Special Issue "Grand Celebration: 10th Anniversary of the Human Genome Project"
A special issue of Genes (ISSN 2073-4425).
Deadline for manuscript submissions: closed (30 November 2013)
Prof. Dr. Karen E. Nelson
J. Craig Venter Institute (JCVI), 9704 Medical Center Drive, Rockville, MD 20850, USA
Prof. Sir John Burn
Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
Prof. Dr. James R. Lupski
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, MS BCM225, Houston, TX, 77030, USA
Phone: +1 713 798 6530
Fax: +1 713 798 5073
Interests: genomic disorders; genome rearrrangements; neurogenetics; genomics; human genetics; personal genome sequencing; medical genetics
Prof. Pabulo Henrique Rampelotto
Interdisciplinary Center for Biotechnology Research, Federal University of Pampa, Antônio Trilha Avenue, P.O.Box 1847, 97300-000, São Gabriel–RS, Brazil
Interests: origins of life; extremophiles; astrobiology; metagenomics; next generation sequencing; molecular biology and biochemistry of microorganisms; biotechnology; and space science (Solar System exploration)
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
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 quarterly 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 500 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.
- 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
Genes 2014, 5(1), 1-12; doi:10.3390/genes5010001
Received: 15 November 2013; in revised form: 2 December 2013 / Accepted: 8 January 2014 / Published: 22 January 2014| Download PDF Full-text (99 KB) | Download XML Full-text
Review: 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; in revised form: 8 January 2014 / Accepted: 10 January 2014 / Published: 22 January 2014| Download PDF Full-text (887 KB) | Download XML Full-text | Supplementary Files
Genes 2014, 5(1), 33-50; doi:10.3390/genes5010033
Received: 9 December 2013; in revised form: 9 January 2014 / Accepted: 10 January 2014 / Published: 23 January 2014| Download PDF Full-text (1572 KB) | Download XML Full-text
Review: 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; in revised form: 3 January 2014 / Accepted: 20 January 2014 / Published: 27 January 2014| Download PDF Full-text (179 KB) | Download XML Full-text
Genes 2014, 5(1), 65-83; doi:10.3390/genes5010065
Received: 18 December 2013; in revised form: 31 January 2014 / Accepted: 8 February 2014 / Published: 26 February 2014| Download PDF Full-text (1914 KB) | Download XML Full-text | Supplementary Files
Review: 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; in revised form: 11 February 2014 / Accepted: 12 February 2014 / Published: 26 February 2014| Download PDF Full-text (543 KB) | Download XML Full-text
Review: 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; in revised form: 17 February 2014 / Accepted: 18 February 2014 / Published: 27 February 2014| Download PDF Full-text (353 KB) | Download XML Full-text
Genes 2014, 5(1), 108-146; doi:10.3390/genes5010108
Received: 9 December 2013; in revised form: 7 February 2014 / Accepted: 11 February 2014 / Published: 5 March 2014| Download PDF Full-text (559 KB) | Download XML Full-text
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: Lessons from Genome-Wide Search for Disease-Related Genes
Author: Katsushi Tokunaga
Affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Japan; E-Mail: firstname.lastname@example.org
Abstract: Single nucleotide polymorphisms (SNPs) are the most abundant polymorphisms in human genome. By means of SNP-based genome-wide association studies (GWAS), we have identified new susceptibility genes to various complex diseases in addition to response genes to different drugs. From these studies, we have learned the followings: (a) Multiple susceptibility genes to type 2 diabetes (T2D), narcolepsy, rheumatoid arthritis (RA), tuberculosis (TB), and primary biliary cirrhosis (PBC) showed significant ethnic differences between European ancestry and East Asian populations; (b) There are susceptibility genes shared by different diseases in nephrotic syndrome and in autoimmune diseases, suggesting common pathogenic mechanisms among these diseases; (c) International collaborations and large-scale meta-analyses identified a number of new susceptibility genes to narcolepsy, PBC, RA, and T2D, suggesting multiple pathogenic mechanisms; (d) The response gene to interferon-alpha and ribavirin therapy for chronic hepatitis C served a new target for drug development as well as a gene testing for treatment decision; (e) HLA genes are associated with susceptibilities to various diseases including narcolepsy, RA, PBC, hepatitis B, and Stevens-Johnson syndrome, and our functional study suggests a new mechanism for the disease associations. Furthermore, establishment of public databases for sharing massive data produced by new technologies for genome analysis and development of new methods in bioinformatics and statistical genetics are essential for elucidating genetic architecture of complex diseases.
Type of Paper: Article
Title: Theoretical Conditions of the DNA Region for the Regulation of Gene Expression
Author: Hiroshi Kobayashi
Affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan; E-Mail: email@example.com
Abstract: After the human genome has been analyzed, various kinds of bioinformatics based on the human genome have been developed. However, inadequate arguments have been proposed. One is the functional argument of the DNA sequences outside of reading frames, namely binding sites for proteins to regulate the gene expression. Theoretically, a sequence consisting of less than 16 base pairs presents randomly in the genome consisting of 3 billions base pairs. Nevertheless, sequences consisting of less than 16 base pairs have been proposed to have a function to regulate gene expression with no experimental evidence. I have carried out the following two simulations using a computer. One is to examine which random sequences consisting of 10 to 15 base pairs are found in the human genome. If a given random sequence is found, it is questionable that such sequence has a specific function. In reverse, if a proposed consensus sequence is found in the artificial genome created randomly by a computer, it is also questionable that such sequence has a specific function. Based on these simulation data, I would like to discuss theoretical conditions of the DNA region for a specific function to regulate the gene expression.
Type of Paper: Review
Title: Biomedical Discovery Enabled by Whole Genome Genetic Association Studies in Mice
Authors: Haili Zhang 1, David Dill 2, Gary Peltz 1 and Ming Zheng 1
1 Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA
2 Department of Computer Science, Stanford University, Stanford, CA 94305, USA
Abstract: Although the mouse has been the premier model organism for biomedical research, mouse genetic studies have overall produced rather disappointing results. However, the prospects of genetic mapping in mice have been substantially improved through the ability of next generation sequence (NGS) data to provide complete genome-wide variant information for an expanded number of inbred strains. We have recently used NGS to produce a whole genome SNP database covering 26 inbred mouse strains. This database was combined with haplotype-based computational genetic mapping (HBCGM) to produce a whole genome sequence-based method for genetically analyzing biomedical traits in mice. This method was used to analyze a multiple murine genetic traits, and to uncover the genetic basis for biomedical traits of interest.
Type of Paper: Review
Title: The Revolution in Human Monogenic Disease Mapping
Authors: Eileen M. Shore 1,*, Matthew Brown 2 and Emma Duncan 3
1 Departments of Orthopaedic Surgery and Genetics and the Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, PA 19104-6081, Philadelphia, Pennsylvania, USA. * Email: firstname.lastname@example.org; 2 University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia; 3 University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, and Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
Abstract: The Human Genome Project (HGP) has been instrumental in identifying causative mutations for rare genetic diseases, including the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP). Building on the initial technology, computation, and scientific information generated through the HGP, the continued advance in mapping disease genes has been extraordinarily rapid. Faced today with the challenge of identifying a rare gene mutation in a disease like FOP, high-throughput exome and whole genome sequencing approaches would rapidly identify the genetic mutation. These breakthroughs are leading to a new explosion in disease gene discoveries with their associated benefits. However, after mapping a disease-causing gene, many challenges remain in understanding additional genetic contributions to disease onset and progression. With further development of genome technologies, the ability to understand phenotypic variability and the participation of genetic modifiers is becoming a reality.
Type of Paper: Review
Title: Mouse ENU Mutagenesis: A Strategy for Identifying Genes, Proteins and Signaling Pathways of Infectious Diseases and Immunodeficiency
Authors: Grégory Caignard 1, Megan Eva 2, Rebekah Van Bruggen 3, Robert Eveleigh 4, Guillaume Bourque 4, Danielle Malo 2, Philippe Gros 3 and Silvia M Vidal 1,*
1 Department of Human Genetics, Centre for the Study of Host Resistance, McGill University, Montréal, Québec H3G 0B1, Canada
2 Department of Human Genetics and Department of Medicine McGill University, Complex Traits Group, McGill University, Montréal, Québec H3G 0B1, Canada
3 Department of Biochemistry and Complex Traits Group, McGill University, Montréal, Québec H3G 0B1, Canada
4 McGill University and Genome Quebec Innovation Center, Montréal H3A 1A4, Canada; E-Mail: email@example.com
Abstract: Globalization and climate change have led to the emergence or re-emergence of numerous infectious diseases since the latter half of the twentieth century. Human populations must fight with several types of pathogens (virus, bacteria, parasite…) that are responsible for over 25% of death globally. One of the most important enigmas in the field of infectious diseases is the huge clinical variability between individuals in the course of infection. Although the microbe is the main (if not the only) cause of infectious diseases, the outcome of infection results from a set of diverse factors ranging from the environment to host genetics. The first working draft of the human genome in 2003 has paved the way for the study of the genetic etiology of human diseases, such as the genome-wide association study (GWAS) project. In parallel, genetically well-characterized mice have been anticipated as appropriate experimental models to advance the study of human diseases. The recent availability of complete mouse genome sequences has also constituted a substantial step in the development of new genomic approaches, such as phenotype-driven and gene-driven mouse mutagenesis. As a part of this new research area, our team and others have created an innovative discovery platform integrating mouse chemical mutagenesis (ethyl-nitrous-urea or ENU) and large-scale phenotyping to identify host genes that directly impact susceptibility to pathogens of global significance and immunodeficiency. In this review, we highlight the strategies and tools used in ENU mutagenesis to efficiently generate functional mutations for identifying new genes, proteins and signalling pathways of infectious diseases and immunodeficiency.
Type of Paper: Article
Title: GWAS, GCTA and Heritability Study in Twins Study to Estimate the Genetic Effects of Hair Color in a Dutch Population
Authors: Bochao Lin, Hamdi Mbarek, Gonneke Willemsen, Conor Dolan, Eco J. C. de Geus, Dorret I. Boomsma and Jouke Jan Hottenga
Affiliation: Department of Biological Psychology, VU University Amsterdam, The Netherlands
Abstract: Hair color is one of most visible and heritable traits in humans. In this paper a combination of genetic approaches is used to examine the heritability and genetic effects of SNPs within the Netherlands Twin Register. To estimate the heritability and the assortative mating coefficient of hair color we carried out a structural equation liability threshold twin modelin 22899 individuals. The broad heritability was estimated at 87% to 97%. From GCTA analyses, the additive variance in hair color that can be explained in unrelated individuals by well-imputed SNPs on the 1000G reference is between 36% and 75%. Modeling dominant factors seems to be essential and assortative mating cannot be neglected. Genome-wide association studies, for each hair color within a total of 7079 individuals show that SNPs in the MC1R region are significantly associated with red hair pigmentation. Five other genes (HERC2, TPCN2, SLC24A2, SLC24A4 and KITLG) met the criteria for genome-wide significance in the hair colors blond, brown, black, and this fully replicates the body of literature on this trait. In addition, we identified new genetic variants in red hair color and black hair color in the MC4R and RPS6KA2, TSPAN18 genes.
Type of Paper: Article
Title: Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells
Author: Jenny van Dongen, Erik Ehli, Meike Bartels, Gareth Davies, Bastiaan Heijmans, Dorret Boomsma
Affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
Abstract: DNA methylation is one of the most extensively studied epigenetic marks in human tissues. In recent years, it has become clear that DNA methylation patterns show widespread variation between individuals, highlighting this epigenetic mark as a potential source of variation in disease susceptibility. Accumulating evidence suggests that genetic variants (mQTLs), environmental exposures, and stochastic factors can affect DNA methylation patterns, but it is largely unknown how much each of these factors account for overall variation in DNA methylation across different regions in the genome. The comparison of DNA methylation patterns of monozygotic twins offers a unique design to examine the extent to which variation is related to environmental and stochastic events. In this paper, we review twin studies of DNA methylation and describe genome-wide DNA methylation patterns from 10 young monozygotic twin pairs (age 8-19). In this study, DNA methylation was measured in DNA samples derived from of buccal epithelial cells, using the Infinium Human Methylation 450 BeadChip, which assesses more than 480 thousand individual CpG sites throughout the genome, covering 99% of RefSeq genes. Buccal cells are an easily accessible tissue, and it has been suggested that buccal cells might be a more informative tissue than blood for examining associations with disease phenotypes. The aim of our study was to assess the similarity of DNA methylation in buccal cells from genetically identical subjects across different genomic features interrogated by the Illumina 450 k array, including promoter regions, transcriptional start sites, 5’UTR, gene body, first exon, and 3’UTR. To this end, we computed for each CpGsite the correlation between methylation levels of MZ twins and describe the range of correlations for different genomic regions. Methylation sites that are less strongly correlated between monozygotic twins may be more vulnerable to stochastic drift or environmental exposures and thus give insight into the variation of DNA methylation under an identical genetic background, and into the distribution of this variation across important regulatory sites in the genome.
Type of Paper: Review
Title: Mechanisms of Base Substitution Mutagenesis in Cancer Genomes
Authors: Albino Bacolla1, David N. Cooper 2 and Karen M. Vasquez1
1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA
2Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Abstract: Cancer genome sequence data provide valuable 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 and chromatin status are all now known to contribute to the DNA sequence context dependencies that are characteristic of SBSs. We review current hypotheses as to the major mechanisms that give rise to SBS and evaluate their relative merits 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 reactive oxygen species, a source of genetic variation that may be operative both in cancer and in the germ line during the course of evolutionary divergence.
Type of Paper: Article
Title: Characterization of the Genomic Architecture and Mutational Spectrum of a Small Cell Prostate Carcinoma
Authors: Alan F. Scott 1, David W. Mohr 1, Hua Ling 1, Robert B. Scharpf 2 and Gregory S. Liptak 3,4
1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA
2 Dept of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.
3 Dept of Pediatrics, SUNY Upstate Medical Center, Golisano Children's Hospital, Syracuse, NY 13210, USA
Abstract: Small cell prostate carcinoma (SCPC) is a rare and very aggressive tumor with a poor prognosis. The underlying genomic architecture and mutation spectrum of this tumor type is not 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) and mutations in genes from known cancer pathways. The results showed widespread evidence of chromothripsis and LOH for the regions around the tumor suppressors TP53 and RB1. Predicted damaging somatic mutations were observed in the retained TP53 allele and in other genes that may be functionally relevant. Together, the combination of genotyping and exome sequencing provided more information than either technique alone. The data underscore why SCPC is such a difficult cancer to manage.
Type of Paper: Review
Title: Reading and Language Disorders: The Importance of Both Quantity and Quality
Authors: Dianne F Newbury 1, Anthony P Monaco 2 and Silvia Paracchini 3
Affiliations: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK; E-Mail: firstname.lastname@example.org; 2 Tufts University, Ballou Hall, Medford MA 02155. USA; E-Mail: Anthony.Monaco@tufts.edu; 3 School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK; E-Mail: email@example.com
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 genetic factors to be complex in nature. To date only a few genes have been implicated in these traits. Their functional characterization has contributed significantly to study 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.
Type of Paper: Review
Title: Altered Circadian Clock Genes in Major Depressive Disorder: Mechanisms of Action of Rapid-Acting Antidepressants
Authors: Blynn G Bunneya, Jun Z. Lib, Fan Mengc, Megan H. Hagenauerc, David M. Walsha, Richard Steina Marquis P. Vawtera, Simon J. Evansc, Preston Cartagenaa, Jack D. Barchasd, Alan F. Schatzberge, Richard M. Myersf, Stanley J. Watson, Jr.c, Huda Akilc and William E. Bunneya
aDepartment of Psychiatry and Human Behavior, University of California, Irvine, CA 92697
bDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109
cMolecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109
dDepartment of Psychiatry, Weill Cornell Medical College, New York, NY 10017
eDepartment of Psychiatry, Stanford University, Palo Alto, CA 94305
fHudsonAlpha, Institute for Biotechnology, Huntsville, AL 35806
Abstract: Depressive illness represents a major public health problem worldwide. The World Health Organization (WHO) ranks depression fourth of all medical disorders in terms of lifetime disability. Each year, an estimated 1 million individuals commit suicide worldwide. In the United States, 38,000 suicides are committed each year; 90% of these individuals have a psychiatric diagnosis. This review focuses on circadian abnormalities in depression and a possible mode of action for rapid-acting antidepressants. Abnormal circadian rhythms affecting temperature, mood, hormonal secretion and sleep have been consistently reported in major depressive disorder (MDD). These rhythms are controlled by circadian clock genes. Evidence is presented in this review that patients suffering from MDD have abnormal clock gene rhythms in the periphery and brain. Virtually all current standard antidepressants require 2-10 weeks for clinical efficacy. However, robust data has been obtained that low-dose ketamine and sleep deprivation therapy can produce clinical remission within 24 hours. Based on human and animal data, we hypothesize that a subset of depressed patients have altered clock genes and that ketamine and sleep deprivation therapy can reset clock gene machinery. Further, if patients relapse, abnormal clock genes are reactivated. Future work could involve targeting molecules to rapidly reset and stabilize clock gene function in depression.
Last update: 30 December 2013