C.C. Little and the Jackson Laboratory Archives: some notes on the intersecting histories of eugenics, mammalian genetics, and cancer research.
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Who owns you? A mock trial explores the intersection of patents and genetic-property rights.
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Confidentiality↗
Perceptions of genetics research as harmful to society: differences among samples of African-Americans and European-Americans.
Genetics has the potential not only to find cures for diseases, but to possess the mechanisms to change the bio-social make-up of populations. A specific question that has arisen on this issue is how developments in genetic technology may intersect with existing race and ethnic relations. Evidence of the racialization of some genetic disorders has been demonstrated elsewhere. The purpose of this study is to compare and contrast African-American and European-American attitudes on the benefits of genetics research for society. Findings show that African-Americans were more likely to say genetics research is harmful for society. This relationship remained statistically significant after controls were introduced in a regression model. Demographic characteristics and self-rated knowledge of genetics had no effect on attitudes among African-Americans. A willingness to use genetic services correlated with favorable attitudes. Differences in social position may lead some groups to opposing interpretations and symbolic meanings of genetics. This may be true in the context of this study because the social meanings of genetics may be tainted by racialization, historical attempts at eugenics, and the potential abuse of genetics targeting groups partially defined by superficial genetic characteristics.
Black or African American↗
Genetics, development and evolution of adaptive pigmentation in vertebrates.
The study of pigmentation has played an important role in the intersection of evolution, genetics, and developmental biology. Pigmentation's utility as a visible phenotypic marker has resulted in over 100 years of intense study of coat color mutations in laboratory mice, thereby creating an impressive list of candidate genes and an understanding of the developmental mechanisms responsible for the phenotypic effects. Variation in color and pigment patterning has also served as the focus of many classic studies of naturally occurring phenotypic variation in a wide variety of vertebrates, providing some of the most compelling cases for parallel and convergent evolution. Thus, the pigmentation model system holds much promise for understanding the nature of adaptation by linking genetic changes to variation in fitness-related traits. Here, I first discuss the historical role of pigmentation in genetics, development and evolutionary biology. I then discuss recent empirically based studies in vertebrates, which rely on these historical foundations to make connections between genotype and phenotype for ecologically important pigmentation traits. These studies provide insight into the evolutionary process by uncovering the genetic basis of adaptive traits and addressing such long-standing questions in evolutionary biology as (1) are adaptive changes predominantly caused by mutations in regulatory regions or coding regions? (2) is adaptation driven by the fixation of dominant mutations? and (3) to what extent are parallel phenotypic changes caused by similar genetic changes? It is clear that coloration has much to teach us about the molecular basis of organismal diversity, adaptation and the evolutionary process.
Adaptation, Biological↗
Mitochondrial DNA variability of West New Guinea populations.
This paper reports human mitochondrial DNA variability in West New Guinea (the least known, western side of the island of New Guinea), not yet described from a molecular perspective. The study was carried out on 202 subjects from 12 ethnic groups, belonging to six different Papuan language families, representative of both mountain and coastal plain areas. Mitochondrial DNA hypervariable region 1 (HVS 1) and the presence of the 9-bp deletion (intergenic region COII-tRNA(Lys)) were investigated. HVS 1 sequencing identified 73 polymorphic sites defining 89 haplotypes; the 9-bp deletion, which is considered a marker of Austronesian migration in the Pacific, was found to be absent in the whole West New Guinea study sample. Statistical analysis applied to the resulting haplotypes reveal high heterogeneity and an intersecting distribution of genetic variability in these populations, despite their cultural and geographic diversity. The results of subsequent phylogenetic approaches subdivide mtDNA diversity in West New Guinea into three main clusters (groups I-III), defined by sets of polymorphisms which are also shared by some individuals from Papua New Guinea. Comparisons with worldwide HVS 1 sequences stored in the MitBASE database show the absence of these patterns outside Oceania and a few Indonesian subjects, who also lack the 9-bp deletion. This finding, which is consistent with the effects of genetic drift and prolonged isolation of West New Guinea populations, lead us to regard these patterns as New Guinea population markers, which may harbor the genetic memory of the earliest human migrations to the island.
Base Sequence↗
Klf4 and corticosteroids activate an overlapping set of transcriptional targets to accelerate in utero epidermal barrier acquisition.
Premature infants are at an increased risk for infections and dehydration because of incomplete development of the epidermis, which attains its essential function as a barrier only during the last stages of in utero development. When a premature birth is anticipated, antenatal corticosteroids are administered to accelerate lung epithelium differentiation. One pleiotropic, but beneficial, effect of antenatal corticosteroids is acceleration of skin barrier establishment by an unknown mechanism. In mice, the transcription factor Klf4 is both necessary and sufficient, within a developmental field of competence, to establish this skin barrier, as demonstrated by targeted ablation and transgenic expression of Klf4, respectively. Here, we report that Klf4 and corticosteroid treatment coordinately accelerate barrier acquisition in vivo. Transcriptional profiling reveals that the genes regulated by corticosteroids and Klf4 during the critical window of epidermal development significantly overlap. KLF4 activates the proximal promoters of a significant subset of these genes. Dissecting the intersection of the genetic and pharmacological pathways, regulated by KLF4 and corticosteroids, respectively, leads to a mechanistic understanding of the normal process of epidermal development in utero.
Adrenal Cortex Hormones↗
Genomics--the perfect information-seeking research problem.
The intersection of the genetics era and information age poses unique and daunting challenges for health consumers who may not have the health literacy to keep pace. While rapid advances in genetics research promise enhanced care, the inherent complexities and individualistic nature of genetic information have resulted in a challenging information environment. The technical possibilities for acquiring genomic information are increasing at an exponential pace, as are the scientific advances relating to it. Furthermore, societal reactions to genomics, and possible privacy and discrimination issues, may constitute significant constraints. The health care infrastructure also has its limits, given the severe shortage of qualified cancer genetic counselors and general practitioners who are unprepared to address genetics, creating a demand for creative approaches to service delivery. The combination of individual salience, low health literacy, the consumer movement, and important policy problems, then makes genomics the perfect information seeking research problem.
Consumer Behavior↗
At the interfaces of epidemiology, genetics and genomics.
You come onto the court prepared for tennis but your partner seems to be ready for rugby. Neither of you is at all sure what it is that your opponent wants to play. The only recourse is to teach each other the rules of your own game and then decide whether you can collectively invent a new sport. Welcome to the dialogue at the intersections of epidemiology with genetics and genomics.
Alleles↗
Genetics and behavioral medicine: risk factors for cardiovascular disease.
This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for understanding how risk factors, behavior, and health outcomes are related. The approach synthesizes a number of methods and areas of interest in an attempt to arrive at a comprehensive, whole-organism understanding of health-related risk factors and their response to behavioral interventions.
Adolescent↗
CXCR4 mutations in WHIM syndrome: a misguided immune system?
Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best-characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain-of-function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM syndrome patients are discussed in this review.
Agammaglobulinemia↗
Social, political, and epistemological aspects of genetics and genomics.
The papers in this special issue were first given at a conference in Toronto, Canada, in April 2004 entitled 'Genomics, Genetics, and Society: Bridging the Disciplinary Divides'. The papers fall into four intersecting themes. (1) The introduction of genetic and genomic technologies into communities. (2) Governance, the morals of scientific discourse and policy making. (3) What is a gene? (4) Public knowledge, public trust and improved dialogue between the public and scientists.
Bioethics↗
Longitudinal Gompertzian analysis of pancreatic cancer mortality in the U.S., 1962-1987: distinguishing between competitive and environmental influences upon evolving mortality patterns.
Pancreatic cancer (PanC) is an extraordinarily lethal neoplasm that is currently the fifth leading cause of cancer death in the United States. Annual age-specific mortality rates for PanC in the U.S. from 1962 to 1987 were subjected to longitudinal Gompertzian analysis. Age-specific PanC mortality rate distributions between age 30 and 60 years were determined by a common fixed intersect point and a variable competitive factor. The intersect point for PanC occurred at age 59.5 years and mortality rate 37.4 per 100,000 for men, and at age 53.2 years and mortality rate 7.9 per 100,000 for women. These intersect points are determined by genetic and environmental influences upon mortality. The observation that these points have remained fixed suggests that there has been no significant alteration in environmental etiopathogenic influences upon PanC mortality. Longitudinal Gompertzian analysis suggests that the emergence of PanC in the U.S. as a significant cause of cancer mortality has been the consequence of competitive influences upon PanC mortality dynamics.
Adult↗
Emerging ethical issues in pharmacogenomics: from research to clinical practice.
Pharmacogenomics holds much promise for the application of genetic information to the improvement of clinical care. Ethical issues for pharmacogenomics arise at the intersection of the spheres of drug development and genetic testing. Clinical drug trial designs which use subject selection based on genotype must consider the features of scientific validity, social value and risk-benefit ratio, and later, the impact of this strategy on post-market studies and clinical use of drugs. Although the testing context for pharmacogenomic tests is different from other genetic tests, decisions to use any new clinical tests in medical practice will require evaluation of not only the benefit linked to improved drug use but also the risks arising in part from the scale of testing, predictive value and collateral potential of the genetic test. Integration of pharmacogenomic information into clinical practice will require clinical trials to assess their clinical usefulness, including the impact of tests on therapeutic outcomes. Trials will also be needed to demonstrate the effectiveness of education, informed consent and counseling.
Animals↗
Generation and validation of a Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of disease-associated smooth muscle cell states.
BACKGROUND: Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified secreted phosphoprotein 1 (SPP1) as a prominent marker associated with disease-associated VSMC states, particularly those linked to fibrotic remodeling and vascular calcification. However, the cellular origins and fate of SPP1-associated VSMC populations remain incompletely understood. METHODS AND RESULTS: We generated a novel Spp1-rSTOPr-Cre (Spp1Cre) knock-in mouse line in which Cre recombinase is expressed from the endogenous Spp1 locus following Dre-mediated excision of a rox-flanked transcriptional STOP cassette. Correct targeting of the knock-in allele was validated by internal, 5' junction, 3' junction, and long-range PCR analyses, as well as Sanger sequencing. To establish an intersectional lineage-tracing strategy, Spp1Cre mice were crossed with Myh11DreERT2 and Rosa26-RSR-LSL-tdTomato-LSL-eGFP reporter mice, enabling permanent labeling of VSMC-derived populations following activation of the endogenous Spp1 locus. Under physiological conditions, eGFP-positive cells were detected at low frequency within the vascular wall and were predominantly negative for the contractile markers ACTA2 and MYH11. As a proof-of-principle application, eGFP-positive cells markedly expanded within atherosclerotic lesions induced by AAV-PCSK9D377Y and high-fat diet feeding. These lineage-traced cells remained largely ACTA2- and MYH11-negative, consistent with a modulated phenotype. Notably, only a minority of eGFP-positive cells expressed SPP1 or fibronectin at the time of analysis, demonstrating the utility of permanent lineage tracing for tracking cells with a history of endogenous Spp1 activation during vascular remodeling. CONCLUSION: We report the generation and validation of a novel Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of VSMC-derived populations that have activated the endogenous Spp1 locus. This genetic resource provides a valuable platform for investigating the origin, fate, and phenotypic evolution of Spp1-associated VSMC populations during vascular remodeling and cardiovascular disease.
Animals↗
Experiences of genetic risk: disclosure and the gendering of responsibility.
The question of 'who owns genetic information' is increasingly a focus of ethical inquiry. Applied to predictive testing, several recent critiques suggest that persons with a genetic disorder have a moral duty to disclose that information to other family members. The justification for this obligation is that genetic information belongs to and may benefit not only a single individual, but also members of a biological kinship. This paper considers this issue from a different vantage point: How does gender intersect with the moral duty to disclose genetic information? Scholars have argued that gender is partly comprised of distinct assignments and assumptions of responsibility. Thus, there is a danger that gendered patterns of socialization will make women feel that they should take primary responsibility for disclosing genetic information to others. This article explores issues of responsibility and disclosure of risk information by drawing on an empirical study of women and men who have undergone genetic testing for hereditary breast/ovarian cancer. The research study suggests that disclosure of genetic information is a gendered activity, with both the benefits and burdens of this task falling primarily on women. It also illustrates that when disclosure is understood contextually, it is a far more complicated matter than when viewed through a theoretical lens. The article considers the relevance of these findings on ethical debate and genetic counselling practices.
Breast Neoplasms↗
Tuberculosis transmission based on molecular epidemiologic research.
Molecular genotyping techniques developed during the past decade and conventional epidemiological methods have been used synergistically in studies of the transmission and pathogenesis of Mycobacterium tuberculosis. Research studies assessing contacts and outbreaks, risk factors for ongoing transmission, and exogenous reinfection with M. tuberculosis have advanced with applied molecular epidemiologic techniques. In addition, molecular epidemiologic approaches have enabled scientists to assess the impact of drug resistance on the transmission and pathogenesis of M. tuberculosis and to identify strains with broad temporal and spatial distributions. In the near future, the intersection of molecular epidemiology, bacterial population genetics, comparative genomics, immunology, and other disciplines will further our understanding of tuberculosis transmission and pathogenesis, contributing to the development of effective drugs and a vaccine against this important human pathogen.
Journal Article↗
slimb coordinates wg and dpp expression in the dorsal-ventral and anterior-posterior axes during limb development.
In the Drosophila leg disc, wingless (wg) and decapentaplegic (dpp) are expressed in a ventral-anterior and dorsal-anterior stripe of cells, respectively. This pattern of expression is essential for proper limb development. While the Hedgehog (Hh) pathway regulates dpp and wg expression in the anterior-posterior (A/P) axis, mechanisms specifying their expression in the dorsal-ventral (D/V) axis are not well understood. We present evidence that slimb mutant clones in the disc deregulate wg and dpp expression in the D/V axis. This suggests for the first time that their expression in the D/V axis is actively regulated during imaginal disc development. Furthermore, slimb is unique in that it also deregulates wg and dpp in the A/P axis. The misexpression phenotypes of slimb- clones indicate that the regulation of wg and dpp expression is coordinated in both axes, and that slimb plays an essential role in integrating A/P and D/V signals for proper patterning during development. Our genetic analysis further reveals that slimb intersects the A/P pathway upstream of smoothened (smo).
Amino Acid Sequence↗
Iranian STR variation at the fringes of biogeographical demarcation.
The integrative relationship between population genetics and forensic biology allows for a thorough genetic characterization of extant human populations. This study aimed to genetically characterize 150 unrelated healthy donors from a general population in Iran both forensically and phylogenetically. The allelic frequencies of 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA) were generated. This constitutes the core of polymerase chain reaction (PCR)-based DNA genetic markers in the US Combined DNA Index System (CODIS) plus two additional loci (D2S1338 and D19S433) that together are consistent with several other worldwide database requirements. There were no deviations from Hardy-Weinberg expectations. Based upon the allelic frequencies, several important forensic parameters were calculated including: gene diversity (GD) index, power of discrimination (PD), polymorphic information content (PIC) and power of exclusion (PE). G-tests indicate the allelic frequencies of the Iranians are statistically non-significant compared to two Turkish populations yet, statistically different from the remaining 18 groups obtained from the literature and examined in this study. This suggests that the Iranian dataset may be forensically equivalent to the dataset from the Turkish region of Eastern Anatolia and the general population from Turkey. Phylogenetic analysis of our population with the full set of 15 loci indicate the Iranians occupy an intermediate position relative to the major Caucasian and East Asian clades on a global level. A regional phylogenetic analysis using 13 of the 15 loci indicate the Iranians segregate in a more compact association with groups from southeastern Spain, Arabs from Morocco and Syria, and especially with the general population from Turkey and those from Eastern Anatolia. These groups are flanked by highly differentiated populations from northern India and a Berber group from Tunisia on opposing ends of the regional phylogram. This report also demonstrates the necessity to thoroughly characterize the genetic composition of populations located in geographic intersections in order to choose the appropriate dataset on which to base forensic calculations, not only at an intra-population level, but also at an inter-population level as well.
DNA Fingerprinting↗