Genes

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Open AccessReview

Illuminating the Transcriptome through the Genome

by David J. Elliott

Genes 2014, 5(1), 235-253; https://doi.org/10.3390/genes5010235 - 14 Mar 2014

Cited by 5 | Viewed by 9201

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 [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Genetic Profiling for Risk Reduction in Human Cardiovascular Disease

by Megan J. Puckelwartz and Elizabeth M. McNally

Genes 2014, 5(1), 214-234; https://doi.org/10.3390/genes5010214 - 12 Mar 2014

Cited by 12 | Viewed by 8038

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 genetic [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Association Claims in the Sequencing Era

by Sara L. Pulit, Maarten Leusink, Androniki Menelaou and Paul I. W. De Bakker

Genes 2014, 5(1), 196-213; https://doi.org/10.3390/genes5010196 - 11 Mar 2014

Cited by 5 | Viewed by 9877

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 studies, [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

The Molecular Basis of Retinal Dystrophies in Pakistan

by Muhammad Imran Khan, Maleeha Azam, Muhammad Ajmal, Rob W. J. Collin, Anneke I. Den Hollander, Frans P. M. Cremers and Raheel Qamar

Genes 2014, 5(1), 176-195; https://doi.org/10.3390/genes5010176 - 11 Mar 2014

Cited by 20 | Viewed by 10201

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 most [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Molecular Mechanisms of DNA Replication Checkpoint Activation

by Bénédicte Recolin, Siem Van der Laan, Nikolay Tsanov and Domenico Maiorano

Genes 2014, 5(1), 147-175; https://doi.org/10.3390/genes5010147 - 6 Mar 2014

Cited by 22 | Viewed by 12248

Abstract

The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to [...] Read more.

The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to DNA replication. This signaling pathway ensures coordination of DNA synthesis with cell cycle progression. Failure to activate this checkpoint in response to perturbation of DNA synthesis (replication stress) results in forced cell division leading to chromosome fragmentation, aneuploidy, and genomic instability. In this review, we will describe current knowledge of the molecular determinants of the DNA replication checkpoint in eukaryotic cells and discuss a model of activation of this signaling pathway crucial for maintenance of genomic stability. Full article

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Open AccessReview

Mechanisms of Base Substitution Mutagenesis in Cancer Genomes

by Albino Bacolla, David N. Cooper and Karen M. Vasquez

Genes 2014, 5(1), 108-146; https://doi.org/10.3390/genes5010108 - 5 Mar 2014

Cited by 38 | Viewed by 12521

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 genetic [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessEditorial

Acknowledgement to Reviewers of Genes in 2013

by Genes Editorial Office

Genes 2014, 5(1), 106-107; https://doi.org/10.3390/genes5010106 - 27 Feb 2014

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Abstract

The editors of Genes would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013. [...] Full article

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Open AccessReview

Phenotype-Based Genetic Association Studies (PGAS)—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes

by Hannelore Ehrenreich and Klaus-Armin Nave

Genes 2014, 5(1), 97-105; https://doi.org/10.3390/genes5010097 - 27 Feb 2014

Cited by 16 | Viewed by 7177

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 undertaken [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Lessons from Genome-Wide Search for Disease-Related Genes with Special Reference to HLA-Disease Associations

by Katsushi Tokunaga

Genes 2014, 5(1), 84-96; https://doi.org/10.3390/genes5010084 - 26 Feb 2014

Cited by 9 | Viewed by 6480

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 world. [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

The Genomic Signature of Breast Cancer Prevention

by Jose Russo, Julia Santucci-Pereira and Irma H. Russo

Genes 2014, 5(1), 65-83; https://doi.org/10.3390/genes5010065 - 26 Feb 2014

Cited by 13 | Viewed by 7118

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 by [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Lessons and Implications from Genome-Wide Association Studies (GWAS) Findings of Blood Cell Phenotypes

by Nathalie Chami and Guillaume Lettre

Genes 2014, 5(1), 51-64; https://doi.org/10.3390/genes5010051 - 27 Jan 2014

Cited by 12 | Viewed by 9482

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, large-scale [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

The Past, Present, and Future of Human Centromere Genomics

by Megan E. Aldrup-MacDonald and Beth A. Sullivan

Genes 2014, 5(1), 33-50; https://doi.org/10.3390/genes5010033 - 23 Jan 2014

Cited by 85 | Viewed by 17493

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, limiting [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessReview

Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success

by Vincent Timmerman, Alleene V. Strickland and Stephan Züchner

Genes 2014, 5(1), 13-32; https://doi.org/10.3390/genes5010013 - 22 Jan 2014

Cited by 202 | Viewed by 23890

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 disease-associated [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Open AccessCommentary

Revisiting Respect for Persons in Genomic Research

by Debra J. H. Mathews and Leila Jamal

Genes 2014, 5(1), 1-12; https://doi.org/10.3390/genes5010001 - 22 Jan 2014

Cited by 13 | Viewed by 8111

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 control [...] 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

(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)

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Genes, Volume 5, Issue 1 (March 2014) – 14 articles , Pages 1-253

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