Using mouse models to explore genotype-phenotype relationship in Down syndrome

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of approximately 300 genes on HSA21. Advances in genetics together with the ability to generate genetically well-defined mouse models have been instrumental in understanding the relationships between genotype and phenotype in DS. Indeed, elucidation of these relationships will play an important role in understanding the pathophysiological basis of this disorder and helping to develop therapeutic interventions. A successful example of using such a strategy is our recent studies exploring the relationship between failed nerve growth factor (NGF) transport and amyloid precursor protein (App) overexpression. We found that increased dosage of the gene for App is linked to failed NGF signaling and cholinergic neurodegeneration in a mouse model of DS. Herein, we discuss several mouse models of DS and explore the emergence of exciting new insights into genotype-phenotype relationships, particularly those related to nervous system abnormalities. An important conclusion is that uncovering these relationships is enhanced by working from carefully defined phenotypes to the genes responsible.     

Norm-of-reaction: definition and misinterpretation of animal research

The development of a phenotype is due to an interaction of the genotype with the environment. Two terms have been used to describe the outcome of this interaction, the norm-of-reaction and the reaction range. The first represents the theoretically limitless distribution of the phenotypes that may be expressed by a given genotype. The reaction range implies an upper and lower limit for phenotype expression possible from a given genotype. A critical distinction between the reaction range and the norm-of-reaction is that the norm-of-reaction is a statement of the conceivable interactions found but does not imply any predictability other than that within the conditions previously tested experimentally, that is, the tails of a normal distribution are infinitely variable, whereas the concept of reaction range implies a limitation inherent in the genotype, that is, a finite range. Empirical support for the reaction-range concept is questionable. Animal studies cited in support of the reaction range have been inappropriately and incorrectly interpreted.     

抑郁遗传效应的发展动态性

抑郁的遗传效应存在发展动态性。一方面,在发展过程中,抑郁的遗传率会发生改变,抑郁的风险基因及其与环境的交互作用模式也存在动态变化。另一方面,遗传因素会影响抑郁的发展变化模式。通过梳理既有相关研究,本文从生理成熟因素、表观遗传和发展级联效应三方面分析抑郁遗传效应发展动态性的原因。未来研究应区分重要发展阶段,增加脑功能、性激素、神经生物蛋白以及表观遗传等指标考察抑郁遗传效应的变化模式及其发生机制。     

Developmental imaging genetics: Linking dopamine function to adolescent behavior

Adolescence is a period of development characterized by numerous neurobiological changes that significantly influence behavior and brain function. Adolescence is of particular interest due to the alarming statistics indicating that mortality rates increase two to three-fold during this time compared to childhood, due largely to a peak in risk-taking behaviors resulting from increased impulsivity and sensation seeking. Furthermore, there exists large unexplained variability in these behaviors that are in part mediated by biological factors. Recent advances in molecular genetics and functional neuroimaging have provided a unique and exciting opportunity to non-invasively study the influence of genetic factors on brain function in humans. While genes do not code for specific behaviors, they do determine the structure and function of proteins that are essential to the neuronal processes that underlie behavior. Therefore, studying the interaction of genotype with measures of brain function over development could shed light on critical time points when biologically mediated individual differences in complex behaviors emerge. Here we review animal and human literature examining the neurobiological basis of adolescent development related to dopamine neurotransmission. Dopamine is of critical importance because of (1) its role in cognitive and affective behaviors, (2) its role in the pathogenesis of major psychopathology, and (3) the protracted development of dopamine signaling pathways over adolescence. We will then focus on current research examining the role of dopamine-related genes on brain function. We propose the use of imaging genetics to examine the influence of genetically mediated dopamine variability on brain function during adolescence, keeping in mind the limitations of this approach.     

COMT基因rs6267多态性与青少年期亲子亲合与冲突的关系：性别与父母教养行为的调节作用分析

采用基因－环境设计, 以208名初中生为被试, 系统考察COMT基因rs6267多态性与青少年期亲子亲合与冲突的关系, 以及性别与父母教养行为在其中的调节作用。结果显示rs6267多态性对亲子关系无显著主效应, 但其与亲子亲合、母子情绪冲突的关联模式在男女青少年群体中相反; rs6267多态性与父母积极教养行为对亲子关系无显著交互作用, 但其与母亲消极教养行为对母子冲突具有交互作用趋势。     

反社会行为潜在遗传因素的全基因组关联分析

反社会行为是一种受基因和环境共同影响的复杂性行为, 但单个基因如单胺氧化酶基因(MAOA)、5-羟色胺转运体启动因子基因(5-HTT)、儿茶酚-o-甲基转移酶(COMT)基因的影响并不能全面解释其产生的分子遗传机制。来自分子遗传学研究取向的方法—— 全基因组关联分析(genome-wide association study, GWAS), 把人类基因组中数以百万计的单核苷酸(SNPs)和复制数变异(CNVs)作为遗传标记, 在全基因组层面上, 开展多中心、大样本的关联研究, 经过反复验证来发现与外在表型相关的基因位点, 为进一步了解反社会行为复杂分子遗传机制提供了重要的线索。未来的研究应该通过科学的实验设计将精确的基因分型技术与心理、环境因素相结合, 实现对复杂性行为或特质的基因-心理-环境模型的成因性分析。     

Synaptogenesis and heritable aspects of executive attention

In humans, changes in brain structure and function can be measured non-invasively during postnatal development. In animals, advanced optical imaging measures can track the formation of synapses during learning and behavior. With the recent progress in these technologies, it is appropriate to begin to assess how the physiological processes of synapse, circuit, and neural network formation relate to the process of cognitive development. Of particular interest is the development of executive function, which develops more gradually in humans. One approach that has shown promise is molecular genetics. The completion of the human genome project and the human genome diversity project make it straightforward to ask whether variation in a particular gene correlates with variation in behavior, brain structure, brain activity, or all of the above. Strategies that unify the wealth of biochemical knowledge pertaining to synapse formation with the functional measures of brain structure and activity may lead to new insights in developmental cognitive psychology.     

A Multimethodological Study of Preschoolers' Preferences for Aggressive Television and Video Games

The association between aggressive media and related behavior is complicated, and the role of underlying genetics has not been adequately explored. A better understanding of the role of genetics on the relationship between aggressive media and behavior, especially in young children, is critical. Using a twin/triplets sample (N = 184 children), the authors investigated the association between preschoolers' preferred media choices and their aggressive behaviors. A multimeasure methodology was utilized, examining children's reports of their preferred media games and shows, observed child negativity and aggression in the lab, and parent reports of their own and their children's aggressive behaviors. The results demonstrated a significant relationship between maternal aggression and parent-reported child aggression, especially for boys. Genetic analyses demonstrated significant heritability for children's parent-reported aggressive behaviors, supporting the biological basis of aggression, but not for media aggression preferences. Controlling for genetics, the authors found that the association between media preferences and aggressive behavior may be genetic in origin. These results emphasize the importance of considering shared genetics underlying the relationship between children's aggressive behaviors and their media preferences, as well as environmental influences. By examining preschoolers, the present study provides insight into the importance of media influences in children younger than those previously studied.     

抑郁症的影像遗传学研究:探索基因与环境的交互作用

抑郁症具有中等的遗传度。通过影像遗传学方法探讨抑郁相关基因的多态性对神经活动的影响,发现编码五羟色胺、促肾上腺素释放激素受体、多巴胺等神经递质或受体的基因多态性会影响杏仁核、前扣带等情绪加工脑区的功能或结构,且多数基因与压力生活经历发生交互作用。表明基因与环境的交互作用在抑郁症发病机理中扮演重要角色。未来的研究应拓展遗传和神经影像分析方法,重视环境因素的测量,通过整合遗传、神经影像及环境变量构建抑郁病理模型。     

Myrtle McGraw''s Unrecognized Conceptual Contribution to Developmental Psychology

In the late nineteenth century and through much of the twentieth century, the notion of the early developmental autonomy of motor behavior pervaded behavioral embryology and the developmental psychology of infant behavior. In the midst of this predeterministic climate of opinion concerning motor development, Myrtle McGraw briefly and tentatively broached the probabilistic epigenetic notion of a bidirectional or reciprocal relationship between structural maturation and function, whereby structural maturation of the nervous system is influenced by functional activity as well as the other way around. Myrtle McGraw thus anticipated our current understanding of the role of experience in the cortical and motor maturation of infants in the first year of postnatal life. It is all the more remarkable that she made this contribution when the theoretical climate of opinion was epitomized by predeterministic epigenetic thinking. In the same vein, McGraw's second unrecognized contribution is her clear formulation of a suitably flexible critical period concept in 1935, one that is consonant with our current understanding.     

人类行为遗传学的伦理问题

行为遗传学是试图定位与行为特性有关的特殊基因或基因组及了解基因与环境之间复杂关系的一种研究.行为遗传学是研究正常范围内的非病理变化,与人类疾病遗传学存在差异.行为遗传学研究面临许多伦理学问题,诸如,智力的遗传性,基因能否决定一切,生物社会学与人类文化评估,生命伦理学与行为遗传学的关系等,因此,对行为遗传学研究结果的阐述必须十分谨慎.     

Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms

Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101–1204 genes), and the proportion of genes causing “classic” mitochondrial diseases and their phenocopies ranged widely between labs (18 %–94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %–28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %–49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.     

The basic traumatic situation in the analytical relationship1

The author attempts to develop a concept of psychic trauma which would comply with the nucleus of this Freudian notion, that is, an excess of excitations that cannot be processed by the mental apparatus, but which would also consider the functions and the crucial role of objects in the constitution of the psychism and in traumatic conditions, as well as taking into account the methodological positioning according to which the analytical relationship is the sole possible locus of observation, inference and intervention by the psychoanalyst. He considers as a basic or minimal traumatic psychoanalytical situation that in which a magnitude or quality of emotions exceeds the capacity for containment of the psychoanalytical pair, to the point of generating a period or area of dementalisation in the psyche of one or both of the participants, of requiring analytical work on the matter and promoting a signifi cant positive or negative change in the relationship. Availing himself of Bion's theory about the alpha function and the metapsychological conceptions of Freud and Green concerning psychic representations, he presents two theoretical formulations relating to this traumatic situation, utilising them according to the ‘altered focus’ model proposed by Bion. He presents three clinical examples to illustrate the concept and the relevant theoretical formulations.     

Androgyny and Sex-Typing as Continuous Independent Factors,and a Glimpse of the Future

Models for operationalizing the sex-role constructs androgyny and sex-typing are reviewed, and problems discussed. A new (principal components) model representing an exact solution is derived and shown to solve existing problems. In this model, androgyny is a function of the sum of standardized instrumentality and expressiveness scores, and sex-typing a function of the difference between these scores. Formal operationalization of these constructs reveals that they may have theoretical utility in only very contrived contingencies, and an alternative profile matching model is proposed. This latter theory, which is not yet fully specified, hypothesizes that an individual's performance is maximized when the critical operating characteristics of a contingency (i.e., instrumental and expressive behaviors required for maximal performance to result) exactly match the individual's specific instrumental and expressive predispositions, and that performance decreases as the discrepancy between the instrumental/expressive profiles of the individual and the contingency increases.     

Conditioned reinforcement: Experimental and theoretical issues

The concept of conditioned reinforcement has received decreased attention in learning textbooks over the past decade, in part because of criticisms of its validity by major behavior theorists and in part because its explanatory function in a variety of different conditioning procedures has become uncertain. Critical data from the major procedures that have been used to investigate the concept (second-order schedules, chain schedules, concurrent chains, observing responses, delay-of-reinforcement procedures) are reviewed, along with the major issues of interpretation. Although the role played by conditioned reinforcement in some procedures remains unresolved, the results taken together leave little doubt that the underlying idea of conditioned value is a critical component of behavior theory that is necessary to explain many different types of data. Other processes (marking, bridging) may also operate to produce effects similar to those of conditioned reinforcement, but these clearly cannot explain the full domain of experimental effects ascribed to conditioned reinforcement and should be regarded as complements to the concept rather than theoretical competitors. Examples of practical and theoretical applications of the concept of conditioned reinforcement are also considered.     

Update and Review: Cystic Fibrosis

Cystic fibrosis (CF) is one of the most commonly inherited recessive disorders in U.S. Caucasians, with a carrier frequency of approximately 1 in 29. Genetic counseling and CF mutation analysis has traditionally been offered to the affected patient and his/her extended family, in keeping with policy statements from professional organizations (ASHG, NSGC, ACOG). The target population for CF testing and counseling may be evolving after the release of the 1997 National Institutes of Health Consensus Statement, Genetic Testing for Cystic Fibrosis, which recommends that CF screening be offered to all preconceptional and pregnant couples. Genetic counseling for CF is complicated by reports of polymorphisms in the CF gene that are associated with symptoms that do not meet the diagnostic criteria for CF, such as bilateral congenital absence of the vas deferens, bronchiectasis, and idiopathic pancreatitis. To aid genetic counselors with these issues, this review explores the symptoms of CF, patient management, gene function, genetics, genotype/phenotype correlation, and genetic counseling issues.     

The therapeutic object relationship

This paper introduces the concept of the therapeutic object relationship in order to clarify our understanding of the nature of fully analytic work with the more regressive patient, which has unsystematically developed over the last 30 or 40 years. The need for such a clarifying concept seems to arise from several sources. Our analytic work with the more regressed patient appears to entail a relationship demand factor which cannot be usefully treated only as resistance to the development of the transference. These are patients with what may be described as object hunger emanating from faulted ego development and a disordered internal object world. This object hunger cannot be adequately met within the framework of the tacit, ordinary, good-enough environment of the concerned and nonjudgmental analyst. In addition, the literature on this subject still dichotomizes the relationship factor of treatment from the transference. The concept of the therapeutic object relationship appears to offer the possibility of a clinical and theoretical unification between transference and relationship. The major point of the paper may be described in terms of the manner in which we have progressed from Eissler's parameter paper of 1953 to the widened scope of analytic work made possible by object relations theory, developmental theory and observation of infant and child development. The face of analysis seems to have undergone profound modification from the early classical model to one in which developmental maturation, in addition to making unconscious conflict conscious, has become a matter for our concern. This change seems to require seeing the analyst as a special form of real object with whom the patient passes through a revised version of certain developmental pathways. The therapeutic object relationship is viewed as a potentially unifying concept which may make possible higher degrees of generalization about the variously unsystematized approaches to analyzing the more regressive, but nonpsychotic patient. Some history of definition of the analytic relationship in terms of transference or relationship is presented. In the course of the paper the therapeutic object relationship is gradually defined as one of: primal intimacy; increased permeability of boundaries between self and other; intensive empathic interaction; the evolution of self and object definition in a context of intimate relation with an object that is instrumental in this process; and the activation of transcendant forms of symbolic-creative intercommunication.(ABSTRACT TRUNCATED AT 400 WORDS)