Special Issue "Grand Celebration: 10th Anniversary of the Human Genome Project"

Quicklinks

A special issue of Genes (ISSN 2073-4425).

Deadline for manuscript submissions: closed (30 November 2013)

Special Issue Editors

Guest Editor
Prof. Sir John Burn (Website)

1. Institute of Genetic Medicine, International Centre for Life, University of Newcastle, Newcastle NE1 3BZ, UK
2. Genetics Chair, National Institute of Health Research, Chief Medical Officer, QuantuMDx ltd, UK
Interests: clinical and cancer genetics; cancer chemoprevention; nanowire DNA diagnostics
Guest Editor
Prof. Dr. James R. Lupski (Website)

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, MS BCM225, Houston, TX, 77030, USA
Fax: +1 713 798 5073
Interests: genomic disorders; genome rearrrangements; neurogenetics; genomics; human genetics; personal genome sequencing; medical genetics
Guest Editor
Prof. Dr. Karen E. Nelson (Website)

President, J. Craig Venter Institute (JCVI), 9704 Medical Center Drive, Rockville, MD 20850, USA
Fax: +1 301 838 0208
Interests: microbiology; genomics; metagenomics; proteomics; trancriptomics; microbial physiology
Guest Editor
Prof. Pabulo H. Rampelotto

Center of Biotechnology and PPGBCM, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
Interests: biotechnology; next generation sequencing; metagenomics; molecular biology and biochemistry of microorganisms; extremophiles; grand challenges

Special Issue Information

Dear Colleagues,

In 1990, scientists began working together on one of the largest biological research projects ever proposed. The project proposed to sequence the 3 billion nucleotides in the human genome. The Human Genome Project took 13 years and was completed on April 2003 at a cost of approximately three billion dollars. It was a major scientific achievement that forever changed the understanding of our own nature. The sequencing of the human genome was in many ways a triumph for technology as much as it was for science. From the Human Genome Project powerful technologies have been developed (e.g. microarrays and next generation sequencing) and new branches of science have emerged (e.g. functional genomics and pharmacogenomics), paving new ways for advancing genomic research and medical applications of genomics in the 21th Century. The investigations have provided new tests and drug targets as well as insights into the basis of human development and diagnosis/treatment of cancer and several mysterious humans diseases. This genomic revolution is prompting a new era in medicine, which brings both challenges and opportunities. Parallel to the promising advances over the last decade, the study of the human genome has also revealed how complicated human biology is, and how much remains to be understood. The legacy of the understanding of our genome has just begun. To celebrate the 10th anniversary of the essential completion of the Human Genome Project, Genes launched in April 2013 this special issue which will highlight the recent scientific breakthroughs on human genomics with a collection of papers written by authors who are leading experts in the field.

Prof. Dr. Karen E. Nelson
Prof. Sir John Burn
Prof. Dr. James R. Lupski
Mr. Pabulo Henrique Rampelotto
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).


Print Edition available!
A Print Edition of this Special Issue is available here.

Name Pice* Download or order
Grand Celebration: 10th Anniversary of the Human Genome Project 43.50 CHF here
For contributing authors or bulk orders special prices may apply.
Prices include shipping.

Keywords

  • gene structure, expression and regulation
  • molecular basis of human genetic disease
  • genetics and genomics of model organisms for human diseases
  • human genetics
  • cancer genetics
  • functional genomics
  • stem cells in human genetics
  • pharmacogenomics and gene therapy
  • genetic and genomic technologies
  • genomic medicine
  • gene therapy and personal genomics

Published Papers (41 papers)

View options order results:
result details:
Displaying articles 1-41
Export citation of selected articles as:

Research

Jump to: Review, Other

Open AccessArticle Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease
Genes 2015, 6(1), 24-45; doi:10.3390/genes6010024
Received: 20 August 2014 / Accepted: 12 January 2015 / Published: 6 February 2015
Cited by 1 | PDF Full-text (10924 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on [...] Read more.
The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on many genes. Genetic interaction, defined as contributions to a phenotype that are dependent upon particular digenic allele combinations, could improve prediction of phenotype from complex genotype, but it is difficult to study in human populations. High throughput, systematic analysis of S. cerevisiae gene knockouts or knockdowns in the context of disease-relevant phenotypic perturbations provides a tractable experimental approach to derive gene interaction networks, in order to deduce by cross-species gene homology how phenotype is buffered against disease-risk genotypes. Yeast gene interaction network analysis to date has revealed biology more complex than previously imagined. This has motivated the development of more powerful yeast cell array phenotyping methods to globally model the role of gene interaction networks in modulating phenotypes (which we call yeast phenomic analysis). The article illustrates yeast phenomic technology, which is applied here to quantify gene X media interaction at higher resolution and supports use of a human-like media for future applications of yeast phenomics for modeling human disease. Full article
Figures

Open AccessArticle A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care
Genes 2014, 5(3), 748-766; doi:10.3390/genes5030748
Received: 20 May 2014 / Revised: 20 July 2014 / Accepted: 18 August 2014 / Published: 1 September 2014
Cited by 2 | PDF Full-text (109 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessArticle Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders
Genes 2014, 5(3), 709-725; doi:10.3390/genes5030709
Received: 13 May 2014 / Revised: 23 July 2014 / Accepted: 14 August 2014 / Published: 25 August 2014
Cited by 4 | PDF Full-text (543 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Figures

Open AccessArticle An Efficient Estimator of the Mutation Parameter and Analysis of Polymorphism from the 1000 Genomes Project
Genes 2014, 5(3), 561-575; doi:10.3390/genes5030561
Received: 27 March 2014 / Revised: 20 June 2014 / Accepted: 24 June 2014 / Published: 22 July 2014
PDF Full-text (8945 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessArticle Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
Genes 2014, 5(3), 604-614; doi:10.3390/genes5030604
Received: 9 April 2014 / Revised: 4 July 2014 / Accepted: 10 July 2014 / Published: 22 July 2014
Cited by 4 | PDF Full-text (164 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessArticle Imprinted Genes and the Environment: Links to the Toxic Metals Arsenic, Cadmium and Lead
Genes 2014, 5(2), 477-496; doi:10.3390/genes5020477
Received: 8 April 2014 / Revised: 24 May 2014 / Accepted: 27 May 2014 / Published: 11 June 2014
Cited by 5 | PDF Full-text (364 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Imprinted genes defy rules of Mendelian genetics with their expression tied to the parent from whom each allele was inherited. They are known to play a role in various diseases/disorders including fetal growth disruption, lower birth weight, obesity, and cancer. There is [...] Read more.
Imprinted genes defy rules of Mendelian genetics with their expression tied to the parent from whom each allele was inherited. They are known to play a role in various diseases/disorders including fetal growth disruption, lower birth weight, obesity, and cancer. There is increasing interest in understanding their influence on environmentally-induced disease. The environment can be thought of broadly as including chemicals present in air, water and soil, as well as food. According to the Agency for Toxic Substances and Disease Registry (ATSDR), some of the highest ranking environmental chemicals of concern include metals/metalloids such as arsenic, cadmium, lead and mercury. The complex relationships between toxic metal exposure, imprinted gene regulation/expression and health outcomes are understudied. Herein we examine trends in imprinted gene biology, including an assessment of the imprinted genes and their known functional roles in the cell, particularly as they relate to toxic metals exposure and disease. The data highlight that many of the imprinted genes have known associations to developmental diseases and are enriched for their role in the TP53 and AhR pathways. Assessment of the promoter regions of the imprinted genes resulted in the identification of an enrichment of binding sites for two transcription factor families, namely the zinc finger family II and PLAG transcription factors. Taken together these data contribute insight into the complex relationships between toxic metals in the environment and imprinted gene biology. Full article
Figures

Open AccessArticle GWAS to Sequencing: Divergence in Study Design and Analysis
Genes 2014, 5(2), 460-476; doi:10.3390/genes5020460
Received: 27 December 2013 / Revised: 13 May 2014 / Accepted: 15 May 2014 / Published: 28 May 2014
Cited by 4 | PDF Full-text (766 KB) | HTML Full-text | XML Full-text
Abstract
The success of genome-wide association studies (GWAS) in uncovering genetic risk factors for complex traits has generated great promise for the complete data generated by sequencing. The bumpy transition from GWAS to whole-exome or whole-genome association studies (WGAS) based on sequencing investigations [...] Read more.
The success of genome-wide association studies (GWAS) in uncovering genetic risk factors for complex traits has generated great promise for the complete data generated by sequencing. The bumpy transition from GWAS to whole-exome or whole-genome association studies (WGAS) based on sequencing investigations has highlighted important differences in analysis and interpretation. We show how the loss in power due to the allele frequency spectrum targeted by sequencing is difficult to compensate for with realistic effect sizes and point to study designs that may help. We discuss several issues in interpreting the results, including a special case of the winner’s curse. Extrapolation and prediction using rare SNPs is complex, because of the selective ascertainment of SNPs in case-control studies and the low amount of information at each SNP, and naive procedures are biased under the alternative. We also discuss the challenges in tuning gene-based tests and accounting for multiple testing when genes have very different sets of SNPs. The examples we emphasize in this paper highlight the difficult road we must travel for a two-letter switch. Full article
Open AccessArticle Genome-Wide Analysis of Alpharetroviral Integration in Human Hematopoietic Stem/Progenitor Cells
Genes 2014, 5(2), 415-429; doi:10.3390/genes5020415
Received: 3 March 2014 / Revised: 30 April 2014 / Accepted: 6 May 2014 / Published: 16 May 2014
Cited by 4 | PDF Full-text (750 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gene transfer vectors derived from gamma-retroviruses or lentiviruses are currently used for the gene therapy of genetic or acquired diseases. Retroviral vectors display a non-random integration pattern in the human genome, targeting either regulatory regions (gamma-retroviruses) or the transcribed portion of expressed [...] Read more.
Gene transfer vectors derived from gamma-retroviruses or lentiviruses are currently used for the gene therapy of genetic or acquired diseases. Retroviral vectors display a non-random integration pattern in the human genome, targeting either regulatory regions (gamma-retroviruses) or the transcribed portion of expressed genes (lentiviruses), and have the potential to deregulate gene expression at the transcriptional or post-transcriptional level. A recently developed alternative vector system derives from the avian sarcoma-leukosis alpha-retrovirus (ASLV) and shows favorable safety features compared to both gamma-retroviral and lentiviral vectors in preclinical models. We performed a high-throughput analysis of the integration pattern of self-inactivating (SIN) alpha-retroviral vectors in human CD34+ hematopoietic stem/progenitor cells (HSPCs) and compared it to previously reported gamma-retroviral and lentiviral vectors integration profiles obtained in the same experimental setting. Compared to gamma-retroviral and lentiviral vectors, the SIN-ASLV vector maintains a preference for open chromatin regions, but shows no bias for transcriptional regulatory elements or transcription units, as defined by genomic annotations and epigenetic markers (H3K4me1 and H3K4me3 histone modifications). Importantly, SIN-ASLV integrations do not cluster in hot spots and target potentially dangerous genomic loci, such as the EVI2A/B, RUNX1 and LMO2 proto-oncogenes at a virtually random frequency. These characteristics predict a safer profile for ASLV-derived vectors for clinical applications. Full article
Open AccessArticle Characterization of the Genomic Architecture and Mutational Spectrum of a Small Cell Prostate Carcinoma
Genes 2014, 5(2), 366-384; doi:10.3390/genes5020366
Received: 17 February 2014 / Revised: 1 April 2014 / Accepted: 15 April 2014 / Published: 12 May 2014
Cited by 2 | PDF Full-text (786 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We present the use of a series of laboratory, analytical and interpretation methods to investigate personalized cancer care for a case of small cell prostate carcinoma (SCPC), a rare and aggressive tumor with poor prognosis, for which the underlying genomic architecture and [...] Read more.
We present the use of a series of laboratory, analytical and interpretation methods to investigate personalized cancer care for a case of small cell prostate carcinoma (SCPC), a rare and aggressive tumor with poor prognosis, for which the underlying genomic architecture and mutational spectrum has not been well characterized. We performed both SNP genotyping and exome sequencing of a Virchow node metastasis from a patient with SCPC. A variety of methods were used to analyze and interpret the tumor genome for copy number variation, loss of heterozygosity (LOH), somatic mosaicism and mutations in genes from known cancer pathways. The combination of genotyping and exome sequencing approaches provided more information than either technique alone. The results showed widespread evidence of copy number changes involving most chromosomes including the possible loss of both alleles of CDKN1B (p27/Kip1). LOH was observed for the regions encompassing the tumor suppressors TP53, RB1, and CHD1. Predicted damaging somatic mutations were observed in the retained TP53 and RB1 alleles. Mutations in other genes that may be functionally relevant were noted, especially the recently reported high confidence cancer drivers FOXA1 and CCAR1. The disruption of multiple cancer drivers underscores why SCPC may be such a difficult cancer to manage. Full article
Figures

Open AccessArticle Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells
Genes 2014, 5(2), 347-365; doi:10.3390/genes5020347
Received: 7 February 2014 / Revised: 31 March 2014 / Accepted: 16 April 2014 / Published: 5 May 2014
Cited by 14 | PDF Full-text (307 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to [...] Read more.
DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment). We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8–19) using the Illumina 450k array and examined twin correlations for methylation level at 420,921 CpGs after QC. After selecting CpGs showing the most variation in the methylation level between subjects, the mean genome-wide correlation (rho) was 0.54. The correlation was higher, on average, for CpGs within CpG islands (CGIs), compared to CGI shores, shelves and non-CGI regions, particularly at hypomethylated CpGs. This finding suggests that individual-specific environmental and stochastic influences account for more variation in DNA methylation in CpG-poor regions. Our findings also indicate that it is worthwhile to examine heritable and shared environmental influences on buccal DNA methylation in larger studies that also include dizygotic twins. Full article
Figures

Open AccessArticle Polygenic Scores Predict Alcohol Problems in an Independent Sample and Show Moderation by the Environment
Genes 2014, 5(2), 330-346; doi:10.3390/genes5020330
Received: 31 December 2013 / Revised: 20 March 2014 / Accepted: 27 March 2014 / Published: 10 April 2014
Cited by 14 | PDF Full-text (166 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants [...] Read more.
Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems—derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)—predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07–0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes. Full article

Review

Jump to: Research, Other

Open AccessReview Somatic Mosaicism in the Human Genome
Genes 2014, 5(4), 1064-1094; doi:10.3390/genes5041064
Received: 20 October 2014 / Revised: 26 November 2014 / Accepted: 28 November 2014 / Published: 11 December 2014
Cited by 6 | PDF Full-text (7601 KB) | HTML Full-text | XML Full-text
Abstract
Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to [...] Read more.
Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny. These mutations affect varying genomic sizes ranging from single nucleotides to entire chromosomes and have been implicated in disease, most prominently cancer. The phenotypic consequences of somatic mosaicism are dependent upon many factors including the developmental time at which the mutation occurs, the areas of the body that are affected, and the pathophysiological effect(s) of the mutation. The advent of second-generation sequencing technologies has augmented existing array-based and cytogenetic approaches for the identification of somatic mutations. We outline the strengths and weaknesses of these techniques and highlight recent insights into the role of somatic mosaicism in causing cancer, neurodegenerative, monogenic, and complex disease. Full article
Open AccessReview Delivery of a Clinical Genomics Service
Genes 2014, 5(4), 1001-1017; doi:10.3390/genes5041001
Received: 7 September 2014 / Revised: 28 October 2014 / Accepted: 30 October 2014 / Published: 6 November 2014
Cited by 7 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
Over the past five years, next generation sequencing has revolutionised the discovery of genes responsible for rare inherited diseases previously resistant to traditional discovery techniques. This review considers how this new technology is being introduced into clinical practice to aid diagnosis and [...] Read more.
Over the past five years, next generation sequencing has revolutionised the discovery of genes responsible for rare inherited diseases previously resistant to traditional discovery techniques. This review considers how this new technology is being introduced into clinical practice to aid diagnosis and improve the clinical management of individuals and families affected by rare diseases where access to genetic testing was previously limited. We compare and contrast the different approaches that have been adopted including panel based tests, exome and genome sequencing. We provide insights from our own clinical practice demonstrating the challenges and benefits of this new technology. Full article
Open AccessReview Mouse ENU Mutagenesis to Understand Immunity to Infection: Methods, Selected Examples, and Perspectives
Genes 2014, 5(4), 887-925; doi:10.3390/genes5040887
Received: 27 June 2014 / Revised: 19 August 2014 / Accepted: 21 August 2014 / Published: 29 September 2014
Cited by 2 | PDF Full-text (3470 KB) | HTML Full-text | XML Full-text
Abstract
Infectious diseases are responsible for over 25% of deaths globally, but many more individuals are exposed to deadly pathogens. The outcome of infection results from a set of diverse factors including pathogen virulence factors, the environment, and the genetic make-up of the [...] Read more.
Infectious diseases are responsible for over 25% of deaths globally, but many more individuals are exposed to deadly pathogens. The outcome of infection results from a set of diverse factors including pathogen virulence factors, the environment, and the genetic make-up of the host. The completion of the human reference genome sequence in 2004 along with technological advances have tremendously accelerated and renovated the tools to study the genetic etiology of infectious diseases in humans and its best characterized mammalian model, the mouse. Advancements in mouse genomic resources have accelerated genome-wide functional approaches, such as gene-driven and phenotype-driven mutagenesis, bringing to the fore the use of mouse models that reproduce accurately many aspects of the pathogenesis of human infectious diseases. Treatment with the mutagen N-ethyl-N-nitrosourea (ENU) has become the most popular phenotype-driven approach. Our team and others have employed mouse ENU mutagenesis to identify host genes that directly impact susceptibility to pathogens of global significance. In this review, we first describe the strategies and tools used in mouse genetics to understand immunity to infection with special emphasis on chemical mutagenesis of the mouse germ-line together with current strategies to efficiently identify functional mutations using next generation sequencing. Then, we highlight illustrative examples of genes, proteins, and cellular signatures that have been revealed by ENU screens and have been shown to be involved in susceptibility or resistance to infectious diseases caused by parasites, bacteria, and viruses. Full article
Open AccessReview DNA Methylation Biomarkers: Cancer and Beyond
Genes 2014, 5(3), 821-864; doi:10.3390/genes5030821
Received: 22 June 2014 / Revised: 17 August 2014 / Accepted: 1 September 2014 / Published: 16 September 2014
Cited by 32 | PDF Full-text (856 KB) | HTML Full-text | XML Full-text
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 [...] 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
Figures

Open AccessReview The Revolution in Human Monogenic Disease Mapping
Genes 2014, 5(3), 792-803; doi:10.3390/genes5030792
Received: 8 August 2014 / Revised: 29 August 2014 / Accepted: 1 September 2014 / Published: 5 September 2014
Cited by 4 | PDF Full-text (83 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessReview Epigenetic Control of the Genome—Lessons from Genomic Imprinting
Genes 2014, 5(3), 635-655; doi:10.3390/genes5030635
Received: 24 January 2014 / Revised: 6 August 2014 / Accepted: 7 August 2014 / Published: 14 August 2014
Cited by 12 | PDF Full-text (615 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessReview Discovery in Genetic Skin Disease: The Impact of High Throughput Genetic Technologies
Genes 2014, 5(3), 615-634; doi:10.3390/genes5030615
Received: 4 April 2014 / Revised: 7 July 2014 / Accepted: 14 July 2014 / Published: 4 August 2014
Cited by 3 | PDF Full-text (657 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessReview From Genotype to Functional Phenotype: Unraveling the Metabolomic Features of Colorectal Cancer
Genes 2014, 5(3), 536-560; doi:10.3390/genes5030536
Received: 18 March 2014 / Revised: 27 May 2014 / Accepted: 27 June 2014 / Published: 22 July 2014
Cited by 3 | PDF Full-text (973 KB) | HTML Full-text | XML Full-text
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 [...] 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
Figures

Open AccessReview The Challenges of Genome Analysis in the Health Care Setting
Genes 2014, 5(3), 576-585; doi:10.3390/genes5030576
Received: 27 May 2014 / Revised: 4 July 2014 / Accepted: 7 July 2014 / Published: 22 July 2014
Cited by 5 | PDF Full-text (75 KB) | HTML Full-text | XML Full-text
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. [...] 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
Open AccessReview Genes and Genetic Testing in Hereditary Ataxias
Genes 2014, 5(3), 586-603; doi:10.3390/genes5030586
Received: 28 April 2014 / Revised: 25 June 2014 / Accepted: 1 July 2014 / Published: 22 July 2014
Cited by 3 | PDF Full-text (107 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Open AccessReview The Impact of the Human Genome Project on Complex Disease
Genes 2014, 5(3), 518-535; doi:10.3390/genes5030518
Received: 4 March 2014 / Revised: 3 June 2014 / Accepted: 24 June 2014 / Published: 16 July 2014
Cited by 3 | PDF Full-text (126 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessReview Changing Histopathological Diagnostics by Genome-Based Tumor Classification
Genes 2014, 5(2), 444-459; doi:10.3390/genes5020444
Received: 7 January 2014 / Revised: 5 May 2014 / Accepted: 8 May 2014 / Published: 28 May 2014
Cited by 5 | PDF Full-text (820 KB) | HTML Full-text | XML Full-text
Abstract
Traditionally, tumors are classified by histopathological criteria, i.e., based on their specific morphological appearances. Consequently, current therapeutic decisions in oncology are strongly influenced by histology rather than underlying molecular or genomic aberrations. The increase of information on molecular changes however, enabled [...] Read more.
Traditionally, tumors are classified by histopathological criteria, i.e., based on their specific morphological appearances. Consequently, current therapeutic decisions in oncology are strongly influenced by histology rather than underlying molecular or genomic aberrations. The increase of information on molecular changes however, enabled by the Human Genome Project and the International Cancer Genome Consortium as well as the manifold advances in molecular biology and high-throughput sequencing techniques, inaugurated the integration of genomic information into disease classification. Furthermore, in some cases it became evident that former classifications needed major revision and adaption. Such adaptations are often required by understanding the pathogenesis of a disease from a specific molecular alteration, using this molecular driver for targeted and highly effective therapies. Altogether, reclassifications should lead to higher information content of the underlying diagnoses, reflecting their molecular pathogenesis and resulting in optimized and individual therapeutic decisions. The objective of this article is to summarize some particularly important examples of genome-based classification approaches and associated therapeutic concepts. In addition to reviewing disease specific markers, we focus on potentially therapeutic or predictive markers and the relevance of molecular diagnostics in disease monitoring. Full article
Open AccessReview Pharmacogenomics: Current State-of-the-Art
Genes 2014, 5(2), 430-443; doi:10.3390/genes5020430
Received: 23 April 2014 / Revised: 5 May 2014 / Accepted: 8 May 2014 / Published: 26 May 2014
Cited by 17 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
The completion of the human genome project 10 years ago was met with great optimism for improving drug therapy through personalized medicine approaches, with the anticipation that an era of genotype-guided patient prescribing was imminent. To some extent this has come to [...] Read more.
The completion of the human genome project 10 years ago was met with great optimism for improving drug therapy through personalized medicine approaches, with the anticipation that an era of genotype-guided patient prescribing was imminent. To some extent this has come to pass and a number of key pharmacogenomics markers of inter-individual drug response, for both safety and efficacy, have been identified and subsequently been adopted in clinical practice as pre-treatment genetic tests. However, the universal application of genetics in treatment guidance is still a long way off. This review will highlight important pharmacogenomic discoveries which have been facilitated by the human genome project and other milestone projects such as the International HapMap and 1000 genomes, and by the continued development of genotyping and sequencing technologies, including rapid point of care pre-treatment genetic testing. However, there are still many challenges to implementation for the many other reported biomarkers which continue to languish within the discovery phase. As technology advances over the next 10 years, and the costs fall, the field will see larger genetic data sets, including affordable whole genome sequences, which will, it is hoped, improve patient outcomes through better diagnostic, prognostic and predictive biomarkers. Full article
Open AccessReview The Little Fly that Could: Wizardry and Artistry of Drosophila Genomics
Genes 2014, 5(2), 385-414; doi:10.3390/genes5020385
Received: 3 March 2014 / Revised: 16 April 2014 / Accepted: 21 April 2014 / Published: 13 May 2014
Cited by 5 | PDF Full-text (1588 KB) | HTML Full-text | XML Full-text
Abstract
For more than 100 years now, the fruit fly Drosophila melanogaster has been at the forefront of our endeavors to unlock the secrets of the genome. From the pioneering studies of chromosomes and heredity by Morgan and his colleagues, to the generation [...] Read more.
For more than 100 years now, the fruit fly Drosophila melanogaster has been at the forefront of our endeavors to unlock the secrets of the genome. From the pioneering studies of chromosomes and heredity by Morgan and his colleagues, to the generation of fly models for human disease, Drosophila research has been at the forefront of genetics and genomics. We present a broad overview of some of the most powerful genomics tools that keep Drosophila research at the cutting edge of modern biomedical research. Full article
Open AccessReview The Epigenome View: An Effort towards Non-Invasive Prenatal Diagnosis
Genes 2014, 5(2), 310-329; doi:10.3390/genes5020310
Received: 17 December 2013 / Revised: 5 March 2014 / Accepted: 27 March 2014 / Published: 9 April 2014
PDF Full-text (376 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic modifications have proven to play a significant role in cancer development, as well as fetal development. Taking advantage of the knowledge acquired during the last decade, great interest has been shown worldwide in deciphering the fetal epigenome towards the development of [...] Read more.
Epigenetic modifications have proven to play a significant role in cancer development, as well as fetal development. Taking advantage of the knowledge acquired during the last decade, great interest has been shown worldwide in deciphering the fetal epigenome towards the development of methylation-based non-invasive prenatal tests (NIPT). In this review, we highlight the different approaches implemented, such as sodium bisulfite conversion, restriction enzyme digestion and methylated DNA immunoprecipitation, for the identification of differentially methylated regions (DMRs) between free fetal DNA found in maternal blood and DNA from maternal blood cells. Furthermore, we evaluate the use of selected DMRs identified towards the development of NIPT for fetal chromosomal aneuploidies. In addition, we perform a comparison analysis, evaluate the performance of each assay and provide a comprehensive discussion on the potential use of different methylation-based technologies in retrieving the fetal methylome, with the aim of further expanding the development of NIPT assays. Full article
Open AccessReview Reading and Language Disorders: The Importance of Both Quantity and Quality
Genes 2014, 5(2), 285-309; doi:10.3390/genes5020285
Received: 2 December 2013 / Revised: 11 March 2014 / Accepted: 12 March 2014 / Published: 4 April 2014
Cited by 8 | PDF Full-text (198 KB) | HTML Full-text | XML Full-text
Abstract
Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing [...] Read more.
Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, only a few genes have been implicated in these traits. Their functional characterization has provided novel insight into the biology of neurodevelopmental disorders. However, the lack of biological markers and clear diagnostic criteria have prevented the collection of the large sample sizes required for well-powered genome-wide screens. One of the main challenges of the field will be to combine careful clinical assessment with high throughput genetic technologies within multidisciplinary collaborations. Full article
Open AccessReview Architecture of Inherited Susceptibility to Colorectal Cancer: A Voyage of Discovery
Genes 2014, 5(2), 270-284; doi:10.3390/genes5020270
Received: 25 December 2013 / Revised: 7 March 2014 / Accepted: 10 March 2014 / Published: 27 March 2014
Cited by 2 | PDF Full-text (157 KB) | HTML Full-text | XML Full-text
Abstract
This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided [...] Read more.
This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided by the existence of multiple dominant predisposition syndromes. Genetic linkage and positional cloning studies identified the first high-penetrance genes for CRC in the 1980s and 1990s. More recent genome-wide association studies have identified common low-penetrance susceptibility loci and provide support for a polygenic model of disease susceptibility. These observations suggest a high proportion of CRC may arise in a group of susceptible individuals as a consequence of the combined effects of common low-penetrance risk alleles and rare variants conferring moderate CRC risks. Despite these advances, however, currently identified loci explain only a small fraction of the estimated heritability to CRC. It is hoped that a new generation of sequencing projects will help explain this missing heritability. Full article
Open AccessReview Illuminating the Transcriptome through the Genome
Genes 2014, 5(1), 235-253; doi:10.3390/genes5010235
Received: 17 January 2014 / Revised: 3 March 2014 / Accepted: 5 March 2014 / Published: 14 March 2014
Cited by 2 | PDF Full-text (1266 KB) | HTML Full-text | XML Full-text
Abstract
Sequencing the human genome was a huge milestone in genetic research that revealed almost the total DNA sequence required to create a human being. However, in order to function, the DNA genome needs to be expressed as an RNA transcriptome. This article [...] Read more.
Sequencing the human genome was a huge milestone in genetic research that revealed almost the total DNA sequence required to create a human being. However, in order to function, the DNA genome needs to be expressed as an RNA transcriptome. This article reviews how knowledge of genome sequence information has led to fundamental discoveries in how the transcriptome is processed, with a focus on new system-wide insights into how pre-mRNAs that are encoded by split genes in the genome are rearranged by splicing into functional mRNAs. These advances have been made possible by the development of new post-genome technologies to probe splicing patterns. Transcriptome-wide approaches have characterised a “splicing code” that is embedded within and has a significant role in deciphering the genome, and is deciphered by RNA binding proteins. These analyses have also found that most human genes encode multiple mRNA isoforms, and in some cases proteins, leading in turn to a re-assessment of what exactly a gene is. Analysis of the transcriptome has given insights into how the genome is packaged and transcribed, and is helping to explain important aspects of genome evolution. Full article
Open AccessReview Genetic Profiling for Risk Reduction in Human Cardiovascular Disease
Genes 2014, 5(1), 214-234; doi:10.3390/genes5010214
Received: 16 January 2014 / Revised: 26 February 2014 / Accepted: 27 February 2014 / Published: 12 March 2014
Cited by 5 | PDF Full-text (712 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular disease is a major health concern affecting over 80,000,000 people in the U.S. alone. Heart failure, cardiomyopathy, heart rhythm disorders, atherosclerosis and aneurysm formation have significant heritable contribution. Supported by familial aggregation and twin studies, these cardiovascular diseases are influenced by [...] Read more.
Cardiovascular disease is a major health concern affecting over 80,000,000 people in the U.S. alone. Heart failure, cardiomyopathy, heart rhythm disorders, atherosclerosis and aneurysm formation have significant heritable contribution. Supported by familial aggregation and twin studies, these cardiovascular diseases are influenced by genetic variation. Family-based linkage studies and population-based genome-wide association studies (GWAS) have each identified genes and variants important for the pathogenesis of cardiovascular disease. The advent of next generation sequencing has ushered in a new era in the genetic diagnosis of cardiovascular disease, and this is especially evident when considering cardiomyopathy, a leading cause of heart failure. Cardiomyopathy is a genetically heterogeneous disorder characterized by morphologically abnormal heart with abnormal function. Genetic testing for cardiomyopathy employs gene panels, and these panels assess more than 50 genes simultaneously. Despite the large size of these panels, the sensitivity for detecting the primary genetic defect is still only approximately 50%. Recently, there has been a shift towards applying broader exome and/or genome sequencing to interrogate more of the genome to provide a genetic diagnosis for cardiomyopathy. Genetic mutations in cardiomyopathy offer the capacity to predict clinical outcome, including arrhythmia risk, and genetic diagnosis often provides an early window in which to institute therapy. This discussion is an overview as to how genomic data is shaping the current understanding and treatment of cardiovascular disease. Full article
Open AccessReview The Molecular Basis of Retinal Dystrophies in Pakistan
Genes 2014, 5(1), 176-195; doi:10.3390/genes5010176
Received: 21 January 2014 / Revised: 14 February 2014 / Accepted: 14 February 2014 / Published: 11 March 2014
PDF Full-text (606 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The customary consanguineous nuptials in Pakistan underlie the frequent occurrence of autosomal recessive inherited disorders, including retinal dystrophy (RD). In many studies, homozygosity mapping has been shown to be successful in mapping susceptibility loci for autosomal recessive inherited disease. RDs are the [...] Read more.
The customary consanguineous nuptials in Pakistan underlie the frequent occurrence of autosomal recessive inherited disorders, including retinal dystrophy (RD). In many studies, homozygosity mapping has been shown to be successful in mapping susceptibility loci for autosomal recessive inherited disease. RDs are the most frequent cause of inherited blindness worldwide. To date there is no comprehensive genetic overview of different RDs in Pakistan. In this review, genetic data of syndromic and non-syndromic RD families from Pakistan has been collected. Out of the 132 genes known to be involved in non-syndromic RD, 35 different genes have been reported to be mutated in families of Pakistani origin. In the Pakistani RD families 90% of the mutations causing non-syndromic RD and all mutations causing syndromic forms of the disease have not been reported in other populations. Based on the current inventory of all Pakistani RD-associated gene defects, a cost-efficient allele-specific analysis of 11 RD-associated variants is proposed, which may capture up to 35% of the genetic causes of retinal dystrophy in Pakistan. Full article
Open AccessReview Association Claims in the Sequencing Era
Genes 2014, 5(1), 196-213; doi:10.3390/genes5010196
Received: 26 December 2013 / Revised: 24 February 2014 / Accepted: 24 February 2014 / Published: 11 March 2014
Cited by 3 | PDF Full-text (356 KB) | HTML Full-text | XML Full-text
Abstract
Since the completion of the Human Genome Project, the field of human genetics has been in great flux, largely due to technological advances in studying DNA sequence variation. Although community-wide adoption of statistical standards was key to the success of genome-wide association [...] Read more.
Since the completion of the Human Genome Project, the field of human genetics has been in great flux, largely due to technological advances in studying DNA sequence variation. Although community-wide adoption of statistical standards was key to the success of genome-wide association studies, similar standards have not yet been globally applied to the processing and interpretation of sequencing data. It has proven particularly challenging to pinpoint unequivocally disease variants in sequencing studies of polygenic traits. Here, we comment on a number of factors that may contribute to irreproducible claims of association in scientific literature and discuss possible steps that we can take towards cultural change. Full article
Figures

Open AccessReview Mechanisms of Base Substitution Mutagenesis in Cancer Genomes
Genes 2014, 5(1), 108-146; doi:10.3390/genes5010108
Received: 9 December 2013 / Revised: 7 February 2014 / Accepted: 11 February 2014 / Published: 5 March 2014
Cited by 13 | PDF Full-text (559 KB) | HTML Full-text | XML Full-text
Abstract
Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of [...] Read more.
Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs). Cytosine methylation, demethylation and deamination, charge transfer reactions in DNA, DNA replication timing, chromatin status and altered DNA proofreading activities are all now known to contribute to the mechanisms leading to base substitution mutagenesis. We review current hypotheses as to the major processes that give rise to SBSs and evaluate their relative relevance in the light of knowledge acquired from cancer genome sequencing projects and the study of base modifications, DNA repair and lesion bypass. Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide. For SBSs at both CG:CG and YC:GR sites, we outline evidence for a prominent role of damage by charge transfer reactions that follow interactions of the DNA with reactive oxygen species (ROS) and other endogenous or exogenous electron-abstracting molecules. Full article
Open AccessReview Phenotype-Based Genetic Association Studies (PGAS)—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes
Genes 2014, 5(1), 97-105; doi:10.3390/genes5010097
Received: 22 January 2014 / Revised: 17 February 2014 / Accepted: 18 February 2014 / Published: 27 February 2014
Cited by 7 | PDF Full-text (353 KB) | HTML Full-text | XML Full-text
Abstract
Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS), were [...] Read more.
Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics. Full article
Figures

Open AccessReview The Genomic Signature of Breast Cancer Prevention
Genes 2014, 5(1), 65-83; doi:10.3390/genes5010065
Received: 18 December 2013 / Revised: 31 January 2014 / Accepted: 8 February 2014 / Published: 26 February 2014
Cited by 2 | PDF Full-text (1914 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The breast of parous postmenopausal women exhibits a specific signature that has been induced by a full term pregnancy. This signature is centered in chromatin remodeling and the epigenetic changes induced by methylation of specific genes which are important regulatory pathways induced [...] Read more.
The breast of parous postmenopausal women exhibits a specific signature that has been induced by a full term pregnancy. This signature is centered in chromatin remodeling and the epigenetic changes induced by methylation of specific genes which are important regulatory pathways induced by pregnancy. Through the analysis of the genes found to be differentially methylated between women of varying parity, multiple positions at which beta-catenin production and use is inhibited were recognized. The biological importance of the pathways identified in this specific population cannot be sufficiently emphasized because they could represent a safeguard mechanism mediating the protection of the breast conferred by full term pregnancy. Full article
Open AccessReview Lessons from Genome-Wide Search for Disease-Related Genes with Special Reference to HLA-Disease Associations
Genes 2014, 5(1), 84-96; doi:10.3390/genes5010084
Received: 8 January 2014 / Revised: 11 February 2014 / Accepted: 12 February 2014 / Published: 26 February 2014
PDF Full-text (543 KB) | HTML Full-text | XML Full-text
Abstract
The relationships between diseases and genetic factors are by no means uniform. Single-gene diseases are caused primarily by rare mutations of specific genes. Although each single-gene disease has a low prevalence, there are an estimated 5000 or more such diseases in the [...] Read more.
The relationships between diseases and genetic factors are by no means uniform. Single-gene diseases are caused primarily by rare mutations of specific genes. Although each single-gene disease has a low prevalence, there are an estimated 5000 or more such diseases in the world. In contrast, multifactorial diseases are diseases in which both genetic and environmental factors are involved in onset. These include a variety of diseases, such as diabetes and autoimmune diseases, and onset is caused by a range of various environmental factors together with a number of genetic factors. With the astonishing advances in genome analysis technology in recent years and the accumulation of data on human genome variation, there has been a rapid progress in research involving genome-wide searches for genes related to diseases. Many of these studies have led to the recognition of the importance of the human leucocyte antigen (HLA) gene complex. Here, the current state and future challenges of genome-wide exploratory research into variations that are associated with disease susceptibilities and drug/therapy responses are described, mainly with reference to our own experience in this field. Full article
Open AccessReview Lessons and Implications from Genome-Wide Association Studies (GWAS) Findings of Blood Cell Phenotypes
Genes 2014, 5(1), 51-64; doi:10.3390/genes5010051
Received: 25 November 2013 / Revised: 3 January 2014 / Accepted: 20 January 2014 / Published: 27 January 2014
Cited by 4 | PDF Full-text (179 KB) | HTML Full-text | XML Full-text
Abstract
Genome-wide association studies (GWAS) have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs) are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, [...] Read more.
Genome-wide association studies (GWAS) have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs) are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, large-scale (epi)genomic studies and bioinformatic analyses strongly suggest that GWAS hits are not randomly distributed in the genome but rather pinpoint specific biological pathways important for disease development or phenotypic variation. In this review, we focus on GWAS discoveries for the three main blood cell types: red blood cells, white blood cells and platelets. We summarize the knowledge gained from GWAS of these phenotypes and discuss their possible clinical implications for common (e.g., anemia) and rare (e.g., myeloproliferative neoplasms) human blood-related diseases. Finally, we argue that blood phenotypes are ideal to study the genetics of complex human traits because they are fully amenable to experimental testing. Full article
Open AccessReview The Past, Present, and Future of Human Centromere Genomics
Genes 2014, 5(1), 33-50; doi:10.3390/genes5010033
Received: 9 December 2013 / Revised: 9 January 2014 / Accepted: 10 January 2014 / Published: 23 January 2014
Cited by 13 | PDF Full-text (1572 KB) | HTML Full-text | XML Full-text
Abstract
The centromere is the chromosomal locus essential for chromosome inheritance and genome stability. Human centromeres are located at repetitive alpha satellite DNA arrays that compose approximately 5% of the genome. Contiguous alpha satellite DNA sequence is absent from the assembled reference genome, [...] Read more.
The centromere is the chromosomal locus essential for chromosome inheritance and genome stability. Human centromeres are located at repetitive alpha satellite DNA arrays that compose approximately 5% of the genome. Contiguous alpha satellite DNA sequence is absent from the assembled reference genome, limiting current understanding of centromere organization and function. Here, we review the progress in centromere genomics spanning the discovery of the sequence to its molecular characterization and the work done during the Human Genome Project era to elucidate alpha satellite structure and sequence variation. We discuss exciting recent advances in alpha satellite sequence assembly that have provided important insight into the abundance and complex organization of this sequence on human chromosomes. In light of these new findings, we offer perspectives for future studies of human centromere assembly and function. Full article
Open AccessReview Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success
Genes 2014, 5(1), 13-32; doi:10.3390/genes5010013
Received: 20 November 2013 / Revised: 8 January 2014 / Accepted: 10 January 2014 / Published: 22 January 2014
Cited by 37 | PDF Full-text (887 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 [...] Read more.
Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs. Full article

Other

Jump to: Research, Review

Open AccessCommentary Open Access Data Sharing in Genomic Research
Genes 2014, 5(3), 739-747; doi:10.3390/genes5030739
Received: 13 June 2014 / Revised: 14 August 2014 / Accepted: 18 August 2014 / Published: 29 August 2014
Cited by 3 | PDF Full-text (75 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessCommentary Revisiting Respect for Persons in Genomic Research
Genes 2014, 5(1), 1-12; doi:10.3390/genes5010001
Received: 15 November 2013 / Revised: 2 December 2013 / Accepted: 8 January 2014 / Published: 22 January 2014
Cited by 4 | PDF Full-text (99 KB) | HTML Full-text | XML Full-text
Abstract
The risks and benefits of research using large databases of personal information are evolving in an era of ubiquitous, internet-based data exchange. In addition, information technology has facilitated a shift in the relationship between individuals and their personal data, enabling increased individual [...] Read more.
The risks and benefits of research using large databases of personal information are evolving in an era of ubiquitous, internet-based data exchange. In addition, information technology has facilitated a shift in the relationship between individuals and their personal data, enabling increased individual control over how (and how much) personal data are used in research, and by whom. This shift in control has created new opportunities to engage members of the public as partners in the research enterprise on more equal and transparent terms. Here, we consider how some of the technological advances driving and paralleling developments in genomics can also be used to supplement the practice of informed consent with other strategies to ensure that the research process as a whole honors the notion of respect for persons upon which human research subjects protections are premised. Further, we suggest that technological advances can help the research enterprise achieve a more thoroughgoing respect for persons than was possible when current policies governing human subject research were developed. Questions remain about the best way to revise policy to accommodate these changes. Full article

Journal Contact

MDPI AG
Genes Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
genes@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Genes
Back to Top