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Human Genetics
& ESHG May eMagazine
1
Contents Click below to explore…
3) Introduction
4) Welcome to the Wiley booth at
ESHG!
5) Welcome to the Wiley booth at
ESHG!
6) Pain Genetics: Basic to Translational
Science
7) Genome‐wide analysis reveals a
role for BRCA1 and PALB2 in
transcriptional co‐activation
8) Cellular Reprogramming: An
Interdisciplinary View
9) Genetic Tests: Clinical Validity and
Clinical Utility
10) The marriage of Cytology and
Cytogenetics
11) From Germ Cell to Implantation –
The Epigenetic Story
12) Play to Cure: Genes in Space - help
Cancer Research UK beat cancer
sooner
BDR Scholar Awards
13) Common genetic variants
associated with disease from genome-
wide association studies are mutually
exclusive in prostate cancer and
rheumatoid arthritis
14) BRCA1 and BRCA2
15) Maternally inherited genetic
variants of CADPS2 are present in
Autism Spectrum Disorders and
Intellectual Disability patients
16) Genetics and genomic medicine
around the world
17) Glioma-Associated Stem Cells: A
Novel Class of Tumor-Supporting Cells
Able to Predict Prognosis of Human
Low-Grade Gliomas
18) Evidence-based Preclinical
Medicine
2
Introduction Welcome to the May Genetics eMagazine!
Are you attending (or wish you were attending) the European Human Genetics
conference (May 31st – June 3rd)? In this edition, find out about how you can take
part in some of our interactive conference discussions between delegates and
editors, sign up to receive our online stand content, and get online ‘ESHG Extras’:
daily free content on key items related to symposia.
Plus, you can read about the latest research in personalised gene medicine, watch
how Cancer Research UK are analysing genetic data using an iTunes space game,
and more! Hope to see you at the Wiley booth soon.
Want to stay up to date with the latest news, research, books, competitions and features in genetics?
Click to Like Click to Follow
Turn the page to discover more…
3
Follow or Like our genetics social media accounts, or choose from our eMailing lists! (To sign up for an eMail list, simply click the button below, enter your email,
select ‘Life Sciences’ and tick your topics of choice).
Click to get eMails
Sunday (11:45am)
Dr Karen Gripp is a board certified pediatrician
and medical geneticist, Professor of Pediatrics
at T. Jefferson University in Philadelphia and
Chief of the Division of Medical Genetics at the
A. I. du Pont Hospital for Children in Wilmington,
DE. She is also an associate editor for the
American Journal of Medical Genetics Part A.
Monday (11:45am)
Maurizio Genuardi, Full Professor of Medical Genetics and
Director of the Institute of Medical Genetics at the Catholic
University in Rome, has been working since 1986 in the
field of inherited predisposition to cancer, contributing to
the definition of the genetic bases of hereditary tumors, in
particular of the colon-rectum. He is also is a
Communicating Editor for the journal Human Mutation.
Welcome to Wiley’s
Get the ESHG Online Stand Library
4
Sample our content Take a break from symposia by coming down to our stand and browsing our
collection of human genetics books and journals. Print copies will be available to
browse, but if you want to continue reading after your visit, all our sample
content is available at our online mini-library of human genetics resources.
Sign up to receive this by clicking here and entering your email address:
Editor Interviews During ESHG we will be interviewing Dr Karen Gripp
and Professor Maurizio Genuardi. Come down to meet
the editors at the Wiley stand, or send your questions for
them to [email protected], or tweet questions to
us at @WileyGenetics. Responses will be posted on the
Wiley Discussions blog (see right!)
Giveaways We’re cutting down on paper and offering you the chance to get some exclusive
human genetics content. Each day at ESHG we will be sending out emails with free
articles, chapters and protocols, on the subject of symposia:
•Friday 30th May: RASopathies
•Saturday 31st May: Genomic Personalised Medicine
•Sunday 1st June: Copy Number Variants
•Monday 2nd June: Cancer Genomics
5
stand at ESHG!
Get ESHG Extras
Wiley Discussions Blog We’re celebrating all things genetics on our
Wiley Discussions blog…
• Take part in our video collage of all things genetics, by
answering what genetics means to YOU in 1 word only!
Visit the stand to record your response on our camera
• Discuss key issues with other geneticists
• Ask questions of leading geneticists from our journals’
editorial boards
Access the blog below or use the iPad at the Wiley stand!
Find the blog here
To receive these ‘ESHG Extras’,
simply click the button below, enter
your email address, and wait to
receive your exclusive free Extras!
Stand
no.
372
Chapter 1: How Do Pain Genes Affect
Pain Experience?
Marshall Devor
There is remarkable variability in the amount pain that different people experience.
Variability is the rule for acute pain in response to noxious stimuli; we each have our
own “pain threshold.” It is also the rule for chronic pain associated with injury and
disease, even when the provoking tissue damage is identical. A dramatic example is
classical trigeminal neuralgia (TN) (type 1). TN is a severe neuropathic pain condition in
which sufferers report feeling intense intermittent electric shock-like pain paroxysms in
the face. The underlying nerve lesion in most cases is microvascular compression of
the trigeminal root near its point of entry into the brainstem. Consistent with early
postmortem reports, a recent magnetic resonance imaging (MRI) study found that 17%
of mature adults have the lesion (Miller et al. 2009). However, only 0.01% of people
suffer from TN pain (population prevalence ca. 10/100 000; Manzoni and Torelli 2005).
That is, only 1 in every 2000 people with the lesion has TN pain.
What is different about those individuals whose lesion causes devastating pain?
Pain Genetics: Basic to
Translational Science
Inna Belfer (Editor), Luda Diatchenko (Editor)
6
Image: Professor Israel Lieblich (1937–1986), a pioneer in pain genetics, was among the first to point out that data on genetic factors that influence the development of chronic pain in rodent neuropathy models “may bear on the fact that after seemingly identical nerve injuries, some humans develop chronic pain syndromes and others do not” (Inbal et al. 1980). (Courtesy of Amia Lieblich.)
Continue reading from this PDF excerpt online
Read More Online
Introduction
Breast and ovarian cancer susceptibility genes
BRCA1 and PALB2 have enigmatic roles in cellular
growth and mammalian development. Although
essential for growth during early developmental
programs, inactivation later in adulthood results in
increased growth and formation of tumors, leading to
their designation as tumor suppressors.
Using genome‐wide analysis derived from
high‐throughput sequencing in breast epithelial cells,
researchers found an intimate association between
BRCA1 and PALB2 chromatin residence and genes
displaying high transcriptional activity. Moreover,
BRCA1 and PALB2 appeared to play a role in
transcriptional responsiveness to NF‐κB, a crucial
mediator of growth and inflammatory response
during development and cancer.
The genes BRCA1 and PALB2 also responded
to retinoic acid (RA), a growth inhibitory signal in
breast cancer cells, which may constitute the basis
for their tumor suppressor activity.
Taken together, results highlight an important role for
these breast cancer proteins in the regulation of
diverse growth regulatory pathways.
Read more from the article online here.
The EMBO Journal
Genome‐wide analysis reveals a role for BRCA1
and PALB2 in transcriptional co‐activation
Alessandro Gardini et al. Read More Online
Image: High‐throughput sequencing reveals chromatin‐binding sites of the breast cancer tumor suppressors BRCA1 and PALB2 and suggests transcription co‐regulatory roles at a subset of genes, including NF‐κB targets and retinoic acid‐responsive genes.
7
Introduction
Cellular reprogramming can either be a natural process (such as adaptation to stress), or
a lab-made process (such as turning creating pluripotent stem cells for disease therapy).
For students and clinicians, this collection features interdisciplinary review articles from
across the WIREs series on cellular reprogramming, including…
Translational reprogramming in cellular stress response
Botao Liu, Shu‐Bing Qian
The molecular circuitry underlying pluripotency
in embryonic stem cells
Aryeh Warmflash, Brigitte L. Arduini,
and Ali H. Brivanlou
Deciphering the complexities of human diseases
and disorders by coupling induced‐pluripotent
stem cells and systems genetics Wing Y. Chang et al.
Engineered genetic information processing circuits
Hao Qi, Andrew Blanchard, and Ting Lu
WIREs Collection
Cellular Reprogramming:
An Interdisciplinary View
Read the collection online
Image: Feedback control, both positive and negative, is used
extensively in engineered genetic regulatory circuits.
8
Introduction
The sequencing of the human genome has led to an increasing array of genetic tests
that are now available for use in health care. But which should clinicians and health
care policymakers use? Three easy criteria exist to help make a choice: analytic
validity, clinical validity, and clinical utility.
Analytic validity refers to the accuracy with which a particular genetic characteristic can
be identified in a given laboratory test. Technical issues arising in the evaluation of
analytic validity include the specific technical requirements of the assay chosen, its
reliability, the degree to which reliability varies from laboratory to laboratory, and the
complexity of test interpretation.
In considering test use, the clinician must also consider clinical validity and clinical
utility. These test properties refer to the accuracy with which a test identifies a patient's
clinical status (clinical validity) and the risks and benefits resulting from test use (clinical
utility).
This unit reviews the implications of these test properties for clinical practice.
Current Protocols: Human Genetics
Genetic Tests: Clinical Validity and
Clinical Utility
Wylie Burke
9
Image: Family with multiple endocrine neoplasia type 2 (MEN2). A definitive diagnosis of MEN2 can be made in the proband (arrow), on the basis of clinical findings of MEN2 (medullary thyroid cancer and hyperparathyroidism), combined with a family pedigree demonstrating autosomal dominant inheritance of the clinical problems associated with MEN2, including medullary thyroid cancer in the proband's father, and pheochromocytoma and C-cell hyperplasia (a precursor of medullary thyroid cancer) in the proband's daughter.
Read More Online
Abstract
“Dearly Beloved, we are gathered here to join in happy matrimony…” Cytology and
Cytogenetics?! Could anyone imagine a more unlikely pair? Cytology: mature,
established, and unpretentious; and Cytogenetics: young, hip, flirtatious. Yet friends
have been noticing the growing attraction between the two in recent years; therefore,
few were truly surprised when the engagement was announced. To understand the
growing connection, it helps to understand the individuals a bit better.
The ability of Cytogenetics to aid in the identification and precise classification of a
variety of neoplasms has not gone unnoticed by Cytology. In particular, Cytology has
recognized Cytogenetics as a welcome companion in the evaluation of soft tissue
tumors, lymphomas, renal and urothelial tumors, and mesothelioma. This relationship
requires a good understanding of the proper handling of specimens for optimal
evaluation by Cytogenetics. The marriage of Cytology and Cytogenetics will likely
grow stronger as more solid tumors (eg, salivary gland neoplasms) are discovered
that harbor characteristic chromosomal abnormalities.
Cancer Cytopathology
The marriage of Cytology and Cytogenetics
Paola Dal Cin, Xiaohua Qian and
Edmund S. Cibas Read More Online
Image: Triaging cytology for cytogenetics is illustrated. The cytologic sample can be apportioned for cytogenetic analysis at several different points, depending on the cytogenetic technique used. A fresh, unfixed sample is needed for a karyotype; this decision is best made at the time of on-site adequacy evaluation. Either fresh or fixed cells can be used for fluorescence in situ hybridization (FISH).
10
When the sperm and egg come together at
fertilization, the genomes of each cell must
be restructured to support embryonic
development.
This Special Issue: From Germ Cell to
Implantation – The Epigenetic Story aims to
better position researchers and students to
understand the dynamic changes in the
chromatin states of gametogenesis, after
fertilization, and during the development of
the resulting embryo. The Special Issue also
provides insight to the special ways in which
stem cells utilize epigenetic mechanisms to
retain their characteristic potency.
Including:
Epigenetic regulation of genomic imprinting from germ line to preimplantation
William A. MacDonald and Mellissa R.W. Mann
DNA methylation and demethylation: A pathway to gametogenesis and
development
Wendy Dean
The epigenetics of early development:
Inferences from stem cells
Theodore P. Rasmussen
… and more!
Molecular Reproduction & Development
Special Issue: From Germ Cell to Implantation –
The Epigenetic Story
Guest-edited by Rocío Melissa Rivera Read More Online
Image: Genomic imprints are established in the germ line in part as differentially methylatedregions (gDMRs) that are
maintained in the preimplantation embryo. Maternally supplied ZFP57 and its cofactor TRIM28 protect gDMRs from demethylation processes by recruiting additional epigenetic modifiers. TRIM28 (immunolabeled in red) localizes to nuclei in the mouse blastocyst. Blastocyst image provided by Michelle M.
Denomme.
11
Cancer Research UK have
devised a genius way of
crowdsourcing gene data analysis-
by embedding it in a mobile space
exploration app! Check out the
video below:
Play to Cure: Genes in Space –
help Cancer Research UK beat cancer sooner
See More Online
12
Birth Defects Research Scholar Awards
The winners of the Birth Defects Research
Distinguished Scholar Awards will be announced at
this year’s Teratology Society meeting in Bellevue,
USA. See here for more information on the award,
awarded for overall impact of highly cited papers to
the field of birth defects research.
Introduction
The link between inflammation and cancer has long been reported and
inflammation is thought to play a role in the pathogenesis of many cancers,
including prostate cancer (PrCa). Nevertheless, very little is known regarding the
underlying aetiology. Age, race and family history of PrCa remain the primary main
risk factors for PrCa.
The estimates from Nordic twin studies suggest that 42% of the risk could be due
to genetic factors. The search for these genetic variants has led to genome-wide
association studies (GWAS), which have so far reported 49 single nucleotide
polymorphisms (SNPs) associated with PrCa risk. These variants alone cannot
explain fully the variation of PrCa incidence seen amongst populations.
Environmental factors such as the immune system and inflammation are also
thought to play a key role in PrCa aetiology.
Researchers aimed to ascertain if there are common genetic risk profiles that might
predispose individuals to both PrCa and the autoimmune inflammatory condition,
rheumatoid arthritis. These results could have potential public heath impact in
terms of screening and chemoprevention.
BJU International
Common genetic variants associated with disease from
genome-wide association studies are mutually exclusive
in prostate cancer and rheumatoid arthritis
Gisela Orozco et al.
Read More Online
13
Introduction
For those working in hereditary breast and
ovarian cancer genetics, 2014 will be a
memorable year, for it marks the 20th
anniversary of both the discovery of BRCA1
on chromosome 17q and of the linkage of
BRCA2 to chromosome 13q. From 20 years
distance, it is clear that these have been the
most influential discoveries in human cancer
genetics. This is because not only are they
medically important discoveries, but also the
identification of these two genes has had
sociopolitical and cultural significance far in
excess of that accorded to other cancer
susceptibility genes.
Find the Special Issue on BRCA1 and
BRCA2 for free here.
Clinical Genetics
Special Issue: BRCA1 and BRCA2
Read More Online
14
Including:
BRCA1 and BRCA2 – update and implications on the genetics of breast cancer: a clinical perspective
WD Foulkes
Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation
KA Metcalfe et al.
The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers
C Borreani et al.
Introduction
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex
neuropsychiatric conditions, with overlapping clinical boundaries in many patients.
Researchers identified a novel intragenic deletion of maternal origin in two siblings
with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein
involved in neurotrophin release and interaction with dopamine receptor type 2
(D2DR).
Mutation screening of 223 additional patients identified a missense change of
maternal origin which disrupted CADPS2/D2DR interaction. CADPS2 allelic
expression was then tested in blood and different adult human brain regions,
revealing that the gene was monoallelically expressed in blood and amygdala, and
the expressed allele was the one of maternal origin.
Cadps2 gene expression performed in mice at different developmental stages was
biallelic in the postnatal and adult stages; however, a monoallelic (maternal)
expression was detected in the embryonal stage, suggesting that CADPS2 is
subjected to tissue‐ and temporal‐specific regulation in human and mice.
This suggests that CADPS2 variants may contribute to ID/ASD development, possibly
through a parent‐of‐origin effect.
EMBO Molecular Medicine
Maternally inherited genetic variants of CADPS2 are
present in Autism Spectrum Disorders and Intellectual
Disability patients
Elena Bonora et al. Read More Online
15
Image: C.Fine mapping of CADPS2 deletion by real‐time qPCR using different probes across the region. All data were normalized using as reference gene FOXP2.
Introduction
To focus on various aspects of genetics and genomic medicine internationally,
Molecular Genetics and Genomic Medicine has begun a new article series, on
‘Genetics and genomic medicine around the world’.
Why establish this feature in Molecular Genetics and Genomic Medicine now?
First, medical genetics is a global practice. Samples are sent to laboratories around the
world for diagnostic testing (for example, the Genetic Testing Registry currently
includes laboratories from 39 countries). Understanding clinical practice in one country
may lead to altered practice in another country, which may be especially important in
working with immigrant populations and understanding their views on genetics and
genomics.
Second, genetics continues to be a rapidly changing field in which we are now learning
to interpret much larger amounts of data from next-generation sequencing. As we are
coming to grips with secondary findings in developed countries, there is uncharted
territory in many areas of the globe such as sub-Saharan Africa, which may not have
the medical infrastructure to evaluate incidental findings.
The first articles in this series are…
Genetics and genomic medicine in
Israel
Joël Zlotogora
Genetics and genomics in Thailand:
challenges and opportunities
Vorasuk Shotelersuk, Chanin Limwongse
and Surakameth Mahasirimongkol
Molecular Genetics & Genomic Medicine
Genetics and genomic medicine around the world
Suzanne Hart and Maximilian Muenke Read More Online
16
Introduction
Translational medicine aims at transferring advances in basic science research
into new approaches for diagnosis and treatment of diseases. Currently, low-grade
gliomas (LGG) can be only partially predicted employing current state-of-the-art
markers, hindering the decision-making process.
To deepen comprehension on tumor heterogeneity, researchers dissected the
mechanism of interaction between tumor cells and relevant components of the
neoplastic environment, isolating proliferating stem cell lines from both the glioma
stroma and the neoplasm.
The microenvironment of both LGG and HGG hosts non-tumorigenic multipotent
stem cells that can increase in vitro the biological aggressiveness of glioma-
initiating cells through the release of exosomes. The clinical importance of this
finding is supported by the strong prognostic value associated with the
characteristics of GASC.
This patient-based approach can provide a groundbreaking method to predict
prognosis and to exploit novel strategies that target the tumor stroma.
STEM CELLS
Glioma-Associated Stem Cells: A Novel Class of Tumor-
Supporting Cells Able to Predict Prognosis of Human
Low-Grade Gliomas
Evgenia Bourkoula et al. Read More Online
Image: Pluripotent state-specific transcription factor expression. GASC express Oct-4 (green fluorescence, C, D), Nanog (red fluorescence, E, F), and Sox-2 (yellow fluorescence, G, H). In D, F, and H, nuclei are depicted by the blue fluorescence of DAPI staining. (I): Results are presented as mean ± SD. (J): Transcripts for OCT3/4, NANOG, SOX2, KLF4 c-MYC, and GAPDH are present in GASC obtained from low-grade (L) and high-grade (H) glioma samples. The neuronally committed human teratocarcinoma cell line (NT2) was used as positive control. 17
Evidence-based Preclinical Medicine
is Wiley’s newest open access journal
and the first of its kind dedicated to
publishing systematic review protocols
and systematic reviews which
summarise data from animal studies on
subjects relevant to human health.
Systematic reviews are a form of meta-
analysis, identifying, appraising,
selecting and synthesising all high
quality research evidence relevant to a
specific question. EBPM’s synthesis of
preclinical evidence will improve
evaluation of the potential success of
future clinical trials, improving the
reliability and value of medical research.
• Edited by Associate Professor David
Howells, (Florey Institute of
Neuroscience and Mental Health) and
Professor Malcolm Macleod (University
of Edinburgh)
• Features a ‘Helpdesk’, to guide
practitioners through the processes of
systematic review, and to help authors
prepare their study datasets for
publication
• Features protocols describing the
proposed approach for a systematic
review
Introducing…
Evidence-based Preclinical Medicine
18
Read More Online