages, are particularly interesting since they evolve in the absence of obvious selective value to the organism. Continuing research utilising an increasing number of emerging cave‐dwelling models offers the exciting prospect of clarifying longstanding problems in contemporary evolutionary biology.

Key Concepts:

Widespread convergence on cave‐associated (troglomorphic) characteristics is often attributed to the paucity of nutrition and overall stability of the cave environment.

Cave‐adapted organisms are excellent models for the study of regressive phenotypic evolution, that is the loss of traits in derived organisms.

The evolutionary mechanism(s) accounting for phenotypic loss in cave‐dwelling organisms (neutralism versus selection) remains unknown.

Hybrid crosses between cave‐dwelling and intra‐specific ‘surface’ forms reveal numerous morphological changes associated with cave adaptation are recessive.

Phenotypic analyses in subsequent generations reveal many cave‐associated characteristics arise through Mendelian (single locus) and complex (polygenic) patterns of inheritance.

The cave environment likely represents an attractive habitat given that over 50 000 cave‐limited species are known worldwide, distributed across broad taxonomic groups.

Contemporary cave research has advanced significantly over the last decade thanks to integrative analyses combining developmental, genetic, genomic, behavioural, physiological and population‐level approaches.
Plastid Origin and Evolution
Authors: Chan Cheong Xin , Bhattacharya Debashish
Published: April 2013

Plastids (or chloroplasts in plants) are organelles within which photosynthesis takes place in eukaryotes. The origin of the widespread plastid traces back to a cyanobacterium that was engulfed and retained by a heterotrophic protist through a process termed primary endosymbiosis. Subsequent (serial) events of endosymbiosis, involving red and green algae and potentially other eukaryotes, yielded the so‐called ‘complex’ plastids found in photosynthetic taxa such as diatoms, dinoflagellates and euglenids. The field of plastid research also includes nonphotosynthetic organelles (apicoplasts) within the parasitic apicomplexans and the temporary sequestration (‘theft’) of plastids by heterotrophic organisms (kleptoplasty) such as the sea slug

Elysia chlorotica

. The gain and loss of plastids, and nonlineal gene transfer (associated with endosymbiosis) are key aspects of algal evolution that have decisive impacts on inference of their phylogenetic positions in the tree of life. Deciphering plastid origin therefore provides general insights into the evolution of eukaryote lineages.

Key Concepts:

The plastid organelle in eukaryotes originated from primary endosymbiosis involving a cyanobacterium.

The secondary (and tertiary) plastids show a history of multiple (serial) endosymbiosis involving red and/or green algae.

Plastid research is complicated by the presence of nonphotosynthetic plastids in parasitic apicomplexans and by the theft of temporary plastids referred to as kleptoplasty.

Understanding plastid origin enhances our understanding of eukaryote evolution.
Evolution of Multicellularity
Authors: Nedelcu Aurora M
Published: April 2013

Multicellularity has evolved multiple times, independently, in lineages from all three domains of life. The transition from a unicellular to a multicellular life‐style entails the integration of previously independent individuals into a new kind of individual. The emergence of individuality at the higher level requires the evolution of cooperative and altruistic behaviours, division of labour (including the separation of reproductive and somatic activities among cells), the reorganisation of basic life properties (such as immortality and totipotency), and the reorganisation of fitness (with cells specialising in one or the other fitness components – survival or reproduction). At a more mechanistic level, a new genotype–phenotype map has to be created to reflect the emergence of a new kind of individual. Notably, many traits associated with multicellularity appear to have involved the co‐option of genes and pathways already present in unicellular lineages. The evolution of multicellularity has been driven by a combination of selective pressures, developmental constraints and life history trade‐offs specific to each lineage.

Key Concepts:

The transition from a unicellular to a multicellular life‐style constitutes a transition in individuality, a process whereby a group of previously independent individuals become stably integrated into a new functional, physiological and reproductively autonomous and indivisible evolutionary unit – that is, a new individual.

The successful integration of previously independent individuals into a new kind of individual requires the evolution of cooperative and altruistic behaviours, division of labour, the reorganisation of basic life properties, and the reorganisation of fitness.

Multicellularity has evolved independently in at least 25 lineages from all three domains of life.

The evolution of multicellularity has been driven by a combination of selective pressures, developmental constraints and life history trade‐offs specific to each lineage.

Many traits associated with multicellularity involved the co‐option of genes and pathways already present in unicellular lineages.