bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics and the Origins of the Polynesians
Authors: Chambers Geoffrey K
Published: April 2013

Anatomically modern humans first arose in Africa. They rapidly spread out across the world with their earliest dispersers reaching as far as Australasia 40 000–60 000 years before present (ybp). Migration routes have been traced pretty thoroughly by molecular methods, but many controversies still remain. Recently debate has been focused on the relative importance of competing alternate pathways and the extent of interaction with other ancient peoples: Neanderthals and Denisovans. The origin of the Polynesian people who settled in Remote Oceania is a particularly long‐standing mystery. Surveys of genetic variation in these populations have helped to distinguish between competing theories arising from anthropology and linguistics. The genetic data show how maternal and paternal lineages combined approximately 3000 ybp giving rise to a new people who spoke Austronesian languages and developed a sophisticated technology for oceanic voyaging.

Key Concepts:

Anatomically modern humans came from Africa and dispersed widely in a relatively short time.

Dispersal patterns plus the timing and extent of gene flow from ancient people have all become controversial topics in recent years.

Pacific Island populations must be described in terms of culture and ancestry as well as their geographic location.

Genetic surveys are powerful tools for testing hypotheses about the migration histories of human populations.

Molecular markers can inform both pattern (origins and pathways) and process (hybridisation, gene flow, founder effects, etc.) in human evolution.

Maternal and paternal markers reveal different ancestors for Pacific people: Austronesian and Papuan, respectively.

Almost all preceding ‘Fast Train’ and ‘Slow Boat’ type models are captured as elements of an extended ‘Synthetic Total Evidence Model’.

Genetic studies of Pacific plants and animals support the emergent view from human genes, language and culture.

In any and all causal explanations of human history, known process elements must fully account for observed patterns.
Origins of the Australian and New Guinean Aborigines
Authors: van Holst Pellekaan Sheila M
Published: April 2013

Mitochondrial deoxyribonucleic acid
(mtDNA), Y chromosome and limited genomic studies indicate deep ancestry for both Australia and New Guinea peoples, with evidence for limited, shared genetic connection as well as ancient lineages specific to both places. Estimates of divergence from the Revised Sapiens Reference Sequence (Behar
et al.
, 2012) indicate that mtDNA haplogroups of living populations in Melanesia and Australia represent some of the oldest lineages outside Africa, founders having arrived there at least 50 000 years ago. Several entry points into Sahul during periods of glacial maxima might explain haplotype distribution. Distinctions between them and other near neighbours also indicate genetic isolation for long periods after sea levels rose. Phylogenies that explore genetic similarities/differences between peoples of Sahul and Asia suggest that migration routes through northern Asia as well as by a southern coastal route are likely scenarios, as no single regional source population is identifiable.

Key Concepts:

Australia and New Guinea were connected by a land bridge during periods of global glaciation forming a land mass known as Sahul, separated from Sunda.

Evidence indicates that people arrived in Sahul approximately 50–60 thousand years ago.

After the Last Glacial Maximum (LGM), Australia and New Guinea were gradually separated and the populations were relatively isolated from each other.

People dispersed throughout the Australian continent by 40 thousand years ago.

Participation in genetic research by descendants of the ‘First Sahulians’ is relatively rare and they are under‐represented in global studies.

There is resistance from some descendants of the First Australians for many reasons including distrust generated by poor research practices of the past.

Studies that include indigenous researchers as well as participants are likely to encourage, facilitate and improve representation.

Those Aboriginal Australians who have participated in genetic research have contributed valuable data that enrich the global story of human diasporation and their own communal and personal history.

Mitochondrial DNA (mtDNA) and Y‐chromosome analyses are particularly suitable for exploring recent human genetic history, whereas genome‐wide analyses are necessary for probing more deeply into population origins.

Complex population histories in Asia suggest different scenarios for likely routes and entry points for founding groups in Sahul.
Endogenous Retroviral Sequences; Their Evolutionary Contribution to the Human Genome
Authors: Mayer Jens
Published: April 2013

Endogenous retroviruses (ERVs) comprise approximately 8% of the human genome. They stem from germ cell invasions of exogenous retroviruses in the evolutionary past. Human ERV transcripts are found in every human tissue, and their expression patterns seem to be regulated by complex mechanisms. HERV transcription is often deregulated in diseased tissue and cells. By introducing numerous regulatory elements into the genome ERVs profoundly influence quite a number of cellular genes regarding gene structure and expression patterns. Although most ERV sequences in the human genome are coding defective, some HERVs still encode proteins that appear to have become essential human genes or that appear to be involved in human diseases. A HERV encoded protein is essentially involved in placenta development. Other HERV encoded proteins may serve as biomarkers for certain tumour types or may be involved in tumour development.

Key Concepts:

Most vertebrate genomes harbour significant amounts of repetitive sequences.

Human endogenous retroviruses are remnants of ancient retroviral infections of the germ line.

Approximately 8% of the human genome are of retroviral origin.

HERV sequences are often severely mutated due to long‐time presence in the genome.

HERV transcripts are found in every human tissue.

HERV transcription is deregulated in some diseases including tumours.

HERV loci can influence transcription of nearby genes.

A HERV encoded protein is essentially involved in placental development.

Other HERV proteins may be involved in tumour development.
Evolution of X‐Chromosome Inactivation
Authors: Shevchenko Alexander I , Zakian Suren M
Published: April 2013

X‐chromosome inactivation is a transcriptional silencing of one of the two X chromosomes that occurs in females of marsupial and eutherian mammals. The process arose and developed as a part of dosage compensation mechanism during differentiation of mammalian X and Y chromosomes. X inactivation started from being imprinted and unstable in marsupials and then was transformed to random and stable in eutherians. The transformation included replacement of the key noncoding nuclearribonucleic acidmaster switch genersxtoxist, and emergency of the X‐inactivation centre responsible for random choice of one of the two X chromosomes. Presumably, further involvement of thexist‐dependent repressive histone modifications together withdeoxyribonucleic acidmethylation and enrichment of the X chromosome with LINE1 mobile elements, allowed for more efficient spread and maintenance of an inactive state and has made the X‐chromosome inactivation process more complete and stable. During eutherian evolution, X‐chromosome inactivation mechanisms have tended to accumulate the taxon‐ and species‐specific differences.

Key Concepts:

X‐chromosome inactivation emerged as part of dosage compensation mechanism caused by differentiation of mammalian X and Y chromosomes.

X‐chromosome inactivation is unique for marsupial and eutherian mammals.

X‐chromosome inactivation has evolved from imprinted, incomplete, and unstable to random, complete, and efficiently maintained.

The long noncoding nuclear RNA controlling X‐chromosome inactivation, initiallyrsxin marsupials, has been replaced forxistin eutherians.

The noncoding nuclear RNA genexist, responsible for initiation of inactivation in eutherians, emerged from a protein coding gene and a set of mobile elements.

Xistand the surrounding genes regulating its expression have formed the inactivation centre that regulate a random choice of one of the two X chromosomes to be transcriptionally silent.

Presumably, the main steps leading to complete and stable X‐chromosome inactivation are involvement of thexist‐dependent repressive histone modifications in gene rich clusters together with DNA methylation of the promoters and enrichment of X chromosome with the mobile elements LINE.

During eutherian evolution, X‐chromosome inactivation mechanisms mainly accumulated taxon‐ and species‐specific differences.
Population Genetics of Lactase Persistence and Lactose Intolerance
Authors: Ingram Catherine JE , Liebert Anke , Swallow Dallas M
Published: April 2013

Variation in the ability of adult humans to digest the lactose in milk is a genetically determined trait that has excited the interest of many for the past 50 years. The trait seems to have risen to high frequencies by one of the strongest selection pressures ever described. This section describes the phenotypic polymorphism and the evidence that the genetic trait involves regulation of expression of the lactase gene and is caused by multiple independent mutations that have reached high frequencies in different populations, because of the benefits of drinking milk. The evolutionary history in Europe and Africa are rather different; there being a single high‐frequency allele in Europe, in contrast to multiple alleles in Africa. Also the selective forces, which are likely to include both the nutritional and water content of milk, may have been different in these regions.

Key Concepts:

The enzyme, lactase, is restricted to the small intestine where it digests lactose in the milk of suckling mammals.

Lactase persists into adult life in some, but not all, people.

Lactase persistence is a genetic trait, which varies in frequency in different populations of the world.

Mutations in an enhancer sequence, at a distance from the lactase gene, appear to be responsible for lactase persistence.

These alleles arose in the last few thousand years and have been under strong positive selection.

The selection may be attributable to one of the nutrients or water in fresh milk and/or its calorific value.
Modelling Cancer in
Drosophila
: The Next Generation
Authors: Cheng Louise Y , Parsons Linda M , Richardson Helena E
Published: April 2013

Drosophila melanogaster

, the vinegar fly, has been utilised as a genetic amenable model organism for more than 100 years. In recent years, its use in modelling human cancer has been greatly expanding. In this article, an update of the recent advances in
Drosophila
research towards understanding cancer development is provided. Genetic analysis in
Drosophila
has provided considerable insight into the mechanisms controlling tissue growth and cell invasion/metastasis during tumourigenesis, as well as the importance of stem cells in tissue regeneration and cancer, and how genes cooperate in tumourigenesis. Several evolutionarily conserved signalling pathways are emerging as playing key roles in many of these processes, including the Jun kinase, Notch, Wnt, Jak/Stat and the Hippo tissue growth control pathway.
Drosophila
has also been specifically utilised to model certain human cancers, by expression of the human versions of cancer‐causing genes, including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Finally, the use of
Drosophila
as a vehicle for anticancer drug discovery is beginning to make an important impact in combating human cancer.

Key Concepts:

Drosophila
is a useful system for modelling human cancer due to the high conservation of critical cancer‐causing genes between humans and flies.

Many signalling pathways contribute to tissue growth; however, the Hippo growth control pathway is emerging as playing a major role.

The Jun kinase signalling pathway plays a context‐dependent role in invasion/metastasis.

Cell polarity and differentiation factors play important roles in controlling the behaviour of stem cells, which can be usurped in cancer.

Cell competition mechanisms are important in removing damaged cells, and the perturbation of this control contributes to tumourigenesis.

Cancer is a cooperative process and
Drosophila
research has revealed many cooperating oncogenes and tumour suppressors.

Drosophila
provides a useful model system to investigate specific human cancers including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia.

Drosophila
can be utilised to screen for anticancer drugs.
Quality Control of Protein Folding in the Cytosol
Authors: McClellan Amie J
Published: April 2013

In order to function properly, newly synthesised proteins must rapidly and efficiently attain their native conformations. If they fail to do so, the cell may be adversely affected due to loss of function or toxic gain of function effects of misfolded polypeptides. Effective quality control mechanisms to recognise and eliminate misfolded proteins are thus critical for cell viability. The primary means by which misfolded proteins are selectively removed from the cell is via the ubiquitin–proteasome system. Although much is known about regulated proteolysis, how any given protein, which could potentially misfold, is recognised and targeted for proteasome‐mediated degradation has been challenging to decipher. Recent progress, much of it in yeast, has identified specific E3 ligases involved in this process, clarified or added to our knowledge of the roles of molecular chaperones, and identified multiple cellular locations where degradation, or failing that, aggregation, occurs.

Key Concepts:

Molecular chaperones facilitate the folding of newly synthesised proteins to their native states and thus are critical for the maintenance of cellular proteome integrity.

Cellular proteostasis reflects the balance between protein folding and degradation.

Proteins that fail to fold properly must be eliminated via cellular quality control systems to avoid potentially damaging effects on the cell.

The ubiquitin–proteasome system is the primary means for the selective removal of misfolded proteins.

Molecular chaperones can tip the balance between protein folding and degradation, and facilitate the destruction of misfolded proteins.

E3 ligases have been identified that either cooperate with chaperones, or that directly interact with nonnative proteins to target them for degradation.

The degradation of misfolded cytosolic proteins in eukaryotes occurs in multiple cellular locations.
Ciona
: A Model for Developmental Genomics
Authors: Satoh Noriyuki
Published: April 2013

The ascidian

Ciona intestinalis

is an excellent model system for studying developmental biology due to the simplicity of its embryogenesis and genomics. The
Ciona
tadpole larva is composed of only 2600 cells and possesses the basic body plan of chordates. The 117‐Mbp‐long euchromatic genome encodes approximately 320 core transcription factors and 125 major signal transduction molecules, the expression profiles of which have been described at the single‐cell level in
Ciona
embryos. Not only the function of developmentally relevant genes can be explored by means of suppressed and/or ectopic expression, but also a convenient electroporation method of reporter gene constructs has been developed to identify
cis
‐regulatory modules. High throughput and genome‐wide approaches can be used to uncover gene regulatory networks involved in cell specification and differentiation. Transposon‐mediated transgenesis also provides a new strategy for elucidating the mechanisms of gene expression and function. These and other advantages of the
Ciona
system recommend future developmental biology studies with this model.

Key Concepts:

The
Ciona
tadpole larva represents the basic and most simplified chordate body plan, and its embryogenesis is well characterised.

The
Ciona intestinalis
genome has been decoded. The 117‐Mbp euchromatic genome, which is packaged into 14 pairs of chromosomes, contains 15 254 genes including ∼320 core TF genes and 125 major signalling molecule genes.

Most of these developmentally relevant genes have been chromosomally mapped.

The spatial and temporal expression profiles of these developmentally relevant genes have been elucidated.

Gene function can be easily studied by suppressed and/or ectopic expression.

A convenient electroporation method allows quantitative and qualitative examination of
cis
‐regulatory modules responsible for gene expression.

The regulatory networks of TF and signalling molecule genes that establish the blueprint of the chordate body plan have been uncovered.

The short generation time allows forward genetics of
Ciona
, a first for a marine invertebrate.

Transgenic lines have been established using
Minos
transposons to reveal gene function and expression.
Micro
RNAs
and Their Role in Cancer
Authors: Ferracin Manuela , Negrini Massimo
Published: April 2013

Microribonucleic acids (miRNAs)
are short, noncoding RNAs that act as post‐transcription regulators and are able to modulate the expression of hundreds of target genes. In the past few years, they gained a very important role in oncology. Indeed, many of them can be now considered tumour suppressor genes or oncogenes. In cancer, they appeared to have a dysregulated expression due to genetic aberrations, altered methylation or irregular processing that finally lead to an altered modulation of their target genes.

Each cancer type displayed specific alterations of specific miRNAs, and their exceptional stability confer to miRNAs a strong potential as cancer therapeutics. Finally, miRNAs are stable and detectable as circulating molecules in blood of cancer patients. For this reason they are going to become useful biomarkers in cancer diagnostics.

Key Concepts:

In the last few years, miRNAs have produced a micro‐revolution in cancer research because of their action as oncogenes or tumour suppressor genes.

miRNA expression profiling may be used for cancer classification and for the identification of cancer subtypes.

A promising role of miRNA in prognosis stratification has been proposed.

Several studies indicated miRNAs as predictors of drug response.

miRNA polymorphisms may modify innate genetic susceptibility to cancer: SNPs in miRNAs and their gene targets may alter cancer susceptibility.

miRNAs as cancer biomarkers detected in plasma or serum of patients seem to be very promising in terms of efficacy and specificity.

miRNA may represent important therapeutic targets and can be effectively targeted
in vivo
.
Molecular Basis of Complex Traits
Authors: Polychronakos Constantin
Published: April 2013

Most genetically determined differences between individuals, including (but not limited to) susceptibility to specific diseases, depend on functional variation at multiple genes (loci). The frequency of these variants (alleles) in the general population varies from common to rare. The contribution of most common alleles, each in isolation, to disease risk is weak. Most uncommon and rare alleles have not been studied to date and some may have strong effects on disease risk even if they contribute to disease cause each in a small subset of cases. This mixture of strong and weak effects by common and rare alleles is referred to as allelic architecture. Defining the allelic architecture of each disease will be the first step towards using an individual's genetic profile to individualise the molecular diagnosis within a group of cases that all bear the same clinical diagnostic label.

Key Concepts:

Most diseases and other human traits have statistically significant familial clustering, indicating the involvement of genetic susceptibility.

Genetic susceptibility to most diseases is determined by a large number of gene variants (loci).

Disease‐associated variants may change the sequence of the protein product, or the control of its transcription, RNA stability or translational efficiency.

Most known loci have a weak genetic association with the disease or trait.

A genetic association may be weak because of weak biology, or because the associated allele is merely an imperfect marker for an untested rare allele with strong effect.

The discovery, among low‐frequency alleles, of those that have the strongest effects, is the next frontier in the genetics of complex traits and the greatest promise to personalised medicine.
Genetic Determinants of Human Life‐Span
Authors: Jylhävä Juulia , Hurme Mikko
Published: April 2013

The contribution of genetic factors to human life‐span and longevity is recognised although the mediators and their molecular mechanisms are currently far from completely understood. However, significant advances have been recently made to unveil the genes and pathways involved in life trajectory determination in humans as well as in model organisms. In humans, more than 100 longevity candidate genes have been presented; however, with the exception of a few loci, the results tend to suffer from a lack of replication. Nevertheless, genetics appears to have moderate control over human life‐span and the impact is known to increase towards the old ages. Currently, the pathways with the most potential for harbouring longevity genes include the insulin/insulin‐like growth factor (IGF) signalling (IIS) and lipid metabolism. It remains to be seen whether future studies can pinpoint additional pathways and elucidate the remaining unexplained genetic variation in human life‐span.

Key Concepts:

Human life‐span is an extremely complex entity with genetic, environmental and stochastic factors modulating the longevity phenotype.

The majority of the proposed longevity gene candidates appear to be population‐ and/or sex‐specific.

Consistent association with human life‐span or longevity has thus far been observed for only the
APOE
,
FOXO3
and
ATK1
loci.
Cardiofaciocutaneous (
CFC
) Syndrome
Authors: Denayer Ellen , Legius Eric
Published: April 2013

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder that is characterised by facial dysmorphism, cardiac defects, mental retardation, typical ectodermal abnormalities and short stature. It is caused by germline mutations in
BRAF
,
MEK1
,
MEK2
or
KRAS
and shows phenotypical overlap with other conditions caused by mutations in the RAS‐MAPK pathway such as neurofibromatosis type 1, Noonan, LEOPARD, Costello and Legius syndromes. The identification of the underlying genetic defect opens new windows for therapeutic strategies in these RASopathies including CFC syndrome.

Key Concepts:

Mutations in genes coding for key components of the RAS‐MAPK pathway are responsible for a group of inherited disorders (RASopathies).

The RASopathies are clinically and molecularly related disorders characterised by variable cognitive deficits, growth retardation, facial dysmorphy, and congenital cardiopathies.

CFC syndrome is characterised by the most severe intellectual disabilities seen in the RASopathies.

Correcting cerebral RAS‐MAPK signalling is a potential targeted treatment for learning disabilities in patients with a RASopathy.
Bacterial Cell Wall Recycling
Authors: Mayer Christoph
Published: April 2013

Cell wall recycling is a process whereby bacteria degrade their own wall during growth, recover released constituents by active transport and reutilise them either to rebuild the wall or to gain energy. Most knowledge about cell wall recycling comes from studies with the Gram‐negative bacteriumEscherichia coli. Within one generation, this organism breaks down and efficiently recycles approximately 60% of the mature peptidoglycan of its side‐wall during cell elongation and approximately 30% of newly deposited septal peptidoglycan during cell division. The reason for the massive turnover of the peptidoglycan is still unclear, although many other bacteria, including Gram‐positives, have been reported to turnover their cell wall and release similar quantities of peptidoglycan fragments during growth and differentiation. Whether these fragments are also recycled is basically unknown. The presence of recycling genes on most bacterial genomes, however, suggests that cell wall recycling is a very common pathway of bacteria.

Key Concepts:

The peptidoglycan of the bacterial cell wall represents a single, giant, reticular macromolecule (i.e. the murein sacculus) that encases the entire bacterial cell.

The peptidoglycan cell wall has to be cleaved continuously during growth to allow cell expansion by insertion of new wall material.

Bacteria possess a huge and partially redundant set of cell wall lytic enzymes that potentially target every covalent bond connecting the amino acid and amino sugar building blocks within the peptidoglycan network (cell wall lytic complement).

Many bacteria release a great amount of cell wall material during bacterial growth (cell elongation and division). The reason for the massive turnover of approximately 50% of the existing peptidoglycan in one generation is still unclear.

Bacteria eventually recover cell wall turnover fragments. The pathways for the continuous recycling of peptidoglycan have been explored in great detail inEscherichia coli.

Cell wall recycling in Gram‐positive bacteria has been appreciated just recently and apparently differs from theE. coliparadigm as well as between Gram‐positive species.

Cell wall‐derived peptidoglycan fragments function as potent biological effectors. They are involved in sensing the cell wall and growth state, inducing expression of antibiotic resistance genes, and triggering cell differentiation and resuscitation of dormant cells.
Aerobic Methanotrophy and Nitrification: Processes and Connections
Authors: Stein Lisa Y , Roy Réal , Dunfield Peter F
Published: April 2013

Ammonia and methane are structurally similar molecules. Not surprisingly therefore, microorganisms that use methane as a sole energy source (methanotrophs) and microorganisms that use ammonia as a sole energy source (ammonia oxidisers or nitrifiers) share many similarities. They have several key enzymes in common, most especially the ammonia monooxygenase/particulate methane monooxygenase enzyme family. The two groups are proposed to have a common evolutionary history. They occupy similar ecological niches, and compete for nitrogen. Enzymatically, nitrifiers are capable of methane oxidation, and methanotrophs are capable of nitrification. Microbial ecologists have attempted to find specific inhibitors for either group in order to study their respective roles in the environment. The contribution of ammonia oxidisers to methanotrophy in natural systems appears to be very minor, however methanotrophs may sometimes have important roles in the nitrogen cycle.

Key Concepts:

Some bacteria and archaea are capable of using methane or ammonia as energy sources.

Methanotrophs and ammonia oxidisers are each highly specialised to living on their particular substrate.

Methanotrophs and ammonia oxidisers have several key enzymes in common, and may share a common evolutionary history.

Both groups must cope with toxic by‐products of ammonia oxidation.

Methanotrophs may be important in the environmental nitrogen cycle, but ammonia oxidisers do not affect the methane cycle.

Ammonia oxidising archaea appear to outcompete ammonia oxidising bacteria under ammonia‐limiting and acidic conditions.
Molecular Genetics of Williams–Beuren Syndrome
Authors: Merla Giuseppe , Micale Lucia , Fusco Carmela , Loviglio Maria Nicla
Published: April 2013

The Williams–Beuren syndrome is a rare genomic disorder caused by a hemizygous microdeletion of approximately 30 genes at 7q11.23 occurring by nonallelic homologous recombination between low copy repeats flanking that region. The 7q11.23 region has been also found duplicated, triplicated and inverted in patients with different and, in some instances, reciprocal phenotypes.

Complementary strategies including mouse models, functional and biochemical studies have been pursued in the recent years to delineate the individual and/or combined contribution of hemizygous genes to the wide spectrum of phenotypes that characterises this syndrome. Haploinsufficiency of several of these genes has been reported to account for parts of the overall phenotypes, suggesting their sensitivity to gene dosage. Notably,
MLXIPL
,
GTF2IRD1
and
GTF2I
hemizygous genes act as transcription factors, therefore is likely that their haploinsufficiency is responsible for some of clinical features by regulating gene expression of a wide number of target genes.

Key Concepts:

Williams–Beuren syndrome is a genomic disorder characterised by a unique cognitive profile and it involves approximately 30 hemizygous genes at 7q11.23.

The 7q11.23 Williams–Beuren syndrome region has been found deleted, duplicated, triplicated and inverted in patients with different phenotypes.

Patients with atypical deletions and mouse models have provided insights about the genotype–phenotype correlations.

Haploinsufficiency of the Williams–Beuren syndrome genes is correlated with the clinical signs.

BAZ1B
has been linked to cardiac, craniofacial and hypercalcemia defects; hemizygosity of
MLXIPL
could be related to the diabetic phenotype of Williams–Beuren syndrome patients through regulation of glucose metabolism.

The GTF2IRD1 transcription factor modulates genes involved in tissue development and differentiation and is a strong candidate for the craniofacial and neurobehavioral features.
Molecular Genetics of Malignant Mesothelioma
Authors: Sekido Yoshitaka
Published: April 2013

Malignant mesothelioma (MM) is an aggressive tumour arising primarily from the pleural or peritoneal cavities. MM develops by asbestos exposure after a long latency, which is highly refractory to conventional therapeutic modalities. Molecular genetic analysis has revealed several key genetic alterations which are responsible for the development and progression of MM. The frequently mutated tumour suppressor genes detected in MM cells areCDKN2A/ ARF,NF2,BAP1, andLATS2. In contrast, frequent activating mutation of any oncogenes has not been clearly identified yet, which is one of the reasons that current molecular target therapy is not very effective for MM patients. Recent studies have also indicated characteristic epigenetic alterations in MM, which include distinctdeoxyribonucleic acid (DNA)methylation patterns and the involvement of noncodingribonucleic acid (RNA). Aberrant histone modification caused byBAP1inactivation may also lead to the disturbance of global expression profiling. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them would be applied for developing a new diagnostic tool and new target therapies against MMs.

Key Concepts:

Malignant mesothelioma cells harbour multiple key genetic mutations, which mainly inactivate tumour suppressor genes.

Asbestos fibre induces chromosome and DNA damages in normal mesothelial cells with several possible mechanisms, but it is not clear why it takes so long from asbestos exposure to mesothelioma development.

People differ in their susceptibility to development of mesothelioma after similar levels of asbestos exposure, possibly due to the differences in genetic polymorphisms or expression levels of genes involved in the DNA repair system and epigenetics modification.

Mesothelioma has long been considered a representative type of tumour primarily caused by environmental factors, especially asbestos, but familial cases of mesothelioma with a specific gene mutation have challenged this idea.

Neurofibromatosis type 2 (NF2) gene inactivation is found in a nearly half of mesothelioma cases and the inactivation of one of its downstream signal transduction cascades, Hippo signalling, plays a significant role in dysregulation of cell proliferation.

Epigenetic alterations such as aberrant histone modification by BAP1 gene inactivation play significant roles in mesothelioma development.

The overall picture of the genetic abnormality landscape of mesothelioma cells lags behind other common human malignancies.

If an oncogene‐type gene with frequent activating mutation in mesothelioma cells were discovered, molecular target strategies aiming at controlling the activated molecule could be aggressively pursued to develop new therapeutic tools against mesothelioma.
Molecular Genetics and Immunopathogenesis of Psoriasis
Authors: Lepre Tiziana , Zampatti Stefania , Novelli Giuseppe , Giardina Emiliano
Published: April 2013

Psoriasis (OMIM #177900) is a common chronic disease of the skin that affects approximately 2–3% of the population. Typical lesions of psoriasis are characterised by red and scaly skin patches, usually found on the scalp, elbows and knees and often associated with severe arthritis. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. The onset of the disease is generally between 10 and 40 years of age. Type 1 begins at or before the age of 40 years; type II begins after the age of 40 years. Psoriasis is a complex disease due to the interaction between environmental factors and susceptibility alleles. Life style, diet, smoking, stress and infections are the best validated environmental factors predisposing to the pathology. During the past several years, researchers have identified different loci related to the disease, namely fromPSORS1toPSORS13.

Key Concepts:

Multifactorial diseases are common disease due to the interaction between environmental factors and different susceptibility loci.

Psoriasis, a chronic disease of the skin, is a common disease affecting approximately 2–3% of the population.

Psoriasis is a complex disease. Different loci are known to be responsible for its development, together with some environmental factors, such us life style, diet, smoking, stress and infections.

Immune system is responsible for the development of psoriasis: HLACw*06:02 is the best replicated and validated susceptibility allele.

Understanding the genetic and epigenetic basis of psoriasis will help to further outline the molecular mechanism of onset and progression.
Capillary Malformation–Arteriovenous Malformation andRASA1Mutations
Authors: Boon Laurence M , Revencu Nicole , Vikkula Miikka
Published: April 2013

Capillary malformation–arteriovenous malformation (CM–AVM) is a subtype of CM that is inherited as an autosomal‐dominant disorder. Patients typically have multiple small pinkish‐reddish CMs, often with a halo. These lesions are randomly distributed on the body. About 15–20% of patients have an associated arteriovenous fistula or malformation often located on head and neck. The fast‐flow lesions involve skin, subcutaneous tissue, muscle and/or bone or the brain or the spine. Parkes Weber syndrome and vein of Galen aneurysmal malformation are also part of CM–AVM. Most CM–AVM patients have a detectableRASA1mutation causing loss‐of‐function of p120RASGAP, a guanosine triphosphatase‐activating protein, which participates in the regulation of the Ras signalling pathway. Most mutations are private and no genotype–phenotype correlation has been identified. A somatic second hit is likely necessary to produce lesional, complete loss‐of‐function of p120RASGAP, as the malformations are localised, and often multifocal. Ras‐pathway modulators may provide futuristic therapies for CM–AVM.

Key Concepts:

Multifocal, often small, capillary malformations may be hereditary.

Lesions with pale reddish‐brownish colour, a halo and/or a good demarcation line suggest CM–AVM.

Numerous miliary telangiectasias (often on extremities) are also suggestive of CM–AVM.

Many, but not all patients, also have a fast‐flow lesion.

Distribution of fast‐flow lesions differs from that of hereditary haemorrhagic telangiectasia.

Until better statistics exist, clinical examination should include T1/T2 brain MRI, when molecular diagnosis is confirmed.

These CMs do not respond well to current lasers.

RASA1‐dominant mutations are mostly private, that is, specific to each family.

Parkes Weber syndrome patients with CMs elsewhere on the body are likely to carry aRASA1mutation.

Family history is not necessarily present, asde novomutations occur.
Molecular Genetics of Migraine
Authors: Stuart Shani , Maher Bridget H , Oikari Lotta , Griffiths Lyn R
Published: April 2013

Migraine is a common neurological disorder with a significantly heritable component. It is a complex disease and despite numerous molecular genetic studies, the exact pathogenesis causing the neurological disturbance remains poorly understood. Although several known molecular mechanisms have been associated with an increased risk for developing migraine, there remains significant scope for future studies. The majority of studies have investigated the most plausible candidate genes involved in common migraine pathogenesis utilising criteria that takes into account a combination of physiological functionality in conjunction with regions of genomic association. Thus, far genes involved in neurological, vascular or hormonal pathways have been identified and investigated on this basis. Genome‐wide association studies (GWAS) studies have helped to identify novel regions that may be associated with migraine and have aided in providing the basis for further molecular investigations. However, further studies utilising sequencing technologies are required to characterise the genetic basis for migraine.

Key Concepts:

Migraine can present with variable phenotypes, which may confound results from gene association studies where some traits are more prevalent than others contributing to variability between populations.

Migraine is a genetically heterogeneous disorder and this may contribute to the difficulty in replicating gene associations in different populations.

Pedigree‐based studies may assist to reduce genetic and phenotypic heterogeneity to identify molecular mechanisms or pathways involved in pathogenesis that may then be investigated at a population level.

Current migraine genetic studies focus on genes involved in hormonal, vascular or neurological pathways.

GWAS have provided some success in identifying novel genomic regions for investigation.

Investigation of the mitochondrial genome is an emerging area of investigation in migraine research.

Sequencing will assist to identify novel rare or family‐specific variants that may implicate genes for further research.
Nuclear Envelope Assembly and Disassembly During the Cell Cycle
Authors: Chen Rey‐Huei
Published: April 2013

The nuclear envelope of metazoa breaks down at the onset of mitosis and reassembles at the end of mitosis. This process is mainly controlled by the cyclin‐dependent kinase that phosphorylates inner nuclear membrane (INM) proteins to disrupt their association with chromatin and to disintegrate the nuclear lamina. Upon nuclear envelope breakdown, the nuclear membrane and integral nuclear membrane proteins retract into the endoplasmic reticulum (ER), whereas other peripheral nuclear membrane proteins and some components of the nuclear pore complex become disperse in the cytosol. At late anaphase, inactivation of the cyclin‐dependent kinase and dephosphorylation of INM proteins allow these proteins to bind the chromatin and brings the ER membrane to the chromatin surface to initiate nuclear envelope assembly around the compact chromosome mass. The nuclear envelope disassembly and assembly are thus coordinated with the segregation of sister chromatids in each cell division cycle to maintain genome stability.

Key Concepts:

The nuclear envelope is a dynamic structure that is continuous with the ER.

The INM proteins associate with and organise the chromatin.

The disassembly of nuclear envelope is triggered by the cyclin‐dependent kinase at the onset of mitosis.

Phosphorylation of INM proteins disrupts their interaction with chromatin.

Nuclear envelope breakdown is essential for sister chromatid segregation.

Integral nuclear membrane proteins diffuse into the ER after nuclear envelope breakdown.

The nuclear envelope reassembles around compact chromosome mass at late anaphase/telophase.

Nuclear envelope reassembly is mediated by multiple interactions of the INM proteins with chromatin.

Dephosphorylation of INM proteins at late anaphase/telophase is required for nuclear envelope reassembly.
Cellular Basis of Laminopathies
Authors: Cao Kan
Published: April 2013

The nuclear lamina is the main architectural component of a eukaryotic nucleus. More than an inert scaffold, the lamina is essential for maintaining proper nuclear organisation, epigenetic composition, transcriptional regulation and cell cycle progression. Mutations within lamin genes lead to a wide range of diseases known as laminopathies, among which the striking premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) is the most well known. Studies regarding the cellular basis of laminopathies have advanced our knowledge of the nuclear lamina and yielded remarkable insights into the process of normal human aging. Understanding the molecular mechanisms responsible for disease manifestations has also led to the development of novel therapeutic strategies to address lamina‐related diseases. Ultimately, scientists and clinicians seek to provide treatment options to laminopathy patients to alleviate symptoms and perhaps to cure these diseases in the future.

Key Concepts:

Mutations in genes encoding lamin proteins lead to a wide range of diseases known as laminopathies.

The nuclear lamina plays essential roles in maintaining nuclear architecture, chromatin organisation, cellular differentiation and gene expression.

Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin structure and function.

Progerin, the mutant form of lamin A expressed in Hutchinson–Gilford progeria syndrome, is also present in normal individuals, albeit at a low level.

Recent advances have led to the development of noval therapeutic options for patients suffering from HGPS.
Cytokinesis
Authors: Gregory Stephen L , Saint Robert
Published: April 2013

Cytokinesis is the term given to the division of a cell into two daughter cells. Cytokinesis in all cells requires the resolution of the single lipid bilayer of the parent cell into separate bilayers enclosing the two daughter cells, yet cytokinesis mechanisms differ markedly in different cell types. In bacteria, a ring of FtsZ protein filaments constricts the membrane. FtsZ‐like proteins operate in some Archeal species, but others use a different mechanism. In plants, vesicles are deposited by microtubules in the centre of the cell to create sheets of membrane that grow outwards until they reach and fuse with the cytoplasmic membrane. In animal cells, actin and myosin form a contractile ring, which draws the membrane inwards. Bundled microtubules and vesicle trafficking then complete the separation (abscission). In all cases, cytokinesis closely follows chromosome segregation and constriction occurs between the separating chromosomes to ensure the genetic integrity of the daughter cells.

Key Concepts:

To make two cells from one, the DNA needs to be copied, the two copies separated and the cell divided (cytokinesis) so that one DNA copy resides in each daughter cell.

The cytoplasmic membrane of the parent cell must resolve into the two cytoplasmic membranes of the daughter cells.

Cell division frequently involves the formation of a ring of protein filaments that attaches to the membrane and constricts, drawing the membrane inwards.

In many bacterial cells, the main component of this ring is the FtsZ protein. In animal cells, the main components are actin and myosin.

In plant cells, microtubules form across the future site of division and deposit membrane vesicles which fuse to form the new membrane.

In many eukaryote cells, the mitotic spindle allows the DNA to separate, and then signals the cell to determine the plane of division.

In animals, the final separation of daughter cells involves vesicles fusing with the cell membrane.

Errors in cytokinesis have serious implications for cancer.
Neurogenesis in the Developing Mammalian Neocortex
Authors: Kelava Iva , Huttner Wieland B
Published: April 2013

The neocortex is the evolutionarily newest and most complex part of the mammalian brain. The neurons of the neocortex are born from different neural stem and progenitor cells (for simplicity collectively referred to as progenitors) that reside in proliferative zones during embryonic development. During the neurogenic period, distinct populations of neural progenitors appear, each having specific molecular and cell biological characteristics. These characteristics and the environment of the neural progenitor are responsible for the self‐renewing or neurogenic potential of each neural progenitor type. The fate of daughter cells after neural progenitor division is determined by the mode of division, intrinsic factors such as transcription factors or regulatoryribonucleic acids(RNAs), and by extrinsic signals coming from the surrounding cells. This tight regulation controls the rate of production of neural progenitor types and neurons. The ratios of different progenitor types have a huge impact on the final number of neurons in the adult neocortex, and are partly responsible for vast differences in the brains of different mammals.

Key Concepts:

Neocortex is a part of the brain characteristic of mammals.

Neocortex is a six‐layered structure comprised of post‐mitotic neurons and glial cells.

Neocortical neurons are born from neural progenitor cells, mostly during embryonic development.

Neural progenitor cells can be classified into different populations based on molecular and cell‐biological features.

The molecular and cell‐biological features of neural progenitor cells influence their propensity to self‐renew or produce neurons.

Neural progenitor cells are under tight intrinsic and extrinsic control, in order to maintain the equilibrium between proliferative and neurogenic divisions.

The relative abundance of different progenitor populations influences the final number of neurons in the adult neocortex.
Animal Mating Systems
Authors: Klug Hope
Published: April 2013

The term mating system refers to the way in which individuals are grouped in relation to mating, and/or characteristics of mate acquisition and mating behaviour. Animal mating systems are incredibly diverse and have been most generally classified as monogamous (a single male and single female mate exclusively with one another) or polygamous (males and/or females mate with multiple individuals). There are three classic polygamous mating systems: polygyny (a male mates with more than one female), polyandry (a female mates with more than one male) and polygynandry (both males and females have more than one mate). Some researchers have developed more specific mating system classifications, and this remains an area of active research. Mating systems are influenced by many factors, including the spatial and temporal distribution of sexually receptive males and females, resource availability and distribution, male and female life history, sexual selection and parental care.

Key Concepts:

Mating system refers to the way in which individuals are grouped in relation to mating and/or details of mating dynamics.

Animal mating systems are highly variable within and between taxonomic groups.

Mating systems are dynamic and change through time.

Common mating systems include monogamy, polygyny, polygamy and polygynandry.

More specific descriptors of mating systems have been developed that account for pair bond duration, resource use and defence and behaviour such as parental care.

Animal mating systems are affected by the spatial and temporal distribution of receptive mates, resource use and defence, male and female life history, sexual selection and parental care.