Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain‐of‐function mutations, in general, has been productive. However, (...) it has been a major challenge to use standard pharmacologic approaches to target loss‐of‐function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. (shrink)

One of the unique insights provided by the growing number of fully sequenced genomes is the pervasiveness of gene duplication and gene loss. Indeed, several metrics now suggest that rates of gene birth and death per gene are only 10–40% lower than nucleotide substitutions per site, and that per nucleotide, the consequent lineage‐specific expansion and contraction of gene families may play at least as large a role in adaptation as changes in orthologous sequences. While (...) gene family evolution is pervasive, it may be especially important in our own evolution since it appears that the “revolving door” of gene duplication and loss has undergone multiple accelerations in the lineage leading to humans. In this paper, we review current understanding of gene family evolution including: methods for inferring copy number change, evidence for adaptive expansion and adaptive contraction of gene families, the origins of new families and deaths of previously established ones, and finally we conclude with a perspective on challenges and promising directions for future research. (shrink)

After gene duplication, mutations cause the gene copies to diverge. The classical model predicts that these mutations will generally lead to the loss of function of one gene copy; rarely, new functions will be created and both duplicate genes are conserved. In contrast, under the subfunctionalization model both duplicates are preserved due to the partition of different functions between the duplicates. A recent study(1) provides support for the subfunctionalization model, identifying several expressed gene duplicates (...) common to humans and mice that contain regions conserved in one duplicate but variable in the other (and vice versa). We discuss both the methodology used in this study and also how gene phylogeny may lead to additional evidence for the importance of subfunctionalization in the evolution of new genes. BioEssays 23:873–876, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In the context of macroevolutionary transitions, environmental changes prompted vertebrates already bearing genetic variations to undergo gradual adaptations resulting in profound anatomical, physiological, and behavioral adaptations. The emergence of new genes led to the genetic variation essential in metazoan evolution, just as was gene loss, both sources of genetic variation resulting in adaptive phenotypic diversity. In this context, F12‐coding protein with defense and hemostatic roles emerged some 425 Mya, and it might have contributed in aquatic vertebrates to the (...) transition from water‐to‐land. Conversely, the F12 loss in marine, air‐breathing mammals like cetaceans has been associated with phenotypic adaptations in some terrestrial mammals in their transition to aquatic lifestyle. More recently, the advent of technological innovations in western lifestyle with blood‐contacting devices and harmful environmental nanoparticles, has unfolded new roles of FXII. Environment operates as either a positive or a relaxed selective pressure on genes, and consequently genes are selected or lost. FXII, an old dog facing environmental novelties can learn new tricks and teach us new therapeutic avenues. (shrink)

DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de‐repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up‐regulation of germline (...) genes and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de‐repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development. (shrink)

Congenital deafness is one of the most common birth defects reported. Approximately 70% of congenital deafness is non-syndromic, and approximately 80% of non-syndromic hearing loss results from a genetic cause. Middleton et al.’s1998 study highlighted the negative attitudes of culturally Deaf individuals towards genetic testing for genes known to cause hearing loss. While studies concerning genetic testing for deafness genes reference Middleton’s study, to our knowledge a re-evaluation of the attitudes of Deaf individuals towards genetic testing has not (...) been conducted recently. The purpose of this study is to re-establish attitudes of Deaf individuals towards genetic testing of genes known to cause hearing loss. A computer-based questionnaire was distributed to members of the Deaf community. Responses of participants were recorded and analyzed. The primary investigator then attended Deaf community events and the 2015 Alabama Association of the Deaf Conference, and recruited individuals interested in participating in the study. The surveys were distributed to these individuals and their anonymous responses were analyzed. Our results show there are more positive attitudes within the Deaf community towards genetic counseling, genetic testing, and prenatal testing of genes known to cause hearing loss than were previously documented, although negative attitudes are still present. Additionally, our study shows there is a desire among members of the Deaf community to learn more about and potentially receive these services, despite the fact they are rarely offered by healthcare providers. (shrink)

A gene is considered essential when its loss of function results in a deleterious phenotype, hugely reducing the organism's viability or fitness. However, the link between the essentiality of a gene and its degree of polymorphism is unclear. In this review, we show that there is a place for a certain degree of variability, even for essential genes. We first study the role of infectious diseases in the prevalence of genetic disorders among humans: balancing selection has selected (...) harmful variants due to the selective pressure of pathogens because the heterozygous carrier can resist them. Then we show that the environment can induce adaptation of species by rapidly evolving genes. We also study the role of positive selection on speciation, particularly upon genes of the immune, reproductive and nervous systems. Finally, we highlight the role of regulatory sequences in changes in morphology between species and adaptation to the environment within species. (shrink)

The significance of horizontal gene transfer (HGT) in eukaryotic evolution remains controversial. Although many eukaryotic genes are of bacterial origin, they are often interpreted as being derived from mitochondria or plastids. Because of their fixed gene pool and gene loss, however, mitochondria and plastids alone cannot adequately explain the presence of all, or even the majority, of bacterial genes in eukaryotes. Available data indicate that no insurmountable barrier to HGT exists, even in complex multicellular eukaryotes. In (...) addition, the discovery of both recent and ancient HGT events in all major eukaryotic groups suggests that HGT has been a regular occurrence throughout the history of eukaryotic evolution. A model of HGT is proposed that suggests both unicellular and early developmental stages as likely entry points for foreign genes into multicellular eukaryotes. (shrink)

The use of socially learned information (culture) is central to human adaptations. We investigate the hypothesis that the process of cultural evolution has played an active, leading role in the evolution of genes. Culture normally evolves more rapidly than genes, creating novel environments that expose genes to new selective pressures. Many human genes that have been shown to be under recent or current selection are changing as a result of new environments created by cultural innovations. Some changed in response to (...) the development of agricultural subsistence systems in the Early and Middle Holocene. Alleles coding for adaptations to diets rich in plant starch (e.g., amylase copy number) and to epidemic diseases evolved as human populations expanded (e.g., sickle cell and G6PD defi- ciency alleles that provide protection against malaria). Large-scale scans using patterns of linkage disequilibrium to detect recent selection suggest that many more genes evolved in response to agriculture. Genetic change in response to the novel social environment of contemporary modern societies is also likely to be occurring. The functional effects of most of the alleles under selection during the last 10,000 years are currently unknown. Also unknown is the role of paleoenvironmental change in regulating the tempo of hominin evolution. Although the full extent of culture-driven gene-culture coevolution is thus far unknown for the deeper history of the human lineage, theory and some evidence suggest that such effects were profound. Genomic methods promise to have a major impact on our understanding of gene-culture coevolution over the span of hominin evolutionary history. (shrink)

The concept of the gene has been the central organizing theme of 20th century biology. Biology has become increasingly influential both for philosophers seeking a naturalized basis for epistemology, ethics, and the understanding of the mind, as well as for the human sciences generally. The central task of this work is to get the story right about genes and in so doing provide a critical and enabling resourse for use in the further pursuit of human self-understanding. ;The work begins (...) with a wide-ranging historical reconstruction and conceptual analysis of the meaning of "the gene" that results in defining and distinguishing two different "genes". Each of these can be seen as an heir to one of the two major historical trends in explaining the source of biological order---preformationism and epigenesis. The preformationist gene predicts phenotypes but only on an instrumental basis where immediate medical and/or economic benefits can be had. The gene of epigenesis , by contrast, is a developmental resource that provides templates for RNA and protein synthesis but has in itself no determinate relationship to organismal phenotypes. The seemingly prevalent idea that genes constitute information for traits is based, I argue, upon an unwarranted conflation of these two senses which is in effect held together by rhetorical glue. Beyond this historical, conceptual, and rhetorical inquiry the bulk of the dissertation then concerns itself with an empirically up-to-date analysis of the cell and molecular basis of biological order and of the pathological loss of same. In each of these chapters I structure my analysis with the idea in mind that the "conflated" view can be held empirically accountable. Major touchpoints in this work include the ideas of I. Kant, J. Blumenbach, K. E. von Baer, J. Muller, R. Virchow, W. Johannsen, R. Falk, J. Sapp, E. Schrodinger, M. Delbruick, G. Gamow, R. Doyle, L. Kay, S. Kauffman, E. Jablonka, J. Rothman, K. Yamamoto, P. Rous, H. Temin, J. M. Bishop, H. Harris, E. Stanbridge, D. L. Smithers, B. Vogelstein, E. Farber and H. Rubin. (shrink)

DNA copy number variation (CNV) represents a considerable source of human genetic diversity. Recently,1 a global map of copy number variation in the human genome has been drawn up which reveals not only the ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than 20 Mb and it is likely that the full extent of CNV still remains to be discovered. Nearly 3000 genes are associated with CNV. This high (...) degree of variability with regard to gene copy number between two individuals challenges definitions of normality. Many CNVs are located in regions of complex genomic structure and this currently limits the extent to which these variants can be genotyped by using tagging SNPs. However, some CNVs are already amenable to genome‐wide association studies so that their influence on human phenotypic diversity and disease susceptibility may soon be determined. BioEssays 29:311–313, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Recent applications of Freud's theory examine the social value of the lost love object as a way of understanding the suffering of non-majority groups. Rather than pathologizing the individual suffering the loss, the lens of racial melancholia pathologizes the discourse that constitutes racially marked others as alien to the majority. Through a close reading of image and text, Sophia Tatiana Sarigianides applies David Eng and Shinhee Han's theory of racial melancholia to Gene Luen Yang's graphic novel American Born (...) Chinese. Sarigianides argues that texts such as American Born Chinese provide grounds for a public language for examining the suffering that ensues from the failure of assimilation as a desired outcome for immigrants in the United States. (shrink)

Behavioural phenotypes have been explained by genetic and environmental factors (E) and their interaction. Here we suggest a rethinking of the E factor. Passively incurred environmental influences (E pass) and actively copied information and behaviour (E act) may be distinguished at shared and non-shared level. We argue that E act underlies mutation and selection and is the base of gene-independent heritability.

The media, perhaps more than any other slice of culture, influence what we think and talk about, what we take to be important, what we worry about. And this was especially true when news of Dolly hit the airwaves and newstands. Most Americans received training in the ethics of cloning before they knew what cloning was. Media coverage fixed the content and outline of the public moral debate, both revealing and creating the dominant public worries about cloning humans. The primary (...) characterization of cloning as an ethical issue centers around three connected concerns: the loss of human uniqueness and individuality, the pathological motivations of a cloner, and the fear of out‐of‐control scientists. (shrink)

One of the most prominent justifications for the use of germline gene editing (GGE) is that it would allow parents to have a “genetically related child” while preventing the transmission of genetic disorders. However, we argue that since future uses of GGE may involve large-scale genetic modifications, they may affect the genetic relatedness between parents and offspring in a meaningful way: Due to certain genetic modifications, children may inherit much less than 50% of their DNA from each parent. We (...) show that the reduction in genetic relatedness between parents and offspring has three important social and legal implications. First, the desire for a genetically related child may end up not being the strong justification it is currently thought to be for the use of GGE. Second, prospective parents may be reluctant to use GGE because of a potential loss of genetic relatedness. Third, in some jurisdictions, parents who would not pass on “enough” DNA to their child may not be recognized as the child's legal parents. We further argue that the reduction in genetic relatedness challenges current conceptions of genetic parenthood that rely on the quantity of DNA shared with the child or on whether the child was directly derived from the parent's genes. We suggest that genetic parenthood should instead be determined based on the nature of the genetic modifications and whether the child's numerical identity has been preserved after the editing process. (shrink)

During evolution, the genomes of eukaryotic cells have undergone major restructuring to meet the new regulatory challenges associated with compartmentalization of the genetic material in the nucleus and the organelles acquired by endosymbiosis (mitochondria and plastids). Restructuring involved the loss of dispensable or redundant genes and the massive translocation of genes from the ancestral organelles to the nucleus. Genomics and bioinformatic data suggest that the process of DNA transfer from organelles to the nucleus still continues, providing raw material for (...) evolutionary tinkering in the nuclear genome. Recent reconstruction of these events in the laboratory has provided a unique tool to observe genome evolution in real time and to study the molecular mechanisms by which plastid genes are converted into functional nuclear genes. Here, we summarize current knowledge about plastid‐to‐nuclear gene transfer in the context of genome evolution and discuss new insights gained from experiments that recapitulate endosymbiotic gene transfer in the laboratory. BioEssays 30:556–566, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

It is tempting to invoke organismal selection as perpetually optimizing the function of any given gene. However, natural selection can drive genic functional change without improvement of biochemical activity, even to the extinction of gene activity. Detrimental mutations can creep in owing to linkage with other selectively favored loci. Selection can promote functional degradation, irrespective of genetic drift, when adaptation occurs by loss of gene function. Even stabilizing selection on a trait can lead to divergence of (...) the underlying molecular constituents. Selfish genetic elements can also proliferate independent of any functional benefits to the host genome. Here we review the logic and evidence for these diverse processes acting in genome evolution. This collection of distinct evolutionary phenomena – while operating through easily understandable mechanisms – all contribute to the seemingly counterintuitive notion that maintenance or improvement of a gene's biochemical function sometimes do not determine its evolutionary fate. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 10.3 (2000) 265-281 [Access article in PDF] Scope Note 39 Genes, Patents, and Bioethics-Will History Repeat Itself? Susan Cartier Poland Gene patenting--the very notion sounds absurd! How can anyone claim to have invented the genes with which one is born? To make matters worse, genetic makeup precedes birth, meaning the existence of the invention predates the existence of the inventor. So, do we (...) really own our genes, or do they belong to our parents, or our governments, or a Supreme Being? Ownership is only one bioethical issue involved in gene patenting. But before looking at the issues, some essential and basic terms must be understood, namely genes and patents. Genes In his book On the Origin of Species, published in 1859, the biologist Charles Darwin proposed a theory called "natural selection," whereby living things changed over time or evolved through generations due to competition and variation. By experimenting with the garden pea in the 1860s, Gregor Mendel, a monk and accomplished horticulturalist, provided the mechanism of inheritance supporting the natural selection theory of his contemporary Darwin. That mechanism is the gene, or, as Mendel described it, a discrete "factor." The gene has also been defined as "the fundamental unit of heredity" (United States 1987, p. 157). Each individual has two copies of a gene, one from each parent, but that individual passes down to offspring only one of the two copies. Because of Mendel, the gene has become a scientific concept and the basis of a new scientific field: genetics.David C. Page (2000) of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology explained today's terms for genetics structures using an analogy taken from the home. In his view, the cell is a kitchen, the genome is a shelf in the kitchen, the chromosome is a cookbook on the shelf, the gene is a recipe in the cookbook, and a base-pair (either adenine with thymine or guanine with cytosine) is a single letter in the recipe. A protein, the [End Page 265] working molecule blueprinted by a gene, is a dish ready to eat, and an ingredient in the dish is an amino acid, which is a building block of the protein as specified by a string of base-pairs.Colin Tudge (1993), a British science journalist, would disagree with Page's description of the gene as a recipe. A recipe is like a blueprint: both are directions that precede the work. But a gene is not passive according to Tudge; it actively administers the cell's work, and it also responds to cellular events (Aldridge 1996).The current focus of scientific research and funding is on the gene and the completion of the sequencing of all the genes that comprise the human genome, portrayed in the press as a race between the U.S. government's Human Genome Project and the private corporation Celera Genomics. The real action, however, is at the protein level. The gene only holds the information to produce a protein; it is the three-dimensional shaped protein that does the work. In order to produce energy, eliminate waste, and perform other functions specific to a cell or tissue, proteins must bind, thus creating "biological pathways." Proteins bind (or not) and detach as a function of their shapes, which are determined by their precise chemical composition as spelled out in their genetic code. IBM will spend the next five years making one computer, Blue Gene, that will then take an entire year to come up with the chemical map for only one protein (Gillis 2000). It is estimated that there are about 40,000 proteins in the human body.Despite these overwhelming numbers, modern biology has been able to achieve significant results within the Human Genome Project's 15-year time frame, from 1990 to 2005. The genetic map was completed in 1993; the physical map was completed in 1995; and the genetic sequence is expected to be completed in 2002, with 97 to 99 percent completed as of 26 June 2000. This... (shrink)

To further comprehend how synthesis and assembly of myofibrillar components is regulated, several laboratories have undertaken genetic studies of muscle development in Drosophila melanogaster. This small fly lends itself well to classical and molecular genetic approaches, and possesses a set of muscle fibers, termed indirect flight muscles (IFM), which is particularly advantageous for such investigations. Structural and functional analyses of cloned Drosophila contractile protein genes have revealed that protein isoforms can be specified either by multigene families or by differentially splicing (...) primary transcripts of a single gene. Characterization of mutations which disrupt flight muscle development has so far revealed that profound abnormalities are caused by defective alleles of actin, tropomyosin, and myosin heavy‐chain genes. Muscle defects associated with particular alleles can be alleviated by integration of corresponding wild‐type gene copies into germ‐line chromosomes. Strategies for further applying genetic techniques to investigations of Drosophila muscle development are discussed. (shrink)

The amdS gene of A. nidulans has proved extremely favourable for the isolation of mutations affecting gene regulation. Trans‐acting regulatory genes involved in amdS induction by small molecular weight effectors have been identified – amdR (ω‐amino acids) facB (acetate) and amdA (acetate). Another gene, the areA gene, has properties expected of a major activator gene involved in nitrogen metabolite repression of amdS. All of these regulatory genes are also involved in the control of various other (...) functions encoded by structural genes unlinked to amdS. Mutations in the 5′‐region adjacent to amdS have been isolated and allow the identification of independent cis‐acting sequences which are the target sites for the regulatory genes. The involvement of these sequences in regulatory product binding has been deduced from titration studies using transformants containing multiple copies of the 5′ sequences. A combination of genetics and molecular analysis is allowing a detailed characterization of this system. (shrink)

A new field of gene expression regulation research is emerging that has previously been overlooked. This new area is concerned with distinguishing the expression of a single gene from the averaged expression of many gene copies within the cell population. This paper reviews research focused on individual genes in inducible gene expression systems. The main experimental strategy is to measure the gene expression level of a single cell containing a single reporter gene molecule. In (...) contrast to the commonly held belief, gene induction is found to be stochastic under certain conditions. The possible mechanisms and implications are discussed. (shrink)

A gene is described as imprinted if its pattern of expression depends on whether it passed the previous generation in a male or female germ line. A recent paper(1) reports that imprinted genes have fewer and smaller introns than a control set of genes. The differences are striking but their interpretation is unclear. The loss of introns after a gene becomes imprinted is not sufficient to explain why imprinted genes have fewer introns than average, because related unimprinted (...) genes also have few introns. Similarly, small introns appear to be a property of chromosomal region rather than of imprinting status itself, because neighboring unimprinted genes also have small introns. (shrink)

The employment of digital technology in recent instances of artwork replication raises important questions about the perceptual and ontological distinction between original and copy, for the latter is purported to be even more authentic than an original that has undergone alterations. Such instances challenge not only Benjamin’s claim about the loss of aura but also Goodman’s distinction between autographic and allographic arts. The article proposes to rethink the original/copy dualism from the perspective of the cult image. In (...) the devotional traditions of Graeco-Roman polytheism as well as Christianity and Buddhism, cult images are approached not as representations, but as animated entities endowed with thaumaturgic powers that can be ritually transferred onto copies. From this perspective, replication is not about reproducing more or less faithfully the original, but engendering a double as effective as the original. Finally, the bearing of this perspective on contemporary works of art is considered. (shrink)

Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of (...) copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

Contrary to one possible interpretation of my title, this paper will not advocate any scepticism or ontological deflation. My concern will rather be with how we should best think about a realm of phenomena the existence of which is in no doubt, what has traditionally been referred to as the genetic. I have no intention of questioning a very well established scientific consensus on this domain. It involves the chemical DNA, which resides in almost all our cells, which is capable (...) of producing copies of itself that accurately reproduce a very long sequence of components, and which plays a role in the physiology of the cell which in certain basic respects is quite well understood. This substance has also achieved a remarkable iconic status in contemporary culture. It is seen as fundamental to personal identity both in the practical sense of providing a criterion of identity through DNA testing, and in the much deeper sense of being seen as, somehow, defining who we are. The latter role is illustrated, for example, by the recent debate about the right of children conceived by sperm donation to know who are their fathers. Such people, it is passionately argued, must be able to find out where they came from, who they really are. On a daily basis we are confronted with claims about the discovery of the genetic basis of—or in fact very often the ‘gene for’—all manner of psychological and physical characteristics, and all kinds of disorders. This holds out apparent possibilities. (shrink)

The relatively simple central nervous system (CNS) of the Drosophila embryo provides a useful model system for investigating the mechanisms that generate and pattern complex nervous systems. Central to the generation of different types of neurons by precursor neuroblasts is the initial specification of neuroblast identity and the Drosophila segment polarity genes, genes that specify regions within a segment or repeating unit of the Drosophila embryo, have emerged recently as significant players in this process. During neurogenesis the segment polarity genes (...) are expressed in the neuroectodermal cells from which neuroblasts delaminate and they continue to be expressed in neuroblasts and their progeny. Loss-of-function mutations in these genes lead to a failure in the formation of neuroblasts and/or specification of neuroblast identity. Results from several recent studies suggest that regulatory interactions between segment polarity genes during neurogenesis lead to an increase in the number of neuroblasts and specification of different identities to neuroblasts within a population of cells. BioEssays 21:472–485, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss‐of‐function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first (...) mutation at the p53 locus resulting in a trans‐dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild‐type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged.The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53. (shrink)

The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine‐rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the (...) growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN. (shrink)

Recombinant DNA technology will soon allow physicians an opportunity to carry out both somatic cell- and Germ-Line gene therapy. While somatic cell gene therapy raises no new ethical problems, gene therapy of gametes, fertilized eggs or early embryos does raise several novel concerns. The first issue discussed here relates to making a distinction between negative and positive eugenics; the second issue deals with the evolutionary consequences of lost genetic diversity. In distinguishing between positive and negative eugenics, the (...) concept of malady is applied as a definitional criterion for identifying genetic disorders that could qualify for Germ-Line therapy. Because gene replacement techniques are currently unavailable for humans, and because even if they were possible the number of people involved would be quite small, the loss of diversity concern seems moot. Finally, we dissuss the issue of iatrogenic disorders associated with gene therapy and discuss several ‘real world considerations.’. (shrink)

Autonomous transposable elements, generally considered as junk and selfish, encode transposition proteins that can bind, copy, break, join or degrade nucleic acids as well as process or interact with other proteins. Such a repertoire of activities might be of interest for the host cell. There is indeed substantial evidence that mobile DNA can serve as a dynamic reservoir for new cellular functions. Transposable element genes encoding transposase, integrase, reverse transcriptase as well as structural and envelope proteins have been repeatedly (...) recruited by their host during evolution in most eukaryotic lineages. Such domesticated sequences protect us against infections, are necessary for our reproduction, allow the replication of our chromosomes and control cell proliferation and death; others are essential for plant development. Many new candidates for domesticated sequences have been revealed by sequencing projects. Their functional analysis will uncover new aspects of evolutionary alchemy, the turning of junk into gold within genomes. BioEssays 28: 913–922, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Mammals have an XX:XY system of chromosomal sex determination in which a small heterochromatic Y controls male development. The Y contains the testis determining factor SRY, as well as several genes important in spermatogenesis. Comparative studies show that the Y was once homologous with the X, but has been progressively degraded, and now consists largely of repeated sequences as well as degraded copies of X linked genes. The small original X and Y have been enlarged by cycles of autosomal addition (...) to one partner, recombination onto the other and continuing attrition of the compound Y. This addition–attrition hypothesis predicts that the pseudoautosomal region of the human X is merely the last relic of the latest addition. Genes (including SRY) on the conserved or added region of the Y evolved functions in male sex determination and differentiation distinct from the general functions of their X‐linked partners. Although the gonadogenesis pathway is highly conserved in vertebrates, its control has probably changed radically and rapidly in vertebrate – even mammalian – evolution. (shrink)

Over 80% of the genes in the E. coli chromosome express fewer than a hundred copies each of their protein products per cell. It is argued here that transcription of these genes is neither constitutive nor regulated by protein factors, but rather, induced by the act of replication. The utility of such replication‐induced (RI) transcription to the temporal regulation of synthesis of determinate quantities of low copy number (LCN) proteins is described. It is suggested that RI transcription may be (...) necessitated, as well as facilitated, by the folding of the bacterial chromosome into a compact nucleoid. Mechanistic aspects of the induction of transcription by replication are discussed with respect to the modulation of transcriptional initiation by negative supercoiling effects, promoter methylation status and derepression. It is shown that RI transcription offers plausible explanations for the constancy of the C period of the E. coli cell cycle and the remarkable conservation of gene order in the chromosomes of enteric bacteria. Some experimental tests of the hypothesis are proposed. (shrink)

Gene therapy has emerged from the idea of inserting a wild‐type copy of a gene in order to restore the proper expression and function of a damaged gene. Initial efforts have focused on finding the proper vector and delivery method to introduce a corrected gene to the affected tissue or cell type. Even though these first attempts are clearly promising, seveal problems remain unsolved. A major problem is the influence of chromatin structure on transgene expression. (...) To overcome chromatin‐dependent repressive transgenic states, researchers have begun to use chromatin regulatory elements to drive transgene expression. Insulators or chromatin boundaries are able to protect a transgene against chromatin position effects at their genomic integration sites, and they are able to maintain transgene expression for long periods of time. Therefore, these elements may be very useful tools in gene therapy applications for ensuring high‐level and stable expression of transgenes. BioEssays 26:796–807, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The very high genome copy number in cytoplasmic organelles is a puzzling fact in cell biology. It is proposed here that high copy number reflects an increased need for organellar ribosomes that can only be satisfied by the increased ribosomal RNA gene number that results from genome multiplication.

The very high genome copy number in cytoplasmic organelles is a puzzling fact in cell biology. It is proposed here that high copy number reflects an increased need for organellar ribosomes that can only be satisfied by the increased ribosomal RNA gene number that results from genome multiplication.

Six essential genes located near the mouse albino locus have been identified as required during specific periods of development. Amongst these six, each is required either during the preimplantation stages of development, at specific times during gastrulation, within 12 hrs after birth or during juvenile development. These genes were identified as a result of extensive genetic complementation analysis using embryos homozygous for the albino deletions. Although, in principal, the associated developmental abnormalities could result from loss of multiple genes, the (...) deletion phenotype in one case is identical to that induced by chemical mutagenesis. These results indicate that the abnormalities observed in deletion homozygotes may result from single gene loss. The deletions have proven useful not only as genetic tools to localize the position of the genes, but also as molecular entry points to the regions containing these genes. The current methodology being used to isolate candidate genes from the albino region is also reviewed here. (shrink)

In 1956, I decided to apply my experience in microbial genetics to developing analogous systems for human cell lines, including the selection of mutants with either a loss or gain of a biochemical function. For instance, mutants resistant to azahypoxanthine showed a loss of the HPRT enzyme (hypoxanthine phosphoribosyl transferase), whereas gain of the same enzyme was accomplished by blocking de novo purine biosynthesis with aminopterin, while supplying hypoxanthine and thymine (HAT selection). Using HAT selection, we: (i) genetically (...) transformed HPRT− mutant cells to HPRT+ wild type by using DNA extracted from HPRT+ cells, and (ii) selected HPRT+ hybrid cells by fusing HPRT− D98/AH2 cells with skin cells. These approaches, which we dubbed in 1962 as a [first step toward gene therapy], contributed to the later development of (i) cell fusion techniques, (ii) the development of monoclonal antibodies, (iii) routine transformation of mammalian cells with cloned genes, and (iv) methods for creating transgenic organisms. (shrink)

The complex process of cell immortalization and transformation is likely to involve the inactivation of growth regulatory genes. Mutations (deletions, missense mutations) in the p53 gene are the most frequently observed genetic alteration in human tumors, making p53 a candidate for a cellular protein involved in the control of cell growth. Two recent studies have examined the role of p53 in immortalization and tumorigenesis(27,28). In the first study(27), p53 expression was examined in both mortal and immortal chick embryo fibroblasts. (...) All mortal clones expressed p53 but the loss of wild‐type p53 expression was observed in every immortal cell line examined. In the second study(28), a line of mice carrying two null p53 alleles has been created and characterized. Although these mice develop normally, they show a predisposition to develop a variety of neoplasms at an early age (< 6 months). Although it is unclear whether p53 regulates the same, different, or overlapping pathways in the two experimental systems, these data demonstrate that p53 function is critical for the maintenance of normal growth control and support the current classification of p53 as a growth suppressive or tumor suppressor gene. (shrink)

Background: We define compassion as an enduring disposition that centers upon empathetic concern for another person's suffering and the motivation to act to alleviate it. The contribution of specific candidate genes to the development of dispositional compassion for others is currently unknown. We examine candidate genes in the oxytocin and dopamine signaling pathways.Methods: In a 32-year follow-up of the Young Finns Study, we examined with multiple indicators latent growth curve modeling the molecular genetic underpinnings of dispositional compassion for others across (...) the life span. We selected five single nucleotide polymorphisms whose functions are known in humans: rs2268498, rs3796863, rs1800497, rs4680, and rs1611115. Compassion was measured with Cloninger's Temperament and Character Inventory on three repeated observations spanning 15 years. Differences between gender were tested.Results: We did not find an effect of the five SNPs in oxytocin and dopamine pathway genes on the initial levels of dispositional compassion for others. Individuals who carry one or two copies of the T-allele of DBH rs1611115, however, tend to increase faster in compassion over time than those homozygotes for the C-allele, b = 0.063. This effect was largely driven by male participants, 0.206, and was not significant in female participants when analyzed separately.Conclusions: Men who are known to have, on average, lower compassion than women seem to reduce this difference over time if they carry the T-allele of DBH rs1611115. The direction of the association indicates that dopamine signaling activity rather than overall dopamine levels might drive the development of compassion. (shrink)

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c‐fos(1), where Wagner and coworkers identify this proto‐oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a (...) link between skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells. (shrink)

During development, large numbers of cells die by a process known as programmed cell death. This loss of cells plays a number of important roles, including the sculpting of the body form and the removal of vestigial tissues. Data obtained from a variety of organisms has suggested that a cell's ‘decision’ to die is a differentiative event, requiring the activation of specific sets of genes. Several putative ‘cell death’ genes have recently been cloned, and one has been identified as (...) the product of the polyubiquitin gene. Accumulation of ubiquitin has been observed not only during programmed cell death, but also in several neurodegenerative disorders, including Alzheimer's Disease. (shrink)

Electronic technologies, in general, and computer-oriented technologies specifically have had a tremendous impact on all aspects of business. One area of increased concern is the protection of intellectual properties -- notably copyrights -- within the boundaries of the broadly defined technology industry. While the ability to share copyrighted information has always existed at the most basic levels, the advent of the information age has allowed the sharing of this information to take place in potentially greater quantities and without a (...) class='Hi'>loss of quality. As such, copying creates a major threat to industries dealing in the production and distribution of copyrightable creations. The focus of this paper is to better understand how the ethical judgments of employees regarding the opportunities to recreate copyrighted works via traditional and newer technologies impact assessments of copying behavior in the workplace. (shrink)

We defend a realistic attitude towards biological species. We argue that two species are not different species because they differ in intrinsic features, be they phenotypic or genomic, but because they are separated with regard to gene flow. There are no intrinsic species essences. However, there are relational ones. We argue that bearing a gene flow relation to conspecifics may serve as the essence of a species. Our view of the species as a Gene-Flow Community differs from (...) Mayr’s definition of the species as a reproductive community. In a reproductive community, each organism is able to successfully reproduce with each other. However, there are species in which geographically distant organisms lost their ability to successfully reproduce, due to strong genetic adaptations to the respective local environmental conditions. Despite this loss of the ability to mutually reproduce, they are still bound by gene flow via continuous intermediate populations. This replacement of Mayr’s notion of an interbreeding potential as a criterion for species membership has important implications for the treatment of populations in allopatry and sympatry. (shrink)

Circadian rhythms in the sleep/wake cycle, along with a range of physiological measures, are severely disrupted in individuals with major depressive disorder (MDD). Moreover, several central circadian genes have been implicated as potential genetic factors underlying the illness through candidate gene studies and some genome wide association studies. However, investigations into the molecular underpinnings of circadian disturbances in the human brain have been quite challenging. In their recent publication, Li and colleagues have used a novel approach to determine the (...) rhythmic patterns of circadian gene expression in several regions of the human brain, and how these patterns are disrupted in MDD. Their findings demonstrate that in healthy subjects, several brain regions outside the suprachiasmatic nucleus (the master clock) exhibit diurnal gene expression patterns that are disrupted in the brains of MDD subjects. These findings will provide the foundation for future studies of gene‐specific drug targets, and biomarkers for the disease. (shrink)

The concept of projection from one space to another, with a consequent loss of information, can be seen in the relationships of gene to protein and language description to real situation. Such a transformation can only be reversed if extra external information is re-supplied. The genetic algorithm embodying this idea is now used in applied mathematics for exploring a configuration space. Such a dialectic – transformation back and forth between two kinds of description – extends the traditional Hegelian (...) concept used by Engels and others of change as resulting from a resolution of the conflict of two opposing tendencies and provides for evolution of the joint system. (shrink)

While previous studies have suggested that there exists a relationship between obesity and executive function (EF), the mechanisms and causal relationship between them remain unclear. There are important clinical implications of determining whether EF can predict and treat obesity. We conducted a multilevel meta-analysis of randomized controlled trials (RCTs) and longitudinal studies. Specifically, we investigate (a) whether EF interventions have an effect on weight loss, (b) whether baseline EF can be a predictor of future weight loss through obesity (...) intervention, and (c) whether early-life EF can predict future weight loss. Eight RCTs and 17 longitudinal studies with a total of 11,393 participants were identified. We found that (a) EF interventions may not have an effect on weight loss, (b) baseline inhibition (β = 0.259,p= 0.03) and delay discounting (β = −0.17,p= 0.04) significantly predict future weight loss through obesity intervention, (c) age (F= 13.666,p= 0.005) moderates the relationship between working memory and weight loss through intervention, but not weight status, type of intervention, and percentage of female, and (d) early life inhibition (β = 0.185,p= 0.07) is a marginally significant predictor of future weight loss. Our results seem to support the assumption that the relationship between EF and obesity is not direct, and a higher-order factor, such as genes, may link obesity and EF. Building on the preliminary findings, further studies focusing on EF and obesity are needed in the future. (shrink)

Studies of Y chromosome evolution often emphasize gene loss, but this loss has been counterbalanced by addition of new genes. The DAZ genes, which are critical to human spermatogenesis, were acquired by the Y chromosome in the ancestor of Old World monkeys and apes. We and our colleagues recently sequenced the rhesus macaque Y chromosome, and comparison of this sequence to human and chimpanzee enables us to reconstruct much of the evolutionary history of DAZ. We report that (...) DAZ arrived on the Y chromosome about 38 million years ago via the transposition of at least 1.1 megabases of autosomal DNA. This transposition also brought five additional genes to the Y chromosome, but all five genes were subsequently lost through mutation or deletion. As the only surviving gene, DAZ experienced extensive restructuring, including intragenic amplification and gene duplication, and has been the target of positive selection in the chimpanzee lineage.Editor's suggested further reading in BioEssays Should Y stay or should Y go: The evolution of non‐recombining sex chromosomes Abstract. (shrink)

Some experts and advocates propose environmental biotechnologies such as genetic engineering, gene drive systems, and synthetic biology as potential solutions to accelerating rates of species loss. While these tools may offer hope for a seemingly intractable problem, they also present potential governance challenges for which innovative decision‐making systems are required. Two of the perennial governance challenges include, when are broader stakeholder groups involved in these decisions and who exactly should be involved? We propose the decision phases framework—which includes (...) research and development, regulatory review, and deployment, management, and monitoring—as a framework for identifying which stakeholders might be best suited for different phases throughout the innovation and deployment of emerging environmental biotechnologies for species protection. (shrink)

생명공학 시대에 과학자들은 인간을 생물학적으로 이해하려고 한다. 물론 인간은 생물학적 영향에서 자유롭지 못한 존재이다. 인간이 생물학적으로나 유전학적으로 해명되는 존재이긴 하지만 인류 공동체에서 인간의 고유한 본성은 보편적 가치를 지니고 있다는 점에서 그것은 우리에게 상당한 의미를 가져다준다. 인간의 본성을 이해하는 것은 어렵다. 하지만 우리는 그것을 밝히기 어렵다고 방관해서는 안 된다.BR 한편 유전자의 개량 기술은 인간의 후천적 노력과 성취로 주어진 인간의 여러 특성들을 잠식하게 될 수 있다. 신체증강 시대에 우수한 유전자를 선별하는 과정에서 그 혜택을 누린 인류는 우연히 주어진 개개인의 잠재력을 무시하게 될 것이다. (...) 인간이 가진 겸손 그리고 개인이 감당해야 할 책임과 연대의 형태는 생명공학 시대에 변화를 피할 수 없게 되었다.BR 신체증강 시대에 인류가 생물학적 완전성을 추구하게 되면 우리가 보편적으로 추구해왔던 공동체적 삶, 연대, 노력 등의 보편적 가치를 외면하기 때문에 연대와 협동을 속성으로 하는 덕윤리는 신체 증강시대에 꼭 필요로 하게 되었다.BR 이에 논자는 생명공학 시대에 맞게 바람직한 덕 윤리의 방향을 제시하고 한다. 신체증강을 통해 공동체의 다양한 형태들의 변화가 생기면서 덕윤리는 더욱 필요로 하게 되었다. 논자는 유전자 차별로서의 사회가 아닌 공동체 연대와 가치를 추구하는 사회를 다시금 요청할 것이다. (shrink)