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1.  Properties and rates of germline mutations in humans 
Trends in genetics : TIG  2013;29(10):575-584.
All genetic variation arises via new mutations, and therefore determining the rate and biases for different classes of mutation is essential for understanding the genetics of human disease and evolution. Decades of mutation rate analyses have focused on a relatively small number of loci because of technical limitations. However, advances in sequencing technology have allowed for empirical assessments of genome-wide rates of mutation. Recent studies have shown that 76% of new mutations originate in the paternal lineage and provide unequivocal evidence for an increase in mutation with paternal age. Although most analyses have been focused on single nucleotide variants (SNVs), studies have begun to provide insight into the mutation rate for other classes of variation, including copy number variants (CNVs), microsatellites, and mobile element insertions. Here, we review the genome-wide analyses for the mutation rate of several types of variants and suggest areas for future research.
PMCID: PMC3785239  PMID: 23684843
germline mutation rate; de novo mutation; paternal bias; paternal age; genome-wide
2.  Ordering gene function: the interpretation of epistasis in regulatory hierarchies 
Trends in genetics : TIG  1992;8(9):312-316.
The order of action of genes in a regulatory hierarchy that is governed by a signal can often be determined by the method of epistasis analysis, in which the phenotype of a double mutant is compared with that of single mutants. The epistatic mutation may be in either the upstream or the downstream gene, depending on the nature of the two mutations and the type of regulation. Nevertheless, when the regulatory hierarchy satisfies certain conditions, simple rules allow the position of the epistatic locus in the pathway to be determined without detailed knowledge of the nature of the mutations, the pathway, or the molecular mechanism of regulation.
PMCID: PMC3955268  PMID: 1365397
3.  What can microbial genetics teach sociobiology? 
Trends in genetics : TIG  2007;23(2):74-80.
Progress in our understanding of sociobiology has occurred with little knowledge of the genetic mechanisms that underlie social traits. However, several recent studies have described microbial genes that affect social traits, thereby bringing genetics to sociobiology. A key finding is that simple genetic changes can have marked social consequences, and mutations that affect cheating and recognition behaviors have been discovered. The study of these mutants confirms a central theoretical prediction of social evolution: that genetic relatedness promotes cooperation. Microbial genetics also provides an important new perspective: that the genome-to-phenome mapping of social organisms might be organized to constrain the evolution of social cheaters. This constraint can occur both through pleiotropic genes that link cheating to a personal cost and through the existence of phoenix genes, which rescue cooperative systems from selfish and destructive strategies. These new insights show the power of studying microorganisms to improve our understanding of the evolution of cooperation.
PMCID: PMC3942651  PMID: 17207887
4.  Amish Revisited: Next Generation Sequencing Studies of Psychiatric Disorders Among the Plain People 
Trends in genetics : TIG  2013;29(7):412-418.
The rapid development of next-generation sequencing (NGS) technology has led to renewed interest in the potential contribution of rarer forms of genetic variation to complex, non-Mendelian phenotypes, such as psychiatric illnesses. Although challenging, family-based studies offer some advantages, especially in communities with large families and a limited number of founders. Here we revisit family-based studies of mental illnesses in traditional Amish and Mennonite communities -- known collectively as the Plain people. We discuss the new opportunities for NGS in these populations, with a particular emphasis on investigating psychiatric disorders. We also address some of the challenges facing NGS-based studies of complex phenotypes in founder populations.
PMCID: PMC3941079  PMID: 23422049
bipolar disorder; identity by descent; homozygosity; Mennonite; Anabaptist
5.  The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis 
Trends in genetics : TIG  2012;29(3):160-169.
Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.
PMCID: PMC3594559  PMID: 23245857
drug resistance; persistence; hypermutation; compensatory mutations; epistasis
6.  Bridging the transgenerational gap with epigenetic memory 
Trends in genetics : TIG  2013;29(3):176-186.
It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are reset between generations. Recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes may result in persistent phenotypes across generations. Here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from C. elegans to humans, and describe approaches and limitations to studying this phenomenon. We also review the current body of evidence implicating chromatin modifications and RNA molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications.
PMCID: PMC3595609  PMID: 23410786
Transgenerational; epigenetic inheritance; chromatin; non-coding RNA; aging; fertility; metabolism; stress stimuli
7.  Horizontal Gene Transfer and the Evolution of Bacterial and Archaeal Population Structure 
Trends in genetics : TIG  2013;29(3):170-175.
Many bacterial and archaeal lineages have a history of extensive and ongoing horizontal gene transfer and loss, as evidenced by the large differences in genome content even among otherwise closely related isolates. How ecologically cohesive populations might evolve and be maintained under such conditions of rapid gene turnover has remained controversial. Here we synthesize recent literature demonstrating the importance of habitat and niche in structuring horizontal gene transfer. This leads to a model of ecological speciation via gradual genetic isolation triggered by differential habitat association of nascent populations. Further, we hypothesize that subpopulations can evolve through local gene exchange networks by tapping into a gene pool that is adaptive towards local, continuously changing organismic interactions and is, to a large degree, responsible for the observed rapid gene turnover. Overall, these insights help explain how bacteria and archaea form populations that display both ecological cohesion and high genomic diversity.
PMCID: PMC3760709  PMID: 23332119
ecological speciation; frequency dependent selection; environmental niche; genotypic clusters
8.  Finding the lost treasures in exome sequencing data 
Trends in genetics : TIG  2013;29(10):593-599.
Exome sequencing is one of the most cost-efficient sequencing approaches for conducting genome research on coding regions. However, significant portions of the reads obtained in exome sequencing come from outside of the designed target regions. These additional reads are generally ignored, potentially wasting an important source of genomic data. There are three major types of unintentionally sequenced read that can be found in exome sequencing data: reads in introns and intergenic regions, reads in the mitochondrial genome, and reads originating in viral genomes. All of these can be used for reliable data mining, extending the utility of exome sequencing. Large-scale exome sequencing data repositories, such as The Cancer Genome Atlas (TCGA), the 1000 Genomes Project, National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project, and The Sequence Reads Archive, provide researchers with excellent secondary data-mining opportunities to study genomic data beyond the intended target regions.
PMCID: PMC3926691  PMID: 23972387
mitochondria; exome capture; virus; virus integration; mtDNA copy number; unmapped read
9.  The many faces of pleiotropy 
Trends in genetics : TIG  2012;29(2):66-73.
Pleiotropy is the well-established phenomenon of a single gene affecting multiple traits. It has long played a central role in theoretical, experimental, and clinical research in genetics, development, molecular biology, evolution, and medicine. In recent years, genomic techniques have brought data to bear on fundamental questions about the nature and extent of pleiotropy. However, these efforts are plagued by conceptual difficulties derived from disparate meanings and interpretations of pleiotropy. Here, we describe distinct uses of the pleiotropy concept and explain the pitfalls associated with applying empirical data to them. We conclude that for any question about the nature or extent of pleiotropy, the appropriate answer is always, “What do you mean?”
PMCID: PMC3558540  PMID: 23140989
pleiotropy; universal pleiotropy; phenotype; fitness
10.  Reversible RNA adenosine methylation in biological regulation 
Trends in genetics : TIG  2012;29(2):108-115.
N6-methyladenosine (m6A) is a ubiquitous modification in messenger RNA (mRNA) and other RNAs across most eukaryotes. For many years, however, the exact functions of m6A were not clearly understood. The discovery that the fat mass and obesity associated protein (FTO) is an m6A demethylase indicates that this modification is reversible and dynamically regulated, suggesting it has regulatory roles. In addition, it has been shown that m6A affects cell fate decisions in yeast and plant development. Recent affinity-based m6A profiling in mouse and human cells further showed that this modification is a widespread mark in coding and non-coding RNA transcripts and is likely dynamically regulated throughout developmental processes. Therefore, reversible RNA methylation, analogous to reversible DNA and histone modifications, may affect gene expression and cell fate decisions by modulating multiple RNA-related cellular pathways, which potentially provides rapid responses to various cellular and environmental signals, including energy and nutrient availability in mammals.
PMCID: PMC3558665  PMID: 23218460
11.  Telomerase at the intersection of cancer and aging 
Trends in genetics : TIG  2013;29(9):513-520.
Although cancer and aging have been studied as independent diseases, mounting evidence suggest that cancer is an aging-associated disease and that cancer and aging share many molecular pathways. In particular, recent studies validated telomerase activation as a potential therapeutic target for age-related diseases, and at the same time, abnormal telomerase expression and telomerase mutations have been associated with many different types of human tumors. Here, we revisit the connection of telomerase to cancer and aging in light of recent findings supporting a role for telomerase not only in telomere elongation, but also in metabolic fitness and Wnt activation. Understanding the physiological impact of telomerase regulation is fundamental considering the therapeutic strategies that are being developed involving telomerase modulation.
PMCID: PMC3896987  PMID: 23876621
Telomerase; aging; cancer
12.  Biodiversity and Functional Genomics in the Human Microbiome 
Trends in genetics : TIG  2012;29(1):51-58.
Over the course of our lives, humans are colonized by a tremendous diversity of commensal microbes, which comprise the human microbiome. The collective genetic potential (metagenome) of the human microbiome is orders of magnitude more than the human genome, and it profoundly affects human health and disease in ways we are only beginning to understand. Advances in computing and high-throughput sequencing have enabled population-level surveys such as MetaHIT and the recently-released Human Microbiome Project, detailed investigations of the microbiome in human disease, and mechanistic studies employing gnotobiotic model organisms. The resulting knowledge of human microbiome composition, function, and range of variation across multiple body sites has begun to assemble a rich picture of commensal host-microbe and microbe- microbe interactions as well as their roles in human health and disease and their potential as diagnostic and therapeutic tools.
PMCID: PMC3534939  PMID: 23140990
Human Microbiome Project; microbiota; metagenomics
13.  ‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes 
Trends in genetics : TIG  2012;28(12):583-585.
PMCID: PMC3523709  PMID: 23131467
DNA methylation; bisulfite sequencing; methylation level; epigenomics
14.  The resurgence and genetic implications of New World primates in biomedical research 
Trends in genetics : TIG  2012;28(12):586-591.
There has been a recent resurgence of interest in New World monkeys within the biomedical research community, driven both by the sequencing of the common marmoset (Callithrix jacchus) genome as well as a growing demand for alternatives to Old World primates. New World monkeys offer attractive advantages over Old World species including cheaper and simpler husbandry while still maintaining a greater evolutionary proximity to humans than other animal models. Although numerous commonalities across primate species exist, there are also important genetic and reproductive differences that can and should play a critical role in selecting appropriate animal models. Common marmosets in particular have significantly reduced diversity at the major histocompatibility complex loci and are born as hematopoietic chimeras. New World primates can make ideal translational models for research, but scientists must necessarily incorporate complete understandings of their genetic and phenotypic differences from humans and other model organisms.
PMCID: PMC3500444  PMID: 23099234
Platyrrhines; Callitrichidae; Callithrix jacchus; Saimiri sp; Saguinus oedipus; Animal Models
15.  Genetic Insights on Sleep Schedules: This Time, It’s PERsonal 
Trends in genetics : TIG  2012;28(12):598-605.
The study of circadian rhythms is emerging as a fruitful opportunity for understanding cellular mechanisms that govern human physiology and behavior, as fueled by evidence directly linking sleep disorders and genetic mutations affecting circadian molecular pathways. Familial Advanced Sleep Phase Disorder (FASPD) is the first recognized Mendelian circadian rhythm trait, and affected individuals exhibit exceptionally early sleep-wake onset due to altered post-translational regulation of period homolog 2 (PER2). Behavioral and cellular circadian rhythms are analogously affected, as the circadian period length of behavior is reduced in the absence of environmental time cues, and cycle duration of the molecular clock is likewise shortened. In light of these findings, we review the PER2 dynamics in the context of circadian regulation to reveal the mechanism of sleep schedule modulation. Understanding PER2 regulation and functionality may shed new light on how our genetic composition can influence our sleep-wake behaviors.
PMCID: PMC3500418  PMID: 22939700
circadian rhythm; post-translational regulation; familial advanced sleep phase disorder; phosphorylation; period homolog 2; casein kinase 1 delta
16.  RECQL4 in genomic instability and aging 
Trends in genetics : TIG  2012;28(12):624-631.
Helicases are ubiquitous proteins that unwind DNA and participate in DNA metabolism including replication, repair, transcription, and chromatin organization. The highly conserved RecQ helicase family proteins are important in these transactions and have been termed the guardians of the genome. Humans have five members of this family: WRN, BLM, RECQL4, RECQL1, and RECQL5. The first three of these members are associated with premature aging and cancer prone syndromes, but the latter two proteins have not yet been implicated in any human disease. Although WRN and BLM have been fairly well characterized, RECQL4 has only recently been intensively investigated. The sum of this work to date has shown that RECQL4 has helicase activity and localizes to telomeres and mitochondria. In addition, new protein partners are emerging, implicating RECQL4 in novel processes. Here, we describe these recent findings, which place RECQL4 at the crossroads of genomic instability and aging processes.
PMCID: PMC3500627  PMID: 22940096
RecQ helicase; cancer; aging; Rothmund-Thomson syndrome
17.  Cancer heterogeneity: origins and implications for genetic association studies 
Trends in genetics : TIG  2012;28(11):538-543.
Genetic association studies have become standard approaches to characterize the genetic and epigenetic variability associated with cancer development, including predispositions and mutations. However, the bewildering genetic and phenotypic heterogeneity inherent in cancer both magnifies the conceptual and methodological problems associated with these approaches and renders the translation of available genetic information into a knowledge that is both biologically sound and clinically relevant difficult. Here, we elaborate on the underlying causes of this complexity, illustrate why it represents a challenge for genetic association studies, and briefly discuss how it can be reconciled with the ultimate goal of identifying targetable disease pathways and successfully treating individual patients.
PMCID: PMC3477266  PMID: 22858414
cancer heterogeneity; genetic predispositions; somatic mutations; genetic association studies
18.  Epigenetic factors influencing resistance to nuclear reprogramming 
Trends in genetics : TIG  2011;27(12):10.1016/j.tig.2011.08.002.
Patient-specific somatic cell reprogramming is likely to have a large impact on medicine by providing a source of cells for disease modelling and regenerative medicine. Several strategies can be used to reprogram cells yet they are generally characterised by a low reprogramming efficiency, reflecting the remarkable stability of the differentiated state. Transcription factors, chromatin modifications, and non-coding RNAs can increase the efficiency of reprogramming. However, the success of nuclear reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient reprogramming. We review here the factors that influence reprogramming efficiency, and especially those that restrict the natural reprogramming mechanisms of eggs and oocytes. We see this as a step towards understanding the mechanisms by which nuclear reprogramming takes place.
PMCID: PMC3814186  PMID: 21940062
efficiency of nuclear reprogramming; resistance to nuclear reprogramming; epigenetic reprogramming; nuclear transfer; cell fusion; induced pluripotency
19.  Host genes associated with HIV/AIDS: advances in gene discovery 
Trends in genetics : TIG  2010;26(3):119-131.
Twenty five years after the discovery of HIV as the cause of AIDS, there is still no effective vaccine and no cure for this disease. HIV susceptibility shows a substantial degree of individual heterogeneity, much of which can be conferred by host genetic variation. In an effort to discover host factors required for HIV replication, identify critical pathogenic pathways, and reveal the full armament of host defenses, there has been a shift from candidate gene studies to unbiased genome wide genetic and functional studies. However, the number of securely identified host factors involved in HIV disease remains small, explaining only ~15–20% of the observed heterogeneity – most of which is attributable to HLA. Multidisciplinary approaches integrating genetic epidemiology to systems biology will be required to fully understand viral-host interactions to effectively combat HIV/AIDS.
PMCID: PMC3792714  PMID: 20149939
20.  Relating Human Genetic Variation to Variation in Drug Responses 
Trends in genetics : TIG  2012;28(10):487-495.
Although sequencing a single human genome was a monumental effort a decade ago, more than one thousand genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology with the ultimate goal of developing more effective personalized clinical treatment strategies.
PMCID: PMC3448823  PMID: 22840197
Pharmacogenomics; genome-wide association studies; next-generation sequencing; 1000 genome project; personalized medicine
21.  Regulation of Chromatin Structure by Long Noncoding RNAs: Focus on Natural Antisense Transcripts 
Trends in genetics : TIG  2012;28(8):389-396.
PMCID: PMC3768148  PMID: 22541732
Antisense RNA; epigenetics; transcriptome; chromatin; ncRNAs; NATs
22.  Epigenetics of major psychosis: progress, problems, and perspectives 
Trends in genetics : TIG  2012;28(9):427-435.
Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals affected with schizophrenia and bipolar disorder. We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.
PMCID: PMC3422438  PMID: 22622229
Epigenetics; DNA methylation; histone modifications; schizophrenia; bipolar disorder; epigenome-wide association study
23.  Nuclear Lamin Functions and Disease 
Trends in genetics : TIG  2012;28(9):464-471.
PMCID: PMC3633455  PMID: 22795640
lamins; progerin; laminopathies; HGPS
24.  Functional modules, mutational load and human genetic disease 
Trends in genetics : TIG  2010;26(4):168-176.
The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically-relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals.
PMCID: PMC3740181  PMID: 20226561
25.  Oxytricha as a modern analog of ancient genome evolution 
Trends in Genetics  2012;28(8):382-388.
Several independent lines of evidence suggest that the modern genetic system was preceded by the ‘RNA world’ in which RNA genes encoded RNA catalysts. Current gaps in our conceptual framework of early genetic systems make it difficult to imagine how a stable RNA genome may have functioned and how the transition to a DNA genome could have taken place. Here we use the single-celled ciliate, Oxytricha, as an analog to some of the genetic and genomic traits that may have been present in organisms before and during the establishment of a DNA genome. Oxytricha and its close relatives have a unique genome architecture involving two differentiated nuclei, one of which encodes the genome on small, linear nanochromosomes. While its unique genomic characteristics are relatively modern, some physiological processes related to the genomes and nuclei of Oxytricha may exemplify primitive states of the developing genetic system.
PMCID: PMC3401270  PMID: 22622227

Results 1-25 (131)