On the meaning of the word 'epimutation'
Abstract The word 'epimutation' is often used in a manner that can be misinterpreted. The strict definition of epimutation is a heritable change in gene activity that is not associated with a DNA mutation but rather with gain or loss of DNA methylation or other heritable modifications of chromatin. Unfortunately, there is a growing tendency in the cancer field to use the word in situations in which underlying DNA sequence changes have occurred. PMID: 25301328 [PubMed - as supplied by publisher] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - October 6, 2014 Category: Genetics & Stem Cells Authors: Oey H, Whitelaw E Tags: Trends Genet Source Type: research
Higher-order genetic interactions and their contribution to complex traits.
Abstract The contribution of genetic interactions involving three or more loci to complex traits is poorly understood. These higher-order genetic interactions (HGIs) are difficult to detect in genetic mapping studies, therefore, few examples of them have been described. However, the lack of data on HGIs should not be misconstrued as proof that this class of genetic effect is unimportant. To the contrary, evidence from model organisms suggests that HGIs frequently influence genetic studies and contribute to many complex traits. Here, we review the growing literature on HGIs and discuss the future of research on thi...
Source: Trends in Genetics : TIG - October 2, 2014 Category: Genetics & Stem Cells Authors: Taylor MB, Ehrenreich IM Tags: Trends Genet Source Type: research
Sex differences in disease genetics: evidence, evolution, and detection.
Abstract Understanding the genetic architecture of disease is an enormous challenge, and should be guided by evolutionary principles. Recent studies in evolutionary genetics show that sexual selection can have a profound influence on the genetic architecture of complex traits. Here, we summarise data from heritability studies and genome-wide association studies (GWASs) showing that common genetic variation influences many diseases and medically relevant traits in a sex-dependent manner. In addition, we discuss how the discovery of sex-dependent effects in population samples is improved by joint interaction analysi...
Source: Trends in Genetics : TIG - September 27, 2014 Category: Genetics & Stem Cells Authors: Gilks WP, Abbott JK, Morrow EH Tags: Trends Genet Source Type: research
Serving epigenetics before its time.
Abstract Society prizes the rapid translation of basic biological science into ways to prevent human illness. However, the premature rush to take murine epigenetic findings in these directions makes impossible demands on prospective parents and triggers serious social and ethical questions. PMID: 25242336 [PubMed - in process] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - September 27, 2014 Category: Genetics & Stem Cells Authors: Juengst ET, Fishman JR, McGowan ML, Settersten RA Tags: Trends Genet Source Type: research
Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implications.
Abstract Thousands of genes encoding long noncoding RNAs (lncRNAs) have been identified in all vertebrate genomes thus far examined. The list of lncRNAs partaking in arguably important biochemical, cellular, and developmental activities is steadily growing. However, it is increasingly clear that lncRNA repertoires are subject to weak functional constraint and rapid turnover during vertebrate evolution. We discuss here some of the factors that may explain this apparent paradox, including relaxed constraint on sequence to maintain lncRNA structure/function, extensive redundancy in the regulatory circuits in which ln...
Source: Trends in Genetics : TIG - September 10, 2014 Category: Genetics & Stem Cells Authors: Kapusta A, Feschotte C Tags: Trends Genet Source Type: research
The overdue promise of short tandem repeat variation for heritability.
Abstract Short tandem repeat (STR) variation has been proposed as a major explanatory factor in the heritability of complex traits in humans and model organisms. However, we still struggle to incorporate STR variation into genotype-phenotype maps. We review here the promise of STRs in contributing to complex trait heritability and highlight the challenges that STRs pose due to their repetitive nature. We argue that STR variants are more likely than single-nucleotide variants to have epistatic interactions, reiterate the need for targeted assays to genotype STRs accurately, and call for more appropriate statistical...
Source: Trends in Genetics : TIG - August 30, 2014 Category: Genetics & Stem Cells Authors: Press MO, Carlson KD, Queitsch C Tags: Trends Genet Source Type: research
Dissecting complex traits using the Drosophila Synthetic Population Resource.
We describe studies using one such panel, the Drosophila Synthetic Population Resource (DSPR), and the implications for our understanding of the genetic basis of complex traits. In particular, we note that many loci of large effect appear to be multiallelic. If multiallelism is a general rule, analytical approaches designed to identify multiallelic variants should be a priority for both genome-wide association studies (GWASs) and multi-parental panels. PMID: 25175100 [PubMed - as supplied by publisher] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - August 27, 2014 Category: Genetics & Stem Cells Authors: Long AD, Macdonald SJ, King EG Tags: Trends Genet Source Type: research
Worms, bacteria, and micronutrients: an elegant model of our diet.
Abstract Micronutrients are required in small proportions in a diet to carry out key metabolic roles for biomass and energy production. Humans receive micronutrients either directly from their diet or from gut microbiota that metabolize other nutrients. The nematode Caenorhabditis elegans and its bacterial diet provide a relatively simple and genetically tractable model to study both direct and microbe-mediated effects of micronutrients. Recently, this model has been used to gain insight into the relationship between micronutrients, physiology, and metabolism. In particular, two B-type vitamins, vitamin B12 and fo...
Source: Trends in Genetics : TIG - August 26, 2014 Category: Genetics & Stem Cells Authors: Yilmaz LS, Walhout AJ Tags: Trends Genet Source Type: research
Alternative splicing regulation of telomerase: a new paradigm?
Abstract Alternative splicing affects approximately 95% of eukaryotic genes, greatly expanding the coding capacity of complex genomes. Although our understanding of alternative splicing has increased rapidly, current knowledge of splicing regulation has largely been derived from studies of highly expressed mRNAs. Telomerase is a key example of a protein that is alternatively spliced, but it is expressed at very low levels and although it is known that misregulation of telomerase splicing is a hallmark of nearly all cancers, the details of this process are unclear. Here we review work showing that hTERT expression ...
Source: Trends in Genetics : TIG - August 26, 2014 Category: Genetics & Stem Cells Authors: Wong MS, Wright WE, Shay JW Tags: Trends Genet Source Type: research
Toward a new history and geography of human genes informed by ancient DNA.
Abstract Genetic information contains a record of the history of our species, and technological advances have transformed our ability to access this record. Many studies have used genome-wide data from populations today to learn about the peopling of the globe and subsequent adaptation to local conditions. Implicit in this research is the assumption that the geographic locations of people today are informative about the geographic locations of their ancestors in the distant past. However, it is now clear that long-range migration, admixture, and population replacement subsequent to the initial out-of-Africa expans...
Source: Trends in Genetics : TIG - August 25, 2014 Category: Genetics & Stem Cells Authors: Pickrell JK, Reich D Tags: Trends Genet Source Type: research
Wisdom from the fly.
Abstract Arguably, almost all research in Drosophila can be considered basic research, yet many of the most essential and fundamental concepts of human genetics were first decoded in the fly. Although the fly genome, which is organized into only four chromosomes, is approximately one-twentieth the size of the human genome, it contains roughly the same number of genes, and up to 75% of human disease-related genes have Drosophila homologues . The fly was prized for its simplicity and utility even before such compelling homology with humans was apparent. Since Thomas Hunt Morgan began his seminal experiments over ...
Source: Trends in Genetics : TIG - August 23, 2014 Category: Genetics & Stem Cells Authors: Rieder LE, Larschan EN Tags: Trends Genet Source Type: research
Functional and genomic context in pathway analysis of GWAS data.
Abstract Gene set analysis (GSA) is a promising tool for uncovering the polygenic effects associated with complex diseases. However, the available techniques reflect a wide variety of hypotheses about how genetic effects interact to contribute to disease susceptibility. The lack of consensus about the best way to perform GSA has led to confusion in the field and has made it difficult to compare results across methods. A clear understanding of the various choices made during GSA - such as how gene sets are defined, how single-nucleotide polymorphisms (SNPs) are assigned to genes, and how individual SNP-level effect...
Source: Trends in Genetics : TIG - August 22, 2014 Category: Genetics & Stem Cells Authors: Mooney MA, Nigg JT, McWeeney SK, Wilmot B Tags: Trends Genet Source Type: research
Connections between TET proteins and aberrant DNA modification in cancer.
We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer. PMID: 25132561 [PubMed - as supplied by publisher] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - August 14, 2014 Category: Genetics & Stem Cells Authors: Huang Y, Rao A Tags: Trends Genet Source Type: research
mRNA transport meets membrane traffic.
e M Abstract Active transport and local translation of mRNAs ensure the appropriate spatial organization of proteins within cells. Recent work has shown that this process is intricately connected to membrane trafficking. Here, we focus on new findings obtained in fungal model systems. Important highlights are that RNA-binding proteins recognize cargo mRNA synergistically and that mRNAs are co-transported with membranous compartments such as the endoplasmic reticulum (ER) and endosomes. We further discuss a novel concept of endosome-coupled translation that loads shuttling endosomes with septin cargo, a process imp...
Source: Trends in Genetics : TIG - August 7, 2014 Category: Genetics & Stem Cells Authors: Jansen RP, Niessing D, Baumann S, Feldbrügge M Tags: Trends Genet Source Type: research
Ten years of next-generation sequencing technology.
Abstract Ten years ago next-generation sequencing (NGS) technologies appeared on the market. During the past decade, tremendous progress has been made in terms of speed, read length, and throughput, along with a sharp reduction in per-base cost. Together, these advances democratized NGS and paved the way for the development of a large number of novel NGS applications in basic science as well as in translational research areas such as clinical diagnostics, agrigenomics, and forensic science. Here we provide an overview of the evolution of NGS and discuss the most significant improvements in sequencing technologies ...
Source: Trends in Genetics : TIG - August 6, 2014 Category: Genetics & Stem Cells Authors: van Dijk EL, Auger H, Jaszczyszyn Y, Thermes C Tags: Trends Genet Source Type: research
Whole-genome sequencing to control antimicrobial resistance.
SJ Abstract Following recent improvements in sequencing technologies, whole-genome sequencing (WGS) is positioned to become an essential tool in the control of antibiotic resistance, a major threat in modern healthcare. WGS has already found numerous applications in this area, ranging from the development of novel antibiotics and diagnostic tests through to antibiotic stewardship of currently available drugs via surveillance and the elucidation of the factors that allow the emergence and persistence of resistance. Numerous proof-of-principle studies have also highlighted the value of WGS as a tool for day-to-day ...
Source: Trends in Genetics : TIG - August 2, 2014 Category: Genetics & Stem Cells Authors: Köser CU, Ellington MJ, Peacock SJ Tags: Trends Genet Source Type: research
Automatic multigenic family annotation: risks and solutions.
and C Abstract A major challenge facing bioinformatics today is the efficient annotation of the exponential flow of genomic data. This has led to an increasing dependence on automatic annotation procedures, despite the relatively high error rates of these programs, particularly for multigenic families. We discuss here the errors and biases introduced by automatic genome annotations, focusing on issues with structural annotations of gene families, and suggest ways to overcome these limitations. PMID: 25017189 [PubMed - as supplied by publisher] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - July 10, 2014 Category: Genetics & Stem Cells Authors: Fawal N, Li Q, Mathé C, Dunand C Tags: Trends Genet Source Type: research
Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches.
Abstract Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. However, tumors rely on residual DNA repair capacities to survive the damage induced by genotoxic stress. This dichotomy might explain why only isolated DNA repair pathways are inactivated in cancer cells. Accordingly, synergism has been observed between DNA-damaging drugs and targeted inhibitors of DNA repair. DNA repair pathways are generally thought of as mutually exclusive mechanistic units handling different types of lesions in distinct cell cycle phases. Recent preclini...
Source: Trends in Genetics : TIG - July 10, 2014 Category: Genetics & Stem Cells Authors: Dietlein F, Thelen L, Reinhardt HC Tags: Trends Genet Source Type: research
The embryo as a laboratory: quantifying transcription in Drosophila.
Abstract Transcriptional regulation of gene expression is fundamental to most cellular processes, including determination of cellular fates. Quantitative studies of transcription in cultured cells have led to significant advances in identifying mechanisms underlying transcriptional control. Recent progress allowed implementation of these same quantitative methods in multicellular organisms to ask how transcriptional regulation unfolds both in vivo and at the single molecule level in the context of embryonic development. Here we review some of these advances in early Drosophila development, which bring the embryo o...
Source: Trends in Genetics : TIG - July 5, 2014 Category: Genetics & Stem Cells Authors: Gregor T, Garcia HG, Little SC Tags: Trends Genet Source Type: research
Transcriptional regulatory functions of nuclear long noncoding RNAs.
Abstract Several nuclear localised intergenic long noncoding RNAs (lncRNAs) have been ascribed regulatory roles in transcriptional control and their number is growing rapidly. Initially, these transcripts were shown to function locally, near their sites of synthesis, by regulating the expression of neighbouring genes. More recently, lncRNAs have been demonstrated to interact with chromatin at several thousand different locations across multiple chromosomes and to modulate large-scale gene expression programs. Although the molecular mechanisms involved in targeting lncRNAs to distal binding sites remain poorly unde...
Source: Trends in Genetics : TIG - June 25, 2014 Category: Genetics & Stem Cells Authors: Vance KW, Ponting CP Tags: Trends Genet Source Type: research
Exposing synonymous mutations.
Abstract Synonymous codon changes, which do not alter protein sequence, were previously thought to have no functional consequence. Although this concept has been overturned in recent years, there is no unique mechanism by which these changes exert biological effects. A large repertoire of both experimental and bioinformatic methods has been developed to understand the effects of synonymous variants. Results from this body of work have provided global insights into how biological systems exploit the degeneracy of the genetic code to control gene expression, protein folding efficiency, and the coordinated expression...
Source: Trends in Genetics : TIG - June 19, 2014 Category: Genetics & Stem Cells Authors: Hunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C Tags: Trends Genet Source Type: research
Genome typing of nonhuman primate models: implications for biomedical research.
Abstract The success of personalized medicine rests on understanding the genetic variation between individuals. Thus, as medical practice evolves and variation among individuals becomes a fundamental aspect of clinical medicine, a thorough consideration of the genetic and genomic information concerning the animals used as models in biomedical research also becomes critical. In particular, nonhuman primates (NHPs) offer great promise as models for many aspects of human health and disease. These are outbred species exhibiting substantial levels of genetic variation; however, understanding of the contribution of this...
Source: Trends in Genetics : TIG - June 18, 2014 Category: Genetics & Stem Cells Authors: Haus T, Ferguson B, Rogers J, Doxiadis G, Certa U, Rose NJ, Teepe R, Weinbauer GF, Roos C Tags: Trends Genet Source Type: research
The emerging era of genomic data integration for analyzing splice isoform function.
We describe here emerging computational approaches that integrate such large-scale whole-transcriptome sequencing (RNA-seq) data for predicting the functions of alternatively spliced isoforms, and we discuss their applications in developmental and cancer biology. We outline future directions for isoform function prediction, emphasizing the need for heterogeneous genomic data integration and tissue-specific, dynamic isoform-level network modeling, which will allow the field to realize its full potential. PMID: 24951248 [PubMed - as supplied by publisher] (Source: Trends in Genetics : TIG)
Source: Trends in Genetics : TIG - June 17, 2014 Category: Genetics & Stem Cells Authors: Li HD, Menon R, Omenn GS, Guan Y Tags: Trends Genet Source Type: research
Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways.
Abstract Eri1 is an evolutionarily conserved 3'-5' exoribonuclease that participates in 5.8S rRNA 3' end processing and turnover of replication-dependent histone mRNAs. Over the course of evolution, Eri1 has also been recruited into a variety of conserved and species-specific regulatory small RNA pathways that include endogenous small interfering (si)RNAs and miRNAs. Recent advances in Eri1 biology illustrate the importance of RNA metabolism in epigenetic gene regulation and illuminate common principles and players in RNA biogenesis and turnover. In this review, we highlight Eri1 as a member of a growing class of ...
Source: Trends in Genetics : TIG - June 11, 2014 Category: Genetics & Stem Cells Authors: Thomas MF, L'Etoile ND, Ansel KM Tags: Trends Genet Source Type: research
GC content evolution in coding regions of angiosperm genomes: a unifying hypothesis.
Ressayre A Abstract In angiosperms (as in other species), GC content varies along and between genes, within a genome, and between genomes of different species, but the reason for this distribution is still an open question. Grass genomes are particularly intriguing because they exhibit a strong bimodal distribution of genic GC content and a sharp 5'-3' decreasing GC content gradient along most genes. Here, we propose a unifying model to explain the main patterns of GC content variation at the gene and genome scale. We argue that GC content patterns could be mainly determined by the interactions between gene struc...
Source: Trends in Genetics : TIG - June 7, 2014 Category: Genetics & Stem Cells Authors: Glémin S, Clément Y, David J, Ressayre A Tags: Trends Genet Source Type: research
Sirtuins: guardians of mammalian healthspan.
Abstract The first link between sirtuins and longevity was made 15 years ago in yeast. These initial studies sparked efforts by many laboratories working in diverse model organisms to elucidate the relations between sirtuins, lifespan, and age-associated dysfunction. Here, we discuss the current understanding of how sirtuins relate to aging. We focus primarily on mammalian sirtuins SIRT1, SIRT3, and SIRT6, the three sirtuins for which the most relevant data are available. Strikingly, a large body of evidence now indicates that these and other mammalian sirtuins suppress a variety of age-related pathologies and pro...
Source: Trends in Genetics : TIG - May 27, 2014 Category: Genetics & Stem Cells Authors: Giblin W, Skinner ME, Lombard DB Tags: Trends Genet Source Type: research
Spatial organization of transcription in bacterial cells.
Abstract Prokaryotic transcription has been extensively studied over the past half a century. However, there often exists a gap between the structural, mechanistic description of transcription obtained from in vitro biochemical studies, and the cellular, phenomenological observations from in vivo genetic studies. It is now accepted that a living bacterial cell is a complex entity; the heterogeneous cellular environment is drastically different from the homogenous, well-mixed situation in vitro. Where molecules are inside a cell may be important for their function; hence, the spatial organization of different molec...
Source: Trends in Genetics : TIG - May 23, 2014 Category: Genetics & Stem Cells Authors: Weng X, Xiao J Tags: Trends Genet Source Type: research
Tissue specificity in DNA repair: lessons from trinucleotide repeat instability.
Abstract DNA must constantly be repaired to maintain genome stability. Although it is clear that DNA repair reactions depend on cell type and developmental stage, we know surprisingly little about the mechanisms that underlie this tissue specificity. This is due, in part, to the lack of adequate study systems. This review discusses recent progress toward understanding the mechanism leading to varying rates of instability at expanded trinucleotide repeats (TNRs) in different tissues. Although they are not DNA lesions, TNRs are hotspots for genome instability because normal DNA repair activities cause changes in rep...
Source: Trends in Genetics : TIG - May 16, 2014 Category: Genetics & Stem Cells Authors: Dion V Tags: Trends Genet Source Type: research
Mechanisms of genome instability induced by RNA-processing defects.
Abstract The role of normal transcription and RNA processing in maintaining genome integrity is becoming increasingly appreciated in organisms ranging from bacteria to humans. Several mutations in RNA biogenesis factors have been implicated in human cancers, but the mechanisms and potential connections to tumor genome instability are not clear. Here, we discuss how RNA-processing defects could destabilize genomes through mutagenic R-loop structures and by altering expression of genes required for genome stability. A compelling body of evidence now suggests that researchers should be directly testing these mechanis...
Source: Trends in Genetics : TIG - May 1, 2014 Category: Genetics & Stem Cells Authors: Chan YA, Hieter P, Stirling PC Tags: Trends Genet Source Type: research
Nervous decision-making: to divide or differentiate.
Abstract The intricate balance between proliferation and differentiation is of fundamental importance in the development of the central nervous system (CNS). The division versus differentiation decision influences both the number and identity of daughter cells produced, thus critically shaping the overall microstructure and function of the CNS. During the past decade, significant advances have been made to characterise the changes in the cell cycle during differentiation, and to uncover the multiple bidirectional links that coordinate these two processes. Here, we explore the nature and mechanistic basis of these ...
Source: Trends in Genetics : TIG - April 30, 2014 Category: Genetics & Stem Cells Authors: Hardwick LJ, Philpott A Tags: Trends Genet Source Type: research
New tools in the box: An evolutionary synopsis of chromatin insulators.
Abstract Despite progress in understanding genome organization and gene expression during the last decade, the evolutionary pathways that led to the intricate patterns of gene expression in different cells of an organism are still poorly understood. Important steps in this regulation take place at the level of chromatin, where the (epi)genomic environment of a gene determines its expression in time and space. Although the basic mechanisms of gene expression apply to all eukaryotes, multicellular organisms face the additional challenge of coordinating gene expression during development. In this review we summarize ...
Source: Trends in Genetics : TIG - April 28, 2014 Category: Genetics & Stem Cells Authors: Heger P, Wiehe T Tags: Trends Genet Source Type: research
Mechanisms of epigenetic memory.
Abstract Although genetics has an essential role in defining the development, morphology, and physiology of an organism, epigenetic mechanisms have an essential role in modulating these properties by regulating gene expression. During development, epigenetic mechanisms establish stable gene expression patterns to ensure proper differentiation. Such mechanisms also allow organisms to adapt to environmental changes and previous experiences can impact the future responsiveness of an organism to a stimulus over long timescales and even over generations. Here, we discuss the concept of epigenetic memory, defined as the...
Source: Trends in Genetics : TIG - April 26, 2014 Category: Genetics & Stem Cells Authors: D'Urso A, Brickner JH Tags: Trends Genet Source Type: research
Evolutionary constraints in variable environments, from proteins to networks.
Abstract Environmental changes can not only trigger a regulatory response, but also impose evolutionary pressures that can modify the underlying regulatory network. Here, we review recent approaches that are beginning to disentangle this complex interplay between regulatory and evolutionary responses. Systematic genetic reconstructions have shown how evolutionary constraints arise from epistatic interactions between mutations in fixed environments. This approach is now being extended to more complex environments and systems. The first results suggest that epistasis is affected dramatically by environmental changes...
Source: Trends in Genetics : TIG - April 26, 2014 Category: Genetics & Stem Cells Authors: Taute KM, Gude S, Nghe P, Tans SJ Tags: Trends Genet Source Type: research
Gene regulation by structured mRNA elements.
Abstract The precise temporal and spatial coordination of gene activity, based on the integration of internal and external signals, is crucial for the accurate functioning of all biological processes. Although the basic principles of gene expression were established some 60 years ago, recent research has revealed a surprising complexity in the control of gene activity. Many of these gene regulatory mechanisms occur at the level of the mRNA, including sophisticated gene control tasks mediated by structured mRNA elements. We now know that mRNA folds can serve as highly specific receptors for various types of molecul...
Source: Trends in Genetics : TIG - April 26, 2014 Category: Genetics & Stem Cells Authors: Wachter A Tags: Trends Genet Source Type: research
Transcription factors: specific DNA binding and specific gene regulation.
Abstract Specific recognition of cis-regulatory regions is essential for correct gene regulation in response to developmental and environmental signals. Such DNA sequences are recognized by transcription factors (TFs) that recruit the transcriptional machinery. Achievement of specific sequence recognition is not a trivial problem; many TFs recognize similar consensus DNA-binding sites and a genome can harbor thousands of consensus or near-consensus sequences, both functional and nonfunctional. Although genomic technologies have provided large-scale snapshots of TF binding, a full understanding of the mechanistic a...
Source: Trends in Genetics : TIG - April 25, 2014 Category: Genetics & Stem Cells Authors: Todeschini AL, Georges A, Veitia RA Tags: Trends Genet Source Type: research
Random monoallelic expression: regulating gene expression one allele at a time.
Abstract Monoallelic gene expression is a remarkable process in which transcription occurs from only one of two homologous alleles in a diploid cell. Interestingly, between 0.5% and 15% of autosomal genes exhibit random monoallelic gene expression, in which different cells express only one allele independently of the underlying genomic sequence, in a cell type-specific manner. Recently, genome-wide studies have increased our understanding of the cell type-specific incidence of random monoallelic gene expression, and how the imbalance in allelic expression is distinguished within the cell and potentially maintained...
Source: Trends in Genetics : TIG - April 25, 2014 Category: Genetics & Stem Cells Authors: Eckersley-Maslin MA, Spector DL Tags: Trends Genet Source Type: research
Histone variants at the transcription start-site.
Abstract The function of a eukaryotic cell crucially depends on accurate gene transcription to ensure the right genes are expressed whereas unrequired genes are repressed. Therefore, arguably, one of the most important regions in the genome is the transcription start-site (TSS) of protein-coding and non-coding genes. Until recently, understanding the mechanisms that define the location of the TSS and how it is created has largely focused on the role of DNA sequence-specific transcription factors. However, within the nucleus of a eukaryotic cell, transcription occurs in a highly compacted nucleosomal environment, a...
Source: Trends in Genetics : TIG - April 22, 2014 Category: Genetics & Stem Cells Authors: Soboleva TA, Nekrasov M, Ryan DP, Tremethick DJ Tags: Trends Genet Source Type: research
Laying a solid foundation for Manhattan - 'setting the functional basis for the post-GWAS era'
Abstract Genome-wide association studies (GWAS) have identified more than 8900 genetic variants, mainly single-nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translation rate, and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of ...
Source: Trends in Genetics : TIG - March 21, 2014 Category: Genetics & Stem Cells Authors: Zhang X, Bailey SD, Lupien M Tags: Trends Genet Source Type: research
Comparative population genomics: power and principles for the inference of functionality.
Abstract The availability of sequenced genomes from multiple related organisms allows the detection and localization of functional genomic elements based on the idea that such elements evolve more slowly than neutral sequences. Although such comparative genomics methods have proven useful in discovering functional elements and ascertaining levels of functional constraint in the genome as a whole, here we outline limitations intrinsic to this approach that cannot be overcome by sequencing more species. We argue that it is essential to supplement comparative genomics with ultra-deep sampling of populations from clos...
Source: Trends in Genetics : TIG - March 20, 2014 Category: Genetics & Stem Cells Authors: Lawrie DS, Petrov DA Tags: Trends Genet Source Type: research
Catch and release: how do kinetochores hook the right microtubules during mitosis?
Abstract Sport fishermen keep tension on their lines to prevent hooked fish from releasing. A molecular version of this angler's trick, operating at kinetochores, ensures accuracy during mitosis: the mitotic spindle attaches randomly to chromosomes and then correctly bioriented attachments are stabilized due to the tension exerted on them by opposing microtubules. Incorrect attachments, which lack tension, are unstable and release quickly, allowing another chance for biorientation. Stabilization of molecular interactions by tension also occurs in other physiological contexts, such as cell adhesion, motility, hemos...
Source: Trends in Genetics : TIG - March 13, 2014 Category: Genetics & Stem Cells Authors: Sarangapani KK, Asbury CL Tags: Trends Genet Source Type: research
Modeling genomic regulatory networks with big data.
Abstract High-throughput sequencing, large-scale data generation projects, and web-based cloud computing are changing how computational biology is performed, who performs it, and what biological insights it can deliver. I review here the latest developments in available data, methods, and software, focusing on the modeling and analysis of the gene regulatory interactions in cells. Three key findings are: (i) although sophisticated computational resources are increasingly available to bench biologists, tailored ongoing education is necessary to avoid the erroneous use of these resources. (ii) Current models of the ...
Source: Trends in Genetics : TIG - March 12, 2014 Category: Genetics & Stem Cells Authors: Bolouri H Tags: Trends Genet Source Type: research
Explaining additional genetic variation in complex traits.
Abstract Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits, discovering>6000 variants associated with>500 quantitative traits and common complex diseases in humans. The associations identified so far represent only a fraction of those that influence phenotype, because there are likely to be many variants across the entire frequency spectrum, each of which influences multiple traits, with only a small average contribution to the phenotypic variance. This presents a considerable challenge to further dissection of the remaining unexplained genetic va...
Source: Trends in Genetics : TIG - March 11, 2014 Category: Genetics & Stem Cells Authors: Robinson MR, Wray NR, Visscher PM Tags: Trends Genet Source Type: research
The four dimensions of noncoding RNA conservation.
Abstract Evolutionary conservation is widely used as an indicator of the functional significance of newly discovered genes. Although the simple search for homology at the nucleotide or amino acid sequence level has proven to be valuable for protein-coding genes, these criteria are too narrow to describe fully the selection process for long noncoding RNAs (lncRNAs). LncRNA conservation includes four dimensions: the sequence, structure, function, and expression from syntenic loci. Two recently described knockout mouse models for the lincRNAs metastasis associated lung adenocarcinoma transcript 1 (Malat1) and HOX ant...
Source: Trends in Genetics : TIG - March 6, 2014 Category: Genetics & Stem Cells Authors: Diederichs S Tags: Trends Genet Source Type: research
HP1a: a structural chromosomal protein regulating transcription.
Abstract Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as 'hub proteins,' able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and ...
Source: Trends in Genetics : TIG - February 17, 2014 Category: Genetics & Stem Cells Authors: Eissenberg JC, Elgin SC Tags: Trends Genet Source Type: research
CRISPR-based technologies: prokaryotic defense weapons repurposed.
Abstract To combat potentially deadly viral infections, prokaryotic microbes enlist small RNA-based adaptive immune systems (CRISPR-Cas systems) that protect through sequence-specific recognition and targeted destruction of viral nucleic acids (either DNA or RNA depending on the system). Here, we summarize rapid progress made in redirecting the nuclease activities of these microbial immune systems to bind and cleave DNA or RNA targets of choice, by reprogramming the small guide RNAs of the various CRISPR-Cas complexes. These studies have demonstrated the potential of Type II CRISPR-Cas systems both as efficient an...
Source: Trends in Genetics : TIG - February 17, 2014 Category: Genetics & Stem Cells Authors: Terns RM, Terns MP Tags: Trends Genet Source Type: research
The role of microhomology in genomic structural variation.
Abstract Genomic structural variation, which can be defined as differences in the copy number, orientation, or location of relatively large DNA segments, is not only crucial in evolution, but also gives rise to genomic disorders. Whereas the major mechanisms that generate structural variation have been well characterised, insights into additional mechanisms are emerging from the identification of short regions of DNA sequence homology, also known as microhomology, at chromosomal breakpoints. In addition, functional studies are elucidating the characteristics of microhomology-mediated pathways, which are mutagenic....
Source: Trends in Genetics : TIG - February 3, 2014 Category: Genetics & Stem Cells Authors: Ottaviani D, Lecain M, Sheer D Tags: Trends Genet Source Type: research
Systemic DNA damage responses: organismal adaptations to genome instability.
Abstract DNA damage checkpoints are important tumor-suppressor mechanisms that halt cell cycle progression to allow time for DNA repair, or induce senescence and apoptosis to remove damaged cells permanently. Non-cell-autonomous DNA damage responses activate the innate immune system in multiple metazoan species. These responses not only enable clearance of damaged cells and contribute to tissue remodeling and regeneration but can also result in chronic inflammation and tissue damage. Germline DNA damage-induced systemic stress resistance (GDISR) is mediated by an ancestral innate immune response and results in org...
Source: Trends in Genetics : TIG - January 15, 2014 Category: Genetics & Stem Cells Authors: Ermolaeva MA, Schumacher B Tags: Trends Genet Source Type: research
Mining cancer methylomes: prospects and challenges.
Abstract There are over 28 million CpG sites in the human genome. Assessing the methylation status of each of these sites will be required to understand fully the role of DNA methylation in health and disease. Genome-wide analysis, using arrays and high-throughput sequencing, has enabled assessment of large fractions of the methylome, but each protocol comes with unique advantages and disadvantages. Notably, except for whole-genome bisulfite sequencing, most commonly used genome-wide methods detect
Source: Trends in Genetics : TIG - December 21, 2013 Category: Genetics & Stem Cells Authors: Stirzaker C, Taberlay PC, Statham AL, Clark SJ Tags: Trends Genet Source Type: research
Neocentromeres: a place for everything and everything in its place.
Abstract Centromeres are essential for chromosome inheritance and genome stability. Centromeric proteins, including the centromeric histone centromere protein A (CENP-A), define the site of centromeric chromatin and kinetochore assembly. In many organisms, centromeres are located in or near regions of repetitive DNA. However, some atypical centromeres spontaneously form on unique sequences. These neocentromeres, or new centromeres, were first identified in humans, but have since been described in other organisms. Neocentromeres are functionally and structurally similar to endogenous centromeres, but lack the added...
Source: Trends in Genetics : TIG - December 13, 2013 Category: Genetics & Stem Cells Authors: Scott KC, Sullivan BA Tags: Trends Genet Source Type: research
'Particle genetics': treating every cell as unique.
Abstract Genotype-phenotype relations are usually inferred from a deterministic point of view. For example, quantitative trait loci (QTL), which describe regions of the genome associated with a particular phenotype, are based on a mean trait difference between genotype categories. However, living systems comprise huge numbers of cells (the 'particles' of biology). Each cell can exhibit substantial phenotypic individuality, which can have dramatic consequences at the organismal level. Now, with technology capable of interrogating individual cells, it is time to consider how genotypes shape the probability laws of s...
Source: Trends in Genetics : TIG - December 5, 2013 Category: Genetics & Stem Cells Authors: Yvert G Tags: Trends Genet Source Type: research