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Genes, Volume 5, Issue 3 (September 2014) – 21 articles , Pages 497-864

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856 KiB  
Review
DNA Methylation Biomarkers: Cancer and Beyond
by Thomas Mikeska and Jeffrey M. Craig
Genes 2014, 5(3), 821-864; https://doi.org/10.3390/genes5030821 - 16 Sep 2014
Cited by 224 | Viewed by 19265
Abstract
Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient’s response to therapy. Epigenetic changes are such characteristics, with most epigenetic [...] Read more.
Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient’s response to therapy. Epigenetic changes are such characteristics, with most epigenetic biomarkers discovered to date based on the epigenetic mark of DNA methylation. Many tissue types are suitable for the discovery of DNA methylation biomarkers including cell-based samples such as blood and tumor material and cell-free DNA samples such as plasma. DNA methylation biomarkers with diagnostic, prognostic and predictive power are already in clinical trials or in a clinical setting for cancer. Outside cancer, strong evidence that complex disease originates in early life is opening up exciting new avenues for the detection of DNA methylation biomarkers for adverse early life environment and for estimation of future disease risk. However, there are a number of limitations to overcome before such biomarkers reach the clinic. Nevertheless, DNA methylation biomarkers have great potential to contribute to personalized medicine throughout life. We review the current state of play for DNA methylation biomarkers, discuss the barriers that must be crossed on the way to implementation in a clinical setting, and predict their future use for human disease. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
Functional Role of the microRNA-200 Family in Breast Morphogenesis and Neoplasia
by Bylgja Hilmarsdottir, Eirikur Briem, Jon Thor Bergthorsson, Magnus Karl Magnusson and Thorarinn Gudjonsson
Genes 2014, 5(3), 804-820; https://doi.org/10.3390/genes5030804 - 11 Sep 2014
Cited by 46 | Viewed by 8577
Abstract
Branching epithelial morphogenesis is closely linked to epithelial-to-mesenchymal transition (EMT), a process important in normal development and cancer progression. The miR-200 family regulates epithelial morphogenesis and EMT through a negative feedback loop with the ZEB1 and ZEB2 transcription factors. miR-200 inhibits expression of [...] Read more.
Branching epithelial morphogenesis is closely linked to epithelial-to-mesenchymal transition (EMT), a process important in normal development and cancer progression. The miR-200 family regulates epithelial morphogenesis and EMT through a negative feedback loop with the ZEB1 and ZEB2 transcription factors. miR-200 inhibits expression of ZEB1/2 mRNA, which in turn can down-regulate the miR-200 family that further results in down-regulation of E-cadherin and induction of a mesenchymal phenotype. Recent studies show that the expression of miR-200 genes is high during late pregnancy and lactation, thereby indicating that these miRs are important for breast epithelial morphogenesis and differentiation. miR-200 genes have been studied intensively in relation to breast cancer progression and metastasis, where it has been shown that miR-200 members are down-regulated in basal-like breast cancer where the EMT phenotype is prominent. There is growing evidence that the miR-200 family is up-regulated in distal breast metastasis indicating that these miRs are important for colonization of metastatic breast cancer cells through induction of mesenchymal to epithelial transition. The dual role of miR-200 in primary and metastatic breast cancer is of interest for future therapeutic interventions, making it important to understand its role and interacting partners in more detail. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Review
The Revolution in Human Monogenic Disease Mapping
by Emma Duncan, Matthew Brown and Eileen M. Shore
Genes 2014, 5(3), 792-803; https://doi.org/10.3390/genes5030792 - 05 Sep 2014
Cited by 19 | Viewed by 7458
Abstract
The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease [...] Read more.
The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such as skeletal dysplasias. In this review, we illustrate the challenges of mapping disease genes in such conditions through the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP) and we discuss the advances that are being made through current massively parallel (“next generation”) sequencing (MPS) technologies. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
Regulation of mRNA Trafficking by Nuclear Pore Complexes
by Amandine Bonnet and Benoit Palancade
Genes 2014, 5(3), 767-791; https://doi.org/10.3390/genes5030767 - 02 Sep 2014
Cited by 29 | Viewed by 11079
Abstract
Over the last two decades, multiple studies have explored the mechanisms governing mRNA export out of the nucleus, a crucial step in eukaryotic gene expression. During transcription and processing, mRNAs are assembled into messenger ribonucleoparticles (mRNPs). mRNPs are then exported through nuclear pore [...] Read more.
Over the last two decades, multiple studies have explored the mechanisms governing mRNA export out of the nucleus, a crucial step in eukaryotic gene expression. During transcription and processing, mRNAs are assembled into messenger ribonucleoparticles (mRNPs). mRNPs are then exported through nuclear pore complexes (NPCs), which are large multiprotein assemblies made of several copies of a limited number of nucleoporins. A considerable effort has been put into the dissection of mRNA export through NPCs at both cellular and molecular levels, revealing the conserved contributions of a subset of nucleoporins in this process, from yeast to vertebrates. Several reports have also demonstrated the ability of NPCs to sort out properly-processed mRNPs for entry into the nuclear export pathway. Importantly, changes in mRNA export have been associated with post-translational modifications of nucleoporins or changes in NPC composition, depending on cell cycle progression, development or exposure to stress. How NPC modifications also impact on cellular mRNA export in disease situations, notably upon viral infection, is discussed. Full article
(This article belongs to the Special Issue Mechanisms of mRNA Nuclear Export)
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Article
A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care
by Scott D. Boyd, Stephen J. Galli, Iris Schrijver, James L. Zehnder, Euan A. Ashley and Jason D. Merker
Genes 2014, 5(3), 748-766; https://doi.org/10.3390/genes5030748 - 01 Sep 2014
Cited by 6 | Viewed by 6673
Abstract
The tremendous increase in DNA sequencing capacity arising from the commercialization of “next generation” instruments has opened the door to innumerable routes of investigation in basic and translational medical science. It enables very large data sets to be gathered, whose interpretation and conversion [...] Read more.
The tremendous increase in DNA sequencing capacity arising from the commercialization of “next generation” instruments has opened the door to innumerable routes of investigation in basic and translational medical science. It enables very large data sets to be gathered, whose interpretation and conversion into useful knowledge is only beginning. A challenge for modern healthcare systems and academic medical centers is to apply these new methods for the diagnosis of disease and the management of patient care without unnecessary delay, but also with appropriate evaluation of the quality of data and interpretation, as well as the clinical value of the insights gained. Most critically, the standards applied for evaluating these new laboratory data and ensuring that the results and their significance are clearly communicated to patients and their caregivers should be at least as rigorous as those applied to other kinds of medical tests. Here, we present an overview of conceptual and practical issues to be considered in planning for the integration of genomic methods or, in principle, any other type of “omics” testing into clinical care. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Commentary
Open Access Data Sharing in Genomic Research
by Stacey Pereira, Richard A. Gibbs and Amy L. McGuire
Genes 2014, 5(3), 739-747; https://doi.org/10.3390/genes5030739 - 29 Aug 2014
Cited by 24 | Viewed by 9061
Abstract
The current emphasis on broad sharing of human genomic data generated in research in order to maximize utility and public benefit is a significant legacy of the Human Genome Project. Concerns about privacy and discrimination have led to policy responses that restrict access [...] Read more.
The current emphasis on broad sharing of human genomic data generated in research in order to maximize utility and public benefit is a significant legacy of the Human Genome Project. Concerns about privacy and discrimination have led to policy responses that restrict access to genomic data as the means for protecting research participants. Our research and experience show, however, that a considerable number of research participants agree to open access sharing of their genomic data when given the choice. General policies that limit access to all genomic data fail to respect the autonomy of these participants and, at the same time, unnecessarily limit the utility of the data. We advocate instead a more balanced approach that allows for individual choice and encourages informed decision making, while protecting against the misuse of genomic data through enhanced legislation. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Article
Enterococcus faecalis Infection and Reactive Oxygen Species Down-Regulates the miR-17-92 Cluster in Gastric Adenocarcinoma Cell Culture
by Jesper A. B. Strickertsson, Lene Juel Rasmussen and Lennart Friis-Hansen
Genes 2014, 5(3), 726-738; https://doi.org/10.3390/genes5030726 - 28 Aug 2014
Cited by 26 | Viewed by 7651
Abstract
Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role [...] Read more.
Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role in the pathogenesis of many human diseases including gastric cancer. Here we studied the impact of infection by the gram-positive bacteria Enterococcus faecalis (E. faecalis) on global miRNA expression as well as the effect of ROS on selected miRNAs. Human gastric adenocarcinoma cell line MKN74 was infected with living E. faecalis for 24 h or for 5 days or with E. faecalis lysate for 5 days. The miRNA expression was examined by microarray analysis using Affymetrix GeneChip miRNA Arrays. To test the effect of ROS, MKN74 cells were treated with 100 mM tert-Butyl hydroperoxide (TBHP). Following 5 days of E. faecalis infection we found 91 differentially expressed miRNAs in response to living bacteria and 2 miRNAs responded to E. faecalis lysate. We verified the down-regulation of the miR-17-92 and miR-106-363 clusters and of other miRNAs involved in the oxidative stress-response by qRT-PCR. We conclude that only infection by living E. faecalis bacteria caused a significant global response in miRNA expression in the MKN74 cell culture. E. faecalis infection as well as ROS stimulation down-regulated the expression of the miR-17-92 cluster. We believe that these changes could reflect a general response of gastric epithelial cells to bacterial infections. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Article
Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders
by Gilberto Paz-Filho, Margaret C.S. Boguszewski, Claudio A. Mastronardi, Hardip R. Patel, Angad S. Johar, Aaron Chuah, Gavin A. Huttley, Cesar L. Boguszewski, Ma-Li Wong, Mauricio Arcos-Burgos and Julio Licinio
Genes 2014, 5(3), 709-725; https://doi.org/10.3390/genes5030709 - 25 Aug 2014
Cited by 21 | Viewed by 10130
Abstract
Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female [...] Read more.
Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
MicroRNAs Related to Polycystic Ovary Syndrome (PCOS)
by Anja Elaine Sørensen, Marie Louise Wissing, Sofia Salö, Anne Lis Mikkelsen Englund and Louise Torp Dalgaard
Genes 2014, 5(3), 684-708; https://doi.org/10.3390/genes5030684 - 25 Aug 2014
Cited by 133 | Viewed by 11410
Abstract
Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, [...] Read more.
Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, chronic low-grade inflammation and an increased life time risk of type 2 diabetes. MicroRNAs (miRNAs) are small, non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that they might serve as potential biomarkers and a new approach for the diagnosis of PCOS. In this review, recent work on miRNAs with respect to PCOS will be summarized. Our understanding of miRNAs, particularly in relation to PCOS, is currently at a very early stage, and additional studies will yield important insight into the molecular mechanisms behind this complex and heterogenic syndrome. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Review
Computational Methods for MicroRNA Target Prediction
by Semih Ekimler and Kaniye Sahin
Genes 2014, 5(3), 671-683; https://doi.org/10.3390/genes5030671 - 22 Aug 2014
Cited by 76 | Viewed by 9672
Abstract
MicroRNAs (miRNAs) have been identified as one of the most important molecules that regulate gene expression in various organisms. miRNAs are short, 21–23 nucleotide-long, single stranded RNA molecules that bind to 3' untranslated regions (3' UTRs) of their target mRNAs. In general, they [...] Read more.
MicroRNAs (miRNAs) have been identified as one of the most important molecules that regulate gene expression in various organisms. miRNAs are short, 21–23 nucleotide-long, single stranded RNA molecules that bind to 3' untranslated regions (3' UTRs) of their target mRNAs. In general, they silence the expression of their target genes via degradation of the mRNA or by translational repression. The expression of miRNAs, on the other hand, also varies in different tissues based on their functions. It is significantly important to predict the targets of miRNAs by computational approaches to understand their effects on the regulation of gene expression. Various computational methods have been generated for miRNA target prediction but the resulting lists of candidate target genes from different algorithms often do not overlap. It is crucial to adjust the bioinformatics tools for more accurate predictions as it is equally important to validate the predicted target genes experimentally. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Review
MicroRNAs as Mediators of the Ageing Process
by Lorna W. Harries
Genes 2014, 5(3), 656-670; https://doi.org/10.3390/genes5030656 - 20 Aug 2014
Cited by 87 | Viewed by 9545
Abstract
Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about [...] Read more.
Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication. Like practically all other cellular processes, genes associated in features of ageing are regulated by miRNAs. In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Review
Epigenetic Control of the Genome—Lessons from Genomic Imprinting
by Bjorn T. Adalsteinsson and Anne C. Ferguson-Smith
Genes 2014, 5(3), 635-655; https://doi.org/10.3390/genes5030635 - 14 Aug 2014
Cited by 67 | Viewed by 10797
Abstract
Epigenetic mechanisms modulate genome function by writing, reading and erasing chromatin structural features. These have an impact on gene expression, contributing to the establishment, maintenance and dynamic changes in cellular properties in normal and abnormal situations. Great effort has recently been undertaken [...] Read more.
Epigenetic mechanisms modulate genome function by writing, reading and erasing chromatin structural features. These have an impact on gene expression, contributing to the establishment, maintenance and dynamic changes in cellular properties in normal and abnormal situations. Great effort has recently been undertaken to catalogue the genome-wide patterns of epigenetic marks—creating reference epigenomes—which will deepen our understanding of their contributions to genome regulation and function with the promise of revealing further insights into disease etiology. The foundation for these global studies is the smaller scale experimentally-derived observations and questions that have arisen through the study of epigenetic mechanisms in model systems. One such system is genomic imprinting, a process causing the mono-allelic expression of genes in a parental-origin specific manner controlled by a hierarchy of epigenetic events that have taught us much about the dynamic interplay between key regulators of epigenetic control. Here, we summarize some of the most noteworthy lessons that studies on imprinting have revealed about epigenetic control on a wider scale. Specifically, we will consider what these studies have revealed about: the variety of relationships between DNA methylation and transcriptional control; the regulation of important protein-DNA interactions by DNA methylation; the interplay between DNA methylation and histone modifications; and the regulation and functions of long non-coding RNAs. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
Discovery in Genetic Skin Disease: The Impact of High Throughput Genetic Technologies
by Thiviyani Maruthappu, Claire A. Scott and David P. Kelsell
Genes 2014, 5(3), 615-634; https://doi.org/10.3390/genes5030615 - 04 Aug 2014
Cited by 9 | Viewed by 6995
Abstract
The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, [...] Read more.
The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, such as harlequin ichthyosis, Olmsted syndrome, and exfoliative ichthyosis, which have provided unique insights into the structure and function of the skin. In addition, through genome wide association studies we now have an understanding of how low penetrance variants contribute to inflammatory skin diseases such as psoriasis vulgaris and atopic dermatitis, and how they contribute to underlying pathophysiological disease processes. In this review we discuss strategies used to unravel the genes underlying both monogenic and complex trait skin diseases in the last 10 years and the implications on mechanistic studies, diagnostics, and therapeutics. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Article
Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
by Anke R. Hammerschlag, Tinca J. C. Polderman, Christiaan De Leeuw, Henning Tiemeier, Tonya White, August B. Smit, Matthijs Verhage and Danielle Posthuma
Genes 2014, 5(3), 604-614; https://doi.org/10.3390/genes5030604 - 22 Jul 2014
Cited by 9 | Viewed by 6896
Abstract
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS) have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of [...] Read more.
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS) have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of several processes important for synaptic function. Therefore, we applied a functional gene-set analysis to formally test whether synaptic functions are associated with ADHD. Gene-set analysis tests the joint effect of multiple genetic variants in groups of functionally related genes. This method provides increased statistical power compared to conventional GWAS. We used data from the Psychiatric Genomics Consortium including 896 ADHD cases and 2455 controls, and 2064 parent-affected offspring trios, providing sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, our results do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
Genes and Genetic Testing in Hereditary Ataxias
by Erin Sandford and Margit Burmeister
Genes 2014, 5(3), 586-603; https://doi.org/10.3390/genes5030586 - 22 Jul 2014
Cited by 28 | Viewed by 6851
Abstract
Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial [...] Read more.
Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
The Challenges of Genome Analysis in the Health Care Setting
by Anneke Lucassen and Richard S. Houlston
Genes 2014, 5(3), 576-585; https://doi.org/10.3390/genes5030576 - 22 Jul 2014
Cited by 17 | Viewed by 5812
Abstract
Genome sequencing is now a sufficiently mature and affordable technology for clinical use. Its application promises not only to transform clinicians’ diagnostic and predictive ability, but also to improve preventative therapies, surveillance regimes, and tailor patient treatment to an individual’s genetic make-up. However, [...] Read more.
Genome sequencing is now a sufficiently mature and affordable technology for clinical use. Its application promises not only to transform clinicians’ diagnostic and predictive ability, but also to improve preventative therapies, surveillance regimes, and tailor patient treatment to an individual’s genetic make-up. However, as with any technological advance, there are associated fresh challenges. While some of the ethical, legal and social aspects resulting from the generation of data from genome sequencing are generic, several nuances are unique. Since the UK government recently announced plans to sequence the genomes of 100,000 Health Service patients, and similar initiatives are being considered elsewhere, a discussion of these nuances is timely and needs to go hand in hand with formulation of guidelines and public engagement activities around implementation of sequencing in clinical practice. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Article
An Efficient Estimator of the Mutation Parameter and Analysis of Polymorphism from the 1000 Genomes Project
by Yunxin Fu
Genes 2014, 5(3), 561-575; https://doi.org/10.3390/genes5030561 - 22 Jul 2014
Cited by 1 | Viewed by 4428
Abstract
The mutation parameter θ is fundamental and ubiquitous in the analysis of population samples of DNA sequences. This paper presents a new highly efficient estimator of θ by utilizing the phylogenetic information among distinct alleles in a sample of DNA sequences. The new [...] Read more.
The mutation parameter θ is fundamental and ubiquitous in the analysis of population samples of DNA sequences. This paper presents a new highly efficient estimator of θ by utilizing the phylogenetic information among distinct alleles in a sample of DNA sequences. The new estimator, called Allelic BLUE, is derived from a generalized linear model about the mutations in the allelic genealogy. This estimator is not only highly accurate, but also computational efficient, which makes it particularly useful for estimating θ for large samples, as well as for a large number of cases, such as the situation of analyzing sequence data from a large genome project, such as the 1000 Genomes Project. Simulation shows that Allelic BLUE is nearly unbiased, with variance nearly as small as the minimum achievable variance, and in many situations, it can be hundreds- or thousands-fold more efficient than a previous method, which was already quite efficient compared to other approaches. One useful feature of the new estimator is its applicability to collections of distinct alleles without detailed frequencies. The utility of the new estimator is demonstrated by analyzing the pattern of θ in the data from the 1000 Genomes Project. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
From Genotype to Functional Phenotype: Unraveling the Metabolomic Features of Colorectal Cancer
by Oliver F. Bathe and Farshad Farshidfar
Genes 2014, 5(3), 536-560; https://doi.org/10.3390/genes5030536 - 22 Jul 2014
Cited by 32 | Viewed by 9389
Abstract
Much effort in recent years has been expended in defining the genomic and epigenetic alterations that characterize colorectal adenocarcinoma and its subtypes. However, little is known about the functional ramifications related to various subtypes. Metabolomics, the study of small molecule intermediates in disease, [...] Read more.
Much effort in recent years has been expended in defining the genomic and epigenetic alterations that characterize colorectal adenocarcinoma and its subtypes. However, little is known about the functional ramifications related to various subtypes. Metabolomics, the study of small molecule intermediates in disease, provides a snapshot of the functional phenotype of colorectal cancer. Data, thus far, have characterized some of the metabolic perturbations that accompany colorectal cancer. However, further studies will be required to identify biologically meaningful metabolic subsets, including those corresponding to specific genetic aberrations. Moreover, further studies are necessary to distinguish changes due to tumor and the host response to tumor. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Review
The Impact of the Human Genome Project on Complex Disease
by Jessica N. Cooke Bailey, Margaret A. Pericak-Vance and Jonathan L. Haines
Genes 2014, 5(3), 518-535; https://doi.org/10.3390/genes5030518 - 16 Jul 2014
Cited by 14 | Viewed by 12104
Abstract
In the decade that has passed since the initial release of the Human Genome, numerous advancements in science and technology within and beyond genetics and genomics have been encouraged and enhanced by the availability of this vast and remarkable data resource. Progress in [...] Read more.
In the decade that has passed since the initial release of the Human Genome, numerous advancements in science and technology within and beyond genetics and genomics have been encouraged and enhanced by the availability of this vast and remarkable data resource. Progress in understanding three common, complex diseases: age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), are three exemplars of the incredible impact on the elucidation of the genetic architecture of disease. The approaches used in these diseases have been successfully applied to numerous other complex diseases. For example, the heritability of AMD was confirmed upon the release of the first genome-wide association study (GWAS) along with confirmatory reports that supported the findings of that state-of-the art method, thus setting the foundation for future GWAS in other heritable diseases. Following this seminal discovery and applying it to other diseases including AD and MS, the genetic knowledge of AD expanded far beyond the well-known APOE locus and now includes more than 20 loci. MS genetics saw a similar increase beyond the HLA loci and now has more than 100 known risk loci. Ongoing and future efforts will seek to define the remaining heritability of these diseases; the next decade could very well hold the key to attaining this goal. Full article
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Article
Genetic versus Non-Genetic Regulation of miR-103, miR-143 and miR-483-3p Expression in Adipose Tissue and Their Metabolic Implications—A Twin Study
by Jette Bork-Jensen, Anne Cathrine Baun Thuesen, Claus Heiner Bang-Bertelsen, Louise Groth Grunnet, Flemming Pociot, Henning Beck-Nielsen, Susan E. Ozanne, Pernille Poulsen and Allan Vaag
Genes 2014, 5(3), 508-517; https://doi.org/10.3390/genes5030508 - 09 Jul 2014
Cited by 22 | Viewed by 7280
Abstract
Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT) and development of type 2 diabetes (T2D). The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance [...] Read more.
Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT) and development of type 2 diabetes (T2D). The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance and T2D. We aimed to explore the genetic and non-genetic factors that regulate these microRNAs in human SAT, and to investigate their impact on metabolism in humans. Levels of miR-103, miR-143 and miR-483-3p were measured in SAT biopsies from 244 elderly monozygotic and dizygotic twins using real-time PCR. Heritability estimates were calculated and multiple regression analyses were performed to study associations between these microRNAs and measures of metabolism, as well as between these microRNAs and possible regulating factors. We found that increased BMI was associated with increased miR-103 expression levels. In addition, the miR-103 levels were positively associated with 2 h plasma glucose levels and hemoglobin A1c independently of BMI. Heritability estimates for all three microRNAs were low. In conclusion, the expression levels of miR-103, miR-143 and miR-483-3p in adipose tissue are primarily influenced by non-genetic factors, and miR-103 may be involved in the development of adiposity and control of glucose metabolism in humans. Full article
(This article belongs to the Special Issue miRNA Regulation)
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Lynch Syndrome: An Updated Review
by Rishabh Sehgal, Kieran Sheahan, Patrick R. O'Connell, Ann M. Hanly, Sean T. Martin and Desmond C. Winter
Genes 2014, 5(3), 497-507; https://doi.org/10.3390/genes5030497 - 27 Jun 2014
Cited by 96 | Viewed by 13761
Abstract
Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the [...] Read more.
Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics. Full article
(This article belongs to the Special Issue Microsatellite Instability)
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