Precision medicine, genomics and drug discovery
The hope for precision medicine has long been on the drug discovery horizon, well before the Human Genome Project gave it promise at the turn of the 21st century. In oncology, the concept has finally been realized and is now firmly embedded in ongoing drug discovery programs, and with many recent therapies involving some level of patient/disease stratification, including some highly personalized treatments. In addition, several drugs for rare diseases have been recently approved or are in late-stage clinical development, and new delivery modalities in cell and gene therapy and oligonucleotide approaches are yielding exciti...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Cardon, L. R., Harris, T. Tags: INVITED REVIEWS Source Type: research
Looking beyond the genes: the role of non-coding variants in human disease
Over the past decades the search for disease causing variants has been focusing exclusively on the coding genome. This highly selective approach has been extremely successful resulting in the identification of thousands of disease genes, but ignores the functional and therefore disease relevance of the rest of the genome. Dropping sequencing costs and new high-throughput technologies such as ChIP-seq and chromosome conformation capture have opened new possibilities for the systematic investigation of the non-coding genome. These data have revealed the importance of non-coding DNA in fundamental processes such as gene regul...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Spielmann, M., Mundlos, S. Tags: INVITED REVIEWS Source Type: research
Challenges and novel approaches for investigating molecular mediation
Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclu...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Richmond, R. C., Hemani, G., Tilling, K., Davey Smith, G., Relton, C. L. Tags: INVITED REVIEWS Source Type: research
Genetics and immunity in the era of single-cell genomics
Recent developments in the field of single-cell genomics (SCG) are changing our understanding of how functional phenotypes of cell populations emerge from the behaviour of individual cells. Some of the applications of SCG include the discovery of new gene networks and novel cell subpopulations, fine mapping of transcription kinetics, and the relationships between cell clonality and their functional phenotypes. Immunology is one of the fields that is benefiting the most from such advancements, providing us with completely new insights into mammalian immunity. In this review, we start by covering new immunological insights o...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Vieira Braga, F. A., Teichmann, S. A., Chen, X. Tags: INVITED REVIEWS Source Type: research
Gene set analysis for interpreting genetic studies
Interpretation of genome-wide association study (GWAS) results is lacking behind the discovery of new genetic associations. Consequently, there is an urgent need for data-driven methods for interpreting genetic association studies. Gene set analysis (GSA) can identify aetiologic pathways and functional annotations and may hence point towards novel biological insights. However, despite the growing availability of GSA tools, the sizeable amount of variants identified for a vast number of complex traits, and many irrefutably trait-associated gene sets, the gap between discovery and interpretation remains. More efficient inter...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Pers, T. H. Tags: INVITED REVIEWS Source Type: research
Pathogenetics of the RASopathies
The RASopathies are defined as a group of medical genetics syndromes that are caused by germ-line mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. Taken together, the RASopathies represent one of the most prevalent groups of malformation syndromes affecting greater than 1 in 1,000 individuals. The Ras/MAPK pathway has been well studied in the context of cancer as it plays essential roles in growth, differentiation, cell cycle, senescence and apoptosis, all of which are also critical to normal development. The consequence of germ-line dysregulation leads to ...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Tidyman, W. E., Rauen, K. A. Tags: INVITED REVIEWS Source Type: research
Mouse models for mitochondrial diseases
Mitochondrial diseases are heterogeneous and incurable conditions typically resulting from deficient ATP production in the cells. Mice, owing to their genetic and physiological similarity to humans as well as their relatively easy maintenance and propagation, are extremely valuable for studying mitochondrial diseases and are also indispensable for the preclinical evaluation of novel therapies for these devastating conditions. Here, we review the recent exciting developments in the field focusing on mouse models for mitochondrial disease genes although models for genes not involved in the pathogenesis of mitochondrial disea...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Ruzzenente, B., Rötig, A., Metodiev, M. D. Tags: INVITED REVIEWS Source Type: research
Proteomics to study DNA-bound and chromatin-associated gene regulatory complexes
High-resolution mass spectrometry (MS)-based proteomics is a powerful method for the identification of soluble protein complexes and large-scale affinity purification screens can decode entire protein interaction networks. In contrast, protein complexes residing on chromatin have been much more challenging, because they are difficult to purify and often of very low abundance. However, this is changing due to recent methodological and technological advances in proteomics. Proteins interacting with chromatin marks can directly be identified by pulldowns with synthesized histone tails containing posttranslational modification...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Wierer, M., Mann, M. Tags: INVITED REVIEWS Source Type: research
Hemoglobin genetics: recent contributions of GWAS and gene editing
The β-hemoglobinopathies are inherited disorders resulting from altered coding potential or expression of the adult β-globin gene. Impaired expression of β-globin reduces adult hemoglobin (α2β2) production, the hallmark of β-thalassemia. A single-base mutation at codon 6 leads to formation of HbS (α2βS2) and sickle cell disease. While the basis of these diseases is known, therapy remains largely supportive. Bone marrow transplantation is the only curative therapy. Patients with elevated levels of fetal hemoglobin (HbF, α22) as adults exhibit reduced symptoms and enhanced surv...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Smith, E. C., Orkin, S. H. Tags: INVITED REVIEWS Source Type: research
Pathway and network-based strategies to translate genetic discoveries into effective therapies
One way to design a drug is to attempt to phenocopy a genetic variant that is known to have the desired effect. In general, drugs that are supported by genetic associations progress further in the development pipeline. However, the number of associations that are candidates for development into drugs is limited because many associations are in non-coding regions or difficult to target genes. Approaches that overlay information from pathway databases or biological networks can expand the potential target list. In cases where the initial variant is not targetable or there is no variant with the desired effect, this may revea...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Greene, C. S., Voight, B. F. Tags: INVITED REVIEWS Source Type: research
Modeling craniofacial and skeletal congenital birth defects to advance therapies
Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes. Here, we review recent studies in which modeling of craniofacial disorders in primary patient cells, patient-derived induced pluripotent stem cells (iPSCs), and mice...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Neben, C. L., Roberts, R. R., Dipple, K. M., Merrill, A. E., Klein, O. D. Tags: INVITED REVIEWS Source Type: research
The Yin and Yang of codon usage
The genetic code is degenerate. With the exception of two amino acids (Met and Trp), all other amino acid residues are each encoded by multiple, so-called synonymous codons. Synonymous codons were initially presumed to have entirely equivalent functions, however, the finding that synonymous codons are not present at equal frequencies in genes/genomes suggested that codon choice might have functional implications beyond amino acid coding. The pattern of non-uniform codon use (known as codon usage bias) varies between organisms and represents a unique feature of an organism. Organism-specific codon choice is related to organ...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Komar, A. A. Tags: INVITED REVIEWS Source Type: research
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Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
