bluuebunny/crossref_metadata_2025 huggingface dataset:
Fitness and Selection
Authors: Charlesworth Brian
Published: April 2013

Selection affects the genetic composition of a population through differences in fitness amongst genotypes. With discrete generations, fitnesses are usually measured relative to the value for some standard genotype because only relative fitnesses matter. For an autosomal locus with two alleles, when the highest fitness is associated with homozygotes for a particular allele, this allele will spread through the population. When the heterozygote has the highest fitness, a polymorphism is maintained by selection. Variation can also be maintained by frequency‐dependent selection, temporal and spatial variation in fitnesses and a balance between the input of deleterious mutations and their elimination by selection. Selection theory can be extended to more complex situations such as overlapping generations. Selection can act at different levels, including selection among gametes produced by the same individual or amongst groups of individuals. Selection at one site in the genome can also influence evolution and variation at linked sites.

Key Concepts:

Evolution by natural or artificial selection involves differences in fitnesses amongst genotypes.

The fitness of a genotype measures its expected genetic contribution to the next generation.

Directional selection at a single diploid genetic locus results in the replacement of one allele at the locus by the alternative allele associated with the fittest homozygote.

Balancing selection, such as heterozygote advantage, results in the maintenance within a population of two or more alleles at a locus.

Mutations to deleterious alleles occur throughout the genome and contribute to variability before the alleles are removed from the population by selection.

Genetic drift in finite populations can cause the loss of beneficial mutations and spread of deleterious mutations.

Selection can act at levels of organisation either below or above that of the individual, which may generate conflicts between its effects at different levels.

Altruistic behaviour may evolve by kin or group selection.

Selection at one site in the genome influences evolution and variation at sites that are genetically linked to it.
Imprinting Disorders
Authors: Henkhaus Rebecca S , Feinberg Andrew P , Niemitz Emily L , Butler Merlin G
Published: April 2013

Genomic imprinting is an example of epigenetic inheritance in which differences in gene function depend on whether the allele was inherited from the mother or father. Many disorders appear to involve epigenetic alterations to imprinted genes. Genes involved in imprinting play important roles in both pre‐ and post‐natal growth and neurodevelopment. Imprinting disorders include several childhood genetic disorders such as Prader–Willi, Angelman and Beckwith–Wiedemann syndromes, as well as several types of cancer including Wilms tumour. Recent evidence suggests a correlation between assisted reproductive technologies (ART) and imprinting disorders, a phenomenon requiring more in‐depth studies as the prevalence of ART is increasing. The mechanism of normal imprinting as well as its perturbation in disease is becoming understood and amenable to experimentation.

Key Concepts:

Imprinted genes are expressed in a parent‐of‐origin‐dependent manner. Imprinting disorders result from genetic abnormalities in imprinted genes.

Approximately 1% of the human genome is imprinted, a process which occurs during gamete development.

Imprinted genes are generally associated with growth, neurodevelopment and epigenetics.

The first imprinted genes discovered were
IGF2
(paternally expressed) and
H19
(maternally expressed), both located at 11p15.

There is an imprinted gene cluster located at 15q11–q13, associated with Prader–Willi and Angelman syndromes. Imprinted genes/transcripts within this region include
NDN
,
MAGEL2
,
SNURF‐SNRPN
,
SNORD116
,
SNORD115
and
UBE3A
.

Well‐characterised imprinting disorders include Prader–Willi syndrome (PWS), Angelman syndrome (AS), Beckwith–Wiedemann syndrome (BWS), Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP), Silver–Russell syndrome (SRS) and transient neonatal diabetes mellitus (TNDM).

Imprinted genes are associated with many types of cancers, primarily due to a process called loss of imprinting (LOI) which leads to aberrant gene expression. Cancers known to be associated with imprinted genes include Wilms tumour in children, and adult cancers of the ovary, lung, colon and liver.

The relationship between artificial reproductive technology (ART) and imprinting disorders is currently being investigated. There is evidence to support a correlation between ART and imprinting disorders which result from loss of maternally imprinted genes such as AS and BWS.
Genetic Imprinting in the Prader–Willi and Angelman Syndromes
Authors: Gurrieri Fiorella , Sangiorgi Eugenio
Published: April 2013

Imprinted genes are expressed from only one of the two parental alleles: they are located in a few, specific chromosomal regions. The parental‐specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fibre and therefore regulate the expression of the underlying genes. Deletions, duplications, mutations or imprinting defects of the only active allele, as well as uniparental disomy or loss of imprinting of the inactive allele lead to an unbalance (loss of function or gain of function) in the dosage of the gene product and do have phenotypic consequences. Two such examples in human pathology are represented by the Prader–Willi and Angelman syndromes, two phenotypically different conditions, whose phenotypes result from loss of paternal or maternal contribution of the 15q11–q13 genomic region, respectively.

Key Concepts:

Prader–Willi and Angelman syndromes are caused by loss of function of different genes located in a genomic region under the control of a single, bipartite imprinting centre.

These two condition represent the prototype of genomic imprinting disorders in humans.

Genomic imprinting regulates allelic expression according to the parental origin.

Imprinted genes are commonly expressed in half dosage.

Imprinted genes can be inactivated by different mechanisms: uniparental disomy, microdeletion, gene mutation, primary or secondary epigenetic mutation of the imprinting centre.
Mitochondrial Disorders: Nuclear Gene Mutations
Authors: Ghezzi Daniele , Zeviani Massimo
Published: April 2013

In addition to mutations of mitochondrialdeoxyribonucleic acid(mtDNA), many mitochondrial syndromes are due to abnormalities in nuclear genes related to oxidative phosphorylation (OXPHOS). Nuclear genes encode hundreds of proteins directly involved in mitochondrial OXPHOS or linked to other metabolic pathways that are related to OXPHOS, such as the tricarboxylic acid (TCA) cycle and fatty acids β‐oxidation, cell signalling and apoptosis. Although the identification of mutations in mtDNA has become relatively easy because its small size and the nearly complete elucidation of its sequence polymorphisms, the analysis of nuclear disease genes is still a formidable challenge. However, with the recent improvement in technology throughput and bio‐computational power, this scenario is rapidly changing. The discovery of several OXPHOS‐related human genes and the identification of mutations responsible for different clinical syndromes indicate that the majority, but not all, of the inherited mitochondrial disorders are due to nuclear genes encoding proteins targeted to mitochondria.

Key Concepts:

Mitochondria are the principal intracellular source of energy through the production of ATP by oxidative phosphorylation (OXPHOS).

Mitochondria contain their own genome, a small, circular double‐stranded DNA (mtDNA).

mtDNA contains 13 genes encoding subunits of the respiratory chain complexes and 24 genes encoding 2 ribosomal and 22 transfer RNAs, which are necessary to carry out intramitochondrial translation.

Mitochondria depend on the nucleus for the supply of all of the other OXPHOS proteins as well as the factors necessary for replication, repair, transcription, translation, maintenance of mtDNA and for the biogenesis, shaping, fusion and fission of the organelles.

Mitochondrial‐inherited diseases may present with a vast range of symptoms, severity, age of onset and outcome.

Because of its dual genetic control, OXPHOS disorders can be due to mutations in mtDNA or nuclear DNA genes.

Recent epidemiological studies show that mitochondrial disorders have a minimal prevalence of 1:5 000.
Animal Rights: Animals in Genetics Research
Authors: Wise Steven M
Published: April 2013

To determine whether it should be legal to use a nonhuman animal in genetics research, one needs to evaluate whether she should have the capacity to possess any legal right at all, that is, whether she should be deemed a ‘legal person’, as a matter of liberty, equality or both. The key trait is dignity and what I call ‘practical autonomy’. If a nonhuman animal has the capacity to possess any legal right, the issue is then whether she should be entitled to such fundamental legal rights as bodily liberty and bodily integrity, and whether she should have the legal right to sue to enforce those rights.

Key Concepts:

Legal personhood is the fundamental building block of legal rights.

Legal persons have the capacity to possess legal rights.

Who should be a legal person is a matter of principle and not policy or precedent.

One may argue for legal personhood either a noncomparative or as a comparative right.

Practical autonomy is a sufficient condition for legal personhood as a noncomparative right.

One has practical autonomy if one can desire, intentionally try to fulfil that desire, and possesses a sense of self‐sufficient to allow one to understand, even dimly, that it is oneself who wants something and is trying to get it.

The more exactly members of a nonhuman species resemble humans in behaviour, and the closer they are to humans taxonomically, the more confident we can be that they possess practical autonomy.

The Normative Model of equality is a hybrid of a comparative and a noncomparative right, as it determines rights against a larger social, political and legal backdrop. It seeks to identify whether some rational connection exists between the means used to accomplish an end and the end it seeks to accomplish and makes a judgement about whether the end itself is appropriate.

Prohibited ends might include a legislative or judicial classification that burdens a plaintiff in a manner that reflects deeply personal social stereotypes that are biologically immutable or changeable only at unacceptable personal costs or that involve morally irrelevant traits.

A Level 1 legal person may possess any of an infinite number of legal rights, again as a matter of liberty and equality.
Genomic Imprinting at the Transcriptional Level
Authors: da Rocha Simão Teixeira , Heard Edith
Published: April 2013

Genomic imprinting is an epigenetic mechanism of gene regulation that causes genes to be expressed from only one of the two parentally inherited chromosomes in mammals. This form of regulation affects less than 1% of genes and has crucial roles in embryonic growth, development and brain function. Imprinted genes are often clustered in large chromosomal domains and their expression is regulated bycis‐acting imprinting control regions (ICRs). ICRs carry a methylation imprint that is laid down in one of the two parental germlines, when the two genomes are separated, to distinguish the paternal and the maternal alleles. To date, regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers orcis‐regulation induced by long noncoding RNAs (ncRNAs). Aberrant expression of imprinted genes leads to human pathologies and is frequent in cancer. Genomic imprinting provides a unique model for studying the epigenetic influence on transcriptional activity and repression.

Key Concepts:

A subset of genes in the mammalian genome (less than 1%) known as imprinted genes are expressed exclusively from one of the two parental alelles.

The existence of genomic imprinting highlights the nonequivalence of parental genomes and precludes the viability of mammalian embryos with exclusive contribution of genetic material from one of the parents.

Imprinted genes are involved in fetal growth and placental development in the uterus, as well as brain function and metabolism in adults.

Genomic imprinting has been reported in placental mammals and marsupials but not in montremes.

Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are co‐ordinatively regulated.

Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alelles during gametogenesis.

DNA methylation is the bona fide imprint mark that distinguishes the two parental alleles at the ICRs, resisting the wave of DNA demethylation after fertilisation and being erased and reset in the germline.

Insulation of common enhancers by the methylated sensitive protein CTCF explains the imprinting regulation at theIgf2/H19region.

Silencing of genes incisby long non‐coding RNAs explains the imprinting regulation for at least three imprinted clusters by yet unknown mechanisms.

Deregulation of genomic imprinting can cause imprinted disorders in humans which exhibit parent of origin effects in their pattern of inheritance.
Darwin and the Idea of Natural Selection
Authors: Dover Gabriel
Published: April 2013

Natural selection is a consequence of differences in reproductive success among distinctly unique individual phenotypes living at a given generation and resulting in a biased representation of genes at the next generation. Reproducing, transient phenotypes, not ‘eternally selfish’ genes, form the arena in which selection takes place in a given biotic and abiotic environment. The evolved, complex relationship between genotype and phenotype is largely unknown and perhaps unknowable given the promiscuity of genes to participate in different functional networks at one and the same time, and given the vagaries of the external environment on individual ontogeny and life cycle. Accordingly, there is a many‐on‐many discourse between genes and traits, making the complex evolutionary role of natural selection difficult to fathom. Hopes for, or fears of, genetic determinism of human behaviour are premature.

Key Concepts:

Natural selection is a simple idea widely misunderstood: ‘Adaptation’ has come to mean both the mechanism of natural selection and its product.

The ephemeral, reproducing individual phenotype is at the heart of natural selection, not the ‘eternally selfish’ gene.

The unique pathway of individual development is not predictable given the ‘degeneracy’ of network interactions among genes, proteins, neurons, etc. within an ever shifting environmental milieu.

There is a many‐on‐many, not a one‐to‐one, relationship between genes and traits.

Natural selection is a means of changing the average genotype/phenotype of a population with the passing of the generations. There are two other means (‘neutral drift’ and ‘molecular drive’) for achieving the same effect.

Natural selection is not a process as such as the internal and external factors that influence differences in reproductive success differ at each generation.

It is not logically possible, without recourse to ‘just‐so’ stories, to determine which of two or more co‐extensive traits in a species was naturally selected and which a ‘free‐rider’.

The pattern of a given set of genetic interactions (network topology) may differ between individuals yet have the same trait outcome (‘degeneracy’).
Distributive Justice and Genetics
Authors: Farrelly Colin
Published: April 2013

What will the demands of distributive justice be in the post‐genetic revolutionary world? Will genetic inheritance be regarded as socially distributed goods? This may seem a more reasonable position to assert as biotechnology progresses further toward human genetic manipulation. Advances in human genetics raise a number of unique considerations for theories of justice, ranging from the realisation of egalitarian ideals and the therapy/enhancement distinction to the scope and limits of reproductive freedom. As new empirical discoveries are made concerning the environmental and natural determinants of human welfare, theories of justice must re‐conceptualise what the demands of justice are and how society can fairly distribute the natural and social goods which influence the life prospects of humans.

Key Concepts:

Aging is the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age.

Distributive justice is concerned with what constitutes a fair distribution of the benefits and burdens of social cooperation.

Luck egalitarianism is the view which maintains that inequalities that are the result of factors beyond a person's control, such as inequalities in natural endowments, are unjust.

The Priority View maintains that it is morally more important to benefit the people who are worse off.

Procreative liberty is freedom in activities and choices related to procreation.

The Sufficiency View maintains that what is morally important is for everyone to have enough.
Comparative Genomic Hybridization in the Study of Human Disease
Authors: Cheung Sau Wai , Pursley Amber Nolen
Published: April 2013

Microarray‐based comparative genomic hybridization (CGH) has made a significant impact on the ability to diagnose human constitutional disease by detecting genomic copy number changes that were previously undetectable by other types of cytogenetic and molecular technologies. Not only can hundreds of well‐characterized genetic syndromes be detected in a single assay, but new genomic disorders and disease‐causing genes are also being discovered through the utilization of this technology. Clinical implementation of array CGH Hybridization has been extended to the prenatal setting, where it is also proving to enhance the diagnostic capabilities in the perinatal period. However, the clinical interpretation of the increasing number of copy number variations detected as the resolution of the microarrays is improved still poses a formidable challenge to laboratorians, health care providers and families.

Key Concepts:

Array comparative genomic Hybridization (aCGH) has several advantages over traditional cytogenetic methods for diagnosing human diseases: higher resolution, more robust and automated, and shorter turn around time since no cell culture is required.

Copy number variation (CNV) is common in the genome making it challenging for the clinical significance to be determined. Parental testing and utilisation of several internet‐based databases assist with the interpretation of CNVs.

The detection rate for clinically relevant CNVs by aCGH (10–20%) is significantly higher than traditional chromosome analysis (3%) making it the recommended first‐tier cytogenetic diagnostic test for patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and multiple congenital anomalies by the International Standard Cytogenomic Array Consortium.

The resolution of aCGH has evolved to be sensitive enough to aid in the diagnosis of single gene disorders.

Array CGH is a useful tool for discovering new disease‐causing genes.

Array CGH has led to the recognition of many new genomic disorders, many of which cannot be diagnosed clinically due to lack cardinal features, variable expressivity and reduced penetrance.

CNVs, particularly those that occur
de novo
, are increasingly being recognised as important in the etiology of both syndromic and nonsyndromic autism as well as other neuropsychiatric disorders.

SNP‐based microarrays can be used to diagnosis uniparental disomy.

Array CGH is increasingly being used in prenatal diagnosis and has demonstrated its usefulness in clarifying the significance of karyotype findings and providing diagnoses not identifiable by chromosome analysis alone.

It is the opinion of The American College of Obstetrician and Gynecologists (2009) that aCGH not currently replace classic cytogenetics for prenatal diagnosis, but that targeted aCGH can be offered as an adjunct tool in prenatal cases with abnormal anatomical findings and normal karyotype, as well as in cases of fetal demise with congenital anomalies and the inability to obtain a conventional karyotype.
Tooth Agenesis
Authors: Luder Hans Ulrich , Mitsiadis Thimios A
Published: April 2013

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

Key Concepts:

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

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

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

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

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

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

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

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

Key Concepts:

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

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

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

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

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

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

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

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

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

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

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

Key Concepts:

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

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

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

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

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

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

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

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

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

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

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

Key Concepts:

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

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

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

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

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

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

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

Key Concepts:

Teeth are specialised ectodermal organs.

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

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

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

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

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

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

Chronic myeloproliferative neoplasms (previously called myeloproliferative diseases) are group of haematopoietic neoplasms characterised by clonal proliferation of differentiated cells from the myeloid lineage. This includes granulocytes, erythrocytes and megakaryocytes. In general, the course of these neoplasms is chronic and some patients may live more than 20 years and die from other causes, however, in some patients, they may manifest aggressively and kill patients in short time. Significant progress have been made in understanding the molecular basis of these diseases and recently new pharmaceutical agents have been developed that specifically target these molecular abnormalities and converted these neoplasms to chronic diseases to live with as any other chronic disease. We find in this group of diseases chronic myeloid leukaemia and polycythaemia vera, which are perhaps the most molecularly defined two neoplasms. TheBCR‐ABL1fused gene is the cause of the first neoplasm and the mutated JAK2 gene cause the second disease, both of which are targeted in the current treatment of these two diseases.

Key Concepts

Mutations cause the uncontrolled growth of cells, but these cells are capable of differentiation.

The ability of these leukaemic cells to differentiate leads to their death at some point making these diseases less aggressive than acute leukaemias.

Chromosomal translocations and mutations in specific genes are implicated in these groups of diseases.

Most of the genomic abnormalities in these diseases lead to activating specific kinases and this leads to uncontrolled cell proliferation.

By targeting these kinases, cell growth can be controlled and these diseases can be managed successfully.

Translocations may lead to fusing two genes and the expression of a fused protein or may lead to a change in the regulation of the gene and its deregulation.

Activation of a geneviatranslocation is usually into other genomic locus and a specific partner gene, but occasionally can be promiscuous and accept other partners.

Historically the Philadelphia chromosome is considered the first hint for the fact cancer is genomic disease was discovered in CML, which is one of the cMPNs discussed here.
Complement System: Evolution
Authors: Nonaka Masaru , Sekiguchi Reo
Published: April 2013

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

Key Concepts:

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

Most complement components have a characteristic modular structure.

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

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

The thioester‐containing protein family is subdivided into two subfamilies, the C3 and A2M subfamilies.
Trypsinogen Genes: Insights into Molecular Evolution from the Study of Pathogenic Mutations
Authors: Chen Jian‐Min , Cooper David N , Férec Claude
Published: April 2013

The basic fuel for evolution is genetic variation that is subsequently acted on by natural selection. Selection may either act conservatively so as to ensure that features of structural or functional importance are retained (purifying selection), or it may act so as to favour those changes, which confer some advantageous characteristics (positive selection). Insights into these divergent evolutionary processes are sometimes generated through the study of pathogenic mutations, an archetypal example being the human trypsinogen genes. The integration of data gleaned from the functional characterisation of pathogenic missense mutations in the human cationic trypsinogen gene (
PRSS1
) with information obtained from comparative sequence analysis has provided evidence for stepwise selective pressures acting against prematurely activated trypsin within the human pancreas. Studies of
PRSS1
mutations have also revealed evidence for past gene conversion events between the various trypsinogen gene family members and have helped to improve our understanding of the evolutionary history of these genes.

Key Concepts:

Trypsinogen plays an important role in digestion.

Prematurely activated trypsin within the pancreas, if not inhibited and/or inactivated, has the potential to trigger the pancreatic zymogen activation cascade, leading to pancreatic autodigestion and pancreatitis.

Gain‐of‐function mutations in the human cationic trypsinogen gene (
PRSS1
) cause chronic pancreatitis.

Pathogenic
PRSS1
mutations have been exploited to understand the molecular evolution of the human trypsinogen family.

Pathogenic mutations in
PRSS1
have revealed the molecular footprints of gene conversion occurring between the highly homologous human trypsinogen genes.

The integration of data gleaned from the functional characterisation of pathogenic
PRSS1
missense mutations with information obtained from comparative sequence analysis has provided evidence for stepwise selective pressures acting against prematurely activated trypsin within the human pancreas.

Genetic data have also helped to improve our understanding of the evolutionary history of the different human trypsinogen genes.
Mitochondrial
DNA
Polymorphisms
Authors: Passarino Giuseppe , Rose Giuseppina
Published: April 2013

The analysis of genetic variation occurring in human
mitochondrial deoxyribonucleic acid
(mtDNA) has characterised the field of human population genetics since this small molecule has been sequenced in 1981. First analyses were carried out by restriction analysis, and they immediately suggested that mtDNA polymorphisms could allow a phylogenetic reconstruction of the human populations. The technical improvements, which made subsequently easier sequence analyses, allowed to refine the previous results and to understand many aspects of the human origin and of the dispersal of human populations in the world. Interestingly, the variability of mtDNA turned out not to be neutral but to affect the adaptation to the environmental factors (such as climate and diet) and many complex traits such as aging and degenerative diseases.

Key Concepts:

The analysis of mitochondrial DNA polymorphisms has characterised the last three decades of human genetics.

The lack of recombination in mitochondrial DNA leads mtDNA polymorphisms to accumulate sequentially along independent lineages.

The availability of a great number of mitochondrial DNA sequences has allowed to find numerous mtDNA polymorphisms.

The phylogenesis of mitochondrial DNA polymorphisms allowed to understand many aspects of human evolution and many aspects of the dispersal of human populations.

The analysis of mitochondrial DNA polymorphisms in groups of subjects with different complex traits has allowed to highlight that mtDNA polymorphisms are not neutral but they affect many phenotypic traits.
Limits of Proteomics: Protein Solubilisation Issues
Authors: Rabilloud Thierry
Published: April 2013

Because of their tremendous chemical heterogeneity, many proteins, such as membrane proteins, are poorly soluble in aqueous solvents. This precludes their analysis by classical proteomics techniques, whether these techniques are based on protein separation (e.g. two‐dimensional gel‐based proteomics) or on peptide separation after in‐solution digestion. For techniques based on peptide separation, the issue is to couple on the one side a complete solubilisation of proteins, a good efficiency of the protease used to produce the peptides, and on the other side minimal interference with the techniques used to separate the peptides. For techniques based on protein separation, the issue is to solubilise the proteins and to keep them soluble under the conditions used for the protein separation. For both type of technologies, combinations of detergents and chaotropes often provide the most performing solution to the protein solubilisation problem, although complete solubilisation can never be guaranteed.

Key Concepts:

Proteins must be extracted from their cellular context into an aqueous‐based solvent for their analysis.

Surfactants/detergents provide the adequate medium to mimic a lipid‐like environment in water.

The structural variety of detergents provides the various solubilisation performances that can be adapted to many proteomics methods.

Chaotropes are often used in conjunction with detergents to improve protein/peptide solubility.
Protein Characterisation in Proteomics
Authors: Meri Seppo , Baumann Marc
Published: April 2013

Proteomics refers to the comprehensive analysis of proteomes – the protein content of complex biological mixtures, that is, a whole proteome of a cell, microbe or a proteome of a certain tissue or just the proteome of the blood, saliva or cerebrospinal fluid. The aim is to separate and identify all the proteins of the chosen proteome and then to determine their interactome and with that their biological relevance and activity in that system at the moment of sample collection. Currently, such analyses would also include the characterisation of possible secondary modifications and determining the expression level of each protein. All this is performed by high‐end mass spectrometers that allow the identification and parallel quantification of several hundred proteins and several of their secondary modifications (e.g. phosphorylations, sumoylations, glycosylations

etc

.) in one analysis step. Thus, a big challenge is also to be able to deal with an enormous amount of complex data in order to make any sense of the results at the end. In this article, the authors will highlight some key issues for such analyses and describe some of the used technologies in greater detail.

Key Concepts:

Proteins are one of the key elements of life.

Proteome is the full content of proteins in a given biological sample.

Proteome content can change dynamically according to, for example, time, location and environmental conditions.

Meaningful results from proteomic analysis can be obtained if the analysis is restricted to a well‐defined and targeted goal.

Main methods include two‐dimensional gel separation, enzyme digestion and multidimensional liquid chromatography mass spectrometry.

Along the flow of proteomic analysis it is important to choose the most appropriate approach (top‐down vs. bottom‐up, focused vs. broad, quantitative vs. qualitative, comparative, selective).

Protein analysis can be subjected to positive and negative selection procedures for desired features.

Post‐translational modifications can change protein characteristics and function.

Large depositories of data are available for comparative analysis.
Biofuels: Ethanol Producers
Authors: Darku Irene D , Richard Thomas L
Published: April 2013

Two groups of microbes, saccharolytic and ethanologenic, are important in ethanol production. The former makes sugar utilisation possible and the latter converts the sugar to ethanol. Many promising or potential ethanologenic and saccharolytic microbes fall within the respective phyla Ascomycota and Neocallimastigomycota for fungi, and Proteobacteria and Fibrobacteres for bacteria.Saccharomycessp. (Ascomycota) andZymomonas mobilis(Proteobacteria) are the only microbes naturally capable of producing ethanol close to theoretical maximum, withSaccharomyces cerevisiaepredominant for current ethanol production based on starch and sugar feedstocks. To enable cellulosic ethanol technologies, microbial capability and efficiency must be enhanced by appropriately designed mixed‐culture systems and/or genetically modified microbes. As cellulosic ethanol nears commercialisation, these two approaches are key to sustainable and economical production.

Key Concepts:

Ethanol producers are known as ethanologens.

Currently, commercial production of bioethanol depends on yeast, especially species ofSaccharomyces cerevisiae, for fermentation of hexose (6‐carbon) sugars.

Zymomonas mobilisis the only bacteria naturally capable of producing ethanol as the sole product and the only ethanologen that uses a nonglycolytic metabolic pathway.

Saccharolytic or hydrolytic microbes are an important complement to ethanologens in ethanol production.

Production of ethanol from carbohydrate oligomers (2–10 monosaccharide units) or polymers (>10 monosaccharide units) usually requires hydrolysis to simple hexose or pentose sugars.

Of the ten major phylogenetic phyla of fungi, only two are currently identified as relevant to ethanol production.

Thermophilic microorganisms and species of the genusclostridiumare expected to play greater roles in future ethanol production.

Microbial consortia, comprising different saccharolytic and diverse sugar fermenting microbes, provide one promising strategy for cellulosic ethanol production.

Other cellulosic ethanol strategies are genetically modifying microbes capable of producing hydrolytic enzymes as well as co‐fermenting 5‐carbon and 6‐carbon sugars.
Biofuels: Fungal, Bacterial and Insect Degraders of Lignocellulose
Authors: Sethi Amit , Scharf Michael E
Published: April 2013

Lignocellulose is the main structural component of plant cell walls and can be degraded into simple sugars with the help of hydrolytic enzymes. Lignocellulose is composed of three polymers: cellulose, hemicellulose and lignin. Certain fungi, bacteria and insects have evolved the ability to degrade lignocellulose. Cellulose is degraded to glucose by the synergistic action of three distinct classes of enzymes: endoglucanases, exoglucanases and β‐glucosidases. Owing to its variable structure and organisation, hemicellulose degradation requires various enzymes with diverse modes of action, which include endoxylanases, endomannanases, β‐xylosidases, β‐mannosidases, β‐galactosidases, α‐glucuronidases, α‐arabinofurnosidases, α‐galactosidases, acetyl xylan esterases, feruloyl esterases and glucuronyl esterases. Lignin degradation is much more difficult due to its complex structure and bonding to carbohydrate complexes. It requires oxidative enzymes, such as lignin peroxidases, manganese peroxidases, versatile peroxidases, laccases, and several other auxiliary enzymes. Commercial biofuel production from lignocellulosic materials can be achieved by artificially producing these cellulases, hemicellulases and lignases in recombinant form.

Key Concepts:

Lignocellulose is the most abundant renewable resource of energy on the Earth.

Lignocellulose is a general term referring to a natural complex of three biopolymers: cellulose, hemicellulose and lignin.

Simple sugar can be released from lignocellulose using three categories of enzymes: cellulases, hemicellulase and lignases.

Released sugars from lignocellulose can be fermented into biofuel (ethanol).

Wood‐rotting fungi such as white‐rot, brown‐rot and soft‐rot fungi can degrade lignocellulose.

Aerobic and anaerobic bacteria such asBacillus, Streptomyces, CellulomonasandClostridiumpossess lignocellulose‐degrading enzymes.

Wood and plant‐feeding insects such termites, roaches, longhorn beetles and grasshoppers are rich sources of novel lignocellulases genes.

Lignocellulases of fungal, bacterial and insect origin can be artificially/recombinantly produced in various protein expression systems.

Fungal, bacterial and insect lignocellulases are expected to play important roles in the development of successful lignocellulose conversion technologies.