Epigenetic determinism in science and society

The epigenetic “revolution” in science cuts across many disciplines, and it is now one of the fastest-growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism – or the belief that epigenetic mechanisms determine the expression of human traits and behaviors – matters for understandings of the influence of biology and society on population health.     

Genome-wide prediction of functional gene-gene interactions inferred from patterns of genetic differentiation in mice and men

The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits is to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting GxG interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidate interactions that can be empirically tested. In both the mouse and human data we observed two-locus genetic differentiation in excess of what can be expected from chance alone based on simulations. In an attempt to validate our hypothesis that pairs of genes showing excess genetic divergence represent potential functional interactions, we selected a small set of gene combinations postulated to be interacting based on our analyses and looked for a combined effect of the selected genes on variation in complex traits in both mice and man. In both cases the individual effect of the genes were not significant, instead we observed marginally significant interaction effects. These results show that genome wide searches for gene-gene interactions based on population genetic data are feasible and can generate interesting candidate gene pairs to be further tested for their contribution to phenotypic variation in complex traits.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

Selection and genetic (co)variance in bighorn sheep

Genetic theory predicts that directional selection should deplete additive genetic variance for traits closely related to fitness, and may favor the maintenance of alleles with antagonistically pleiotropic effects on fitness-related traits. Trait heritability is therefore expected to decline with the degree of association with fitness, and some genetic correlations between selected traits are expected to be negative. Here we demonstrate a negative relationship between trait heritability and association with lifetime reproductive success in a wild population of bighorn sheep (Ovis canadensis) at Ram Mountain, Alberta, Canada. Lower heritability for fitness-related traits, however, was not wholly a consequence of declining genetic variance, because those traits showed high levels of residual variance. Genetic correlations estimated between pairs of traits with significant heritability were positive. Principal component analyses suggest that positive relationships between morphometric traits constitute the main axis of genetic variation. Trade-offs in the form of negative genetic or phenotypic correlations among the traits we have measured do not appear to constrain the potential for evolution in this population.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

The genetics of complex diseases

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.     

Biological explanations and social responsibility

The aim of this paper is to show that critics of biological explanations of human nature may be granting too much to those who oppose such explanations when they argue that the truth of genetic determinism implies an end to critical evaluation and reform of our social institutions. This is the case because when we argue that biological determinism exempts us from social critique we are erroneously presupposing that our social values, practices, and institutions have nothing to do with what makes biological explanations troublesome. My argument is that what constitutes a problem for those who are concerned with social justice is not the fact that particular behaviours may be genetically determined, but the fact that our value system, and social institutions create the conditions that make such behaviours problematic. Thus, I will argue that even if genetic determinism were correct, the requirement of assessing and transforming our social practices and institutions would be far from superfluous. Biology is rarely destiny for human beings and the institutions they create.     

Beyond Mendel: an evolving view of human genetic disease transmission

Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits.     

What are genes “for” or where are traits “from”? What is the question?

For at least a century it has been known that multiple factors play a role in the development of complex traits, and yet the notion that there are genes “for” such traits, which traces back to Mendel, is still widespread. In this paper, we illustrate how the Mendelian model has tacitly encouraged the idea that we can explain complexity by reducing it to enumerable genes. By this approach many genes associated with simple as well as complex traits have been identified. But the genetic architecture of biological traits, or how they are made, remains largely unknown. In essence, this reflects the tension between reductionism as the current “modus operandi” of science, and the emerging knowledge of the nature of complex traits. Recent interest in systems biology as a unifying approach indicates a reawakened acceptance of the complexity of complex traits, though the temptation is to replace “gene for” thinking by comparably reductionistic “network for” concepts. Both approaches implicitly mix concepts of variants and invariants in genetics. Even the basic question is unclear: what does one need to know to “understand” the genetic basis of complex traits? New operational ideas about how to deal with biological complexity are needed.     

Biological races in humans

Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two most commonly used biological concepts of race, chimpanzees are indeed subdivided into races but humans are not. Adaptive traits, such as skin color, have frequently been used to define races in humans, but such adaptive traits reflect the underlying environmental factor to which they are adaptive and not overall genetic differentiation, and different adaptive traits define discordant groups. There are no objective criteria for choosing one adaptive trait over another to define race. As a consequence, adaptive traits do not define races in humans. Much of the recent scientific literature on human evolution portrays human populations as separate branches on an evolutionary tree. A tree-like structure among humans has been falsified whenever tested, so this practice is scientifically indefensible. It is also socially irresponsible as these pictorial representations of human evolution have more impact on the general public than nuanced phrases in the text of a scientific paper. Humans have much genetic diversity, but the vast majority of this diversity reflects individual uniqueness and not race.     

Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice

Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human.     

Genetic mapping of determinants in drug resistance,virulence, disease susceptibility,and interaction of host-rodent malaria parasites

Genetic mapping has been widely employed to search for genes linked to phenotypes/traits of interest. Because of the ease of maintaining rodent malaria parasites in laboratory mice, many genetic crosses of rodent malaria parasites have been performed to map the parasite genes contributing to malaria parasite development, drug resistance, host immune response, and disease pathogenesis. Drs. Richard Carter, David Walliker, and colleagues at the University of Edinburgh, UK, were the pioneers in developing the systems for genetic mapping of malaria parasite traits, including characterization of genetic markers to follow the inheritance and recombination of parasite chromosomes and performing the first genetic cross using rodent malaria parasites. Additionally, many genetic crosses of inbred mice have been performed to link mouse chromosomal loci to the susceptibility to malaria parasite infections. In this chapter, we review and discuss past and recent advances in genetic marker development, performing genetic crosses, and genetic mapping of both parasite and host genes. Genetic mappings using models of rodent malaria parasites and inbred mice have contributed greatly to our understanding of malaria, including parasite development within their hosts, mechanism of drug resistance, and host-parasite interaction.     

Getting under the skin: the immunogenetics of psoriasis

Psoriasis is a chronic inflammatory disorder of the skin that is mediated by T cells, dendritic cells and inflammatory cytokines. We now understand many of the cellular alterations that underlie this disease, and genomic approaches have recently been used to assess the alterations of gene expression in psoriatic skin lesions. Genetic susceptibility factors that contribute to predisposition to psoriasis are now also being identified. It is hoped that we will soon be able to correlate the cellular pathogenesis that occurs in psoriasis with these genetic factors. In this Review article, we describe what is known about genes that confer increased susceptibility to psoriasis, and we integrate this with what is known about the molecular and cellular mechanisms that occur in other inflammatory and autoimmune disorders.     

Mouse model of the human serotonin transporter-linked polymorphic region

Genetic factors play a significant role in risk for mood and anxiety disorders. Polymorphisms in genes that regulate the brain monoamine systems, such as catabolic enzymes and transporters, are attractive candidates for being risk factors for emotional disorders given the weight of evidence implicating monoamines involvement in these conditions. Several common genetic variants have been identified in the human serotonin transporter (5-HTT) gene, including a repetitive sequence located in the promoter region of the locus called the serotonin transporter-linked polymorphic region (5-HTT-LPR). This polymorphism has been associated with a number of mental traits in both humans and primates, including depression, neuroticism, and harm avoidance. Some, but not all, studies found a link between the polymorphism and 5-HTT levels, leaving open the question of whether the polymorphism affects risk for mental traits via changes in 5-HTT expression. To investigate the impact of the polymorphism on gene expression, serotonin homeostasis, and behavioral traits, we set out to develop a mouse model of the human 5-HTT-LPR. Here we describe the creation and characterization of a set of mouse lines with single-copy human transgenes carrying the short and long 5-HTT-LPR variants. Although we were not able to detect differences in expression between the short and long variants, we encountered several technical issues concerning the design of our humanized mice that are likely to have influenced our findings. Our study serves as a cautionary note for future studies aimed at studying human transgene regulation in the context of the living mouse.

     

Understanding quantitative genetic variation

Until recently, it was impracticable to identify the genes that are responsible for variation in continuous traits, or to directly observe the effects of their different alleles. Now, the abundance of genetic markers has made it possible to identify quantitative trait loci (QTL)--the regions of a chromosome or, ideally, individual sequence variants that are responsible for trait variation. What kind of QTL do we expect to find and what can our observations of QTL tell us about how organisms evolve? The key to understanding the evolutionary significance of QTL is to understand the nature of inherited variation, not in the immediate mechanistic sense of how genes influence phenotype, but, rather, to know what evolutionary forces maintain genetic variability.     

Mitochondrial genetic effects on latent class variables associated with susceptibility to alcoholism

We report the results of statistical genetic analyses of data from the Collaborative Study on the Genetics of Alcoholism prepared for the Genetic Analysis Workshop 14 to detect and characterize maternally inherited mitochondrial genetic effects on variation in latent class psychiatric/behavioral variables employed in the diagnosis of alcoholism. Using published extensions to variance decomposition methods for statistical genetic analysis of continuous and discrete traits we: 1) estimated the proportion of the variance in each trait due to the effects of mitochondrial DNA (mtDNA), 2) tested for pleiotropy, both mitochondrial genetic and residual additive genetic, between trait pairs, and 3) evaluated whether the simultaneous estimation of mitochondrial genetic effects on these traits improves our ability to detect and localize quantitative trait loci (QTL) in the nuclear genome. After correction for multiple testing, we find significant (p < 0.009) mitochondrial genetic contributions to the variance for two latent class variables. Although we do detect significant residual additive genetic correlations between the two traits, there is no evidence of a residual mitochondrial genetic correlation between them. Evidence for autosomal QTL for these traits is improved when linkage screens are conditioned on significant mitochondrial genetic effects. We conclude that mitochondrial genes may contribute to variation in some latent class psychiatric/behavioral variables associated with alcoholism.     

甘蓝型油菜矮秆突变材料99CDAM的发现及遗传分析

随着杂种优势的利用,油菜株高增加了20cm以上,导致油菜生长后期倒伏的风险加大。通过利用特殊矮秆基因来控制株高将是解决倒伏问题的有效方法。在甘蓝型油菜自交多代品系中发现了一个株高85cm左右的矮秆突变株99CDAM,该突变株具有开花早、分枝多等优良特性,产量性状和品质性状较好,各性状都能稳定遗传,具有重要的育种价值。对99CDAM和高秆品系2091、7045和7350的正反交F1以及99CDAM和2091的F2、BC1及F2:3代的遗传分析结果表明： 99CDAM的矮秆性状受3对隐性基因控制,存在母体细胞质效应,与以往的甘蓝型矮秆油菜有明显的区别。     

Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. An enormous effort is currently ongoing to recognize and catalogue human CNVs and their associations with abnormal phenotypic outcomes. Recently, several reports related neuropsychiatric diseases (i.e. autism spectrum disorders, schizophrenia, mental retardation, behavioral problems, epilepsy) with specific CNV. Moreover, for some conditions, both the deletion and duplication of the same genomic segment are related to the phenotype. Syndromes associated with CNVs (microdeletion and microduplication) have long been known to display specific neurobehavioral traits. It is important to note that not every gene is susceptible to gene dosage changes and there are only a few dosage sensitive genes. Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes are associated with a reciprocal microdeletion and microduplication within chromosome 17p11.2. in humans. The dosage sensitive gene responsible for most phenotypes in SMS has been identified: the Retinoic Acid Induced 1 (RAI1). Studies on mouse models and humans suggest that RAI1 is likely the dosage sensitive gene responsible for clinical features in PTLS. In addition, the human RAI1 gene has been implicated in several neurobehavioral traits as spinocerebellar ataxia (SCA2), schizophrenia and non syndromic autism. In this review we discuss the evidence of RAI1 as a dosage sensitive gene, its relationship with different neurobehavioral traits, gene structure and mutations, and what is known about its molecular and cellular function, as a first step in the elucidation of the mechanisms that relate dosage sensitive genes with abnormal neurobehavioral outcomes.