Gene-environment interplay

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Gene-environment interplay describes how genes and environments work together to produce a phenotype, or observable trait. Many human traits are influenced by gene-environment interplay. It is a key component in understanding how genes and the environment come together to impact human development. Examples of gene-environment interplay include gene-environment interaction and gene-environment correlation. [1] Another type of gene-environment interplay is epigenetics, which is the study of how environmental factors can affect gene expression without altering DNA sequences. [2]

Contents

To study the effect of the environment on the expression of the human genome, family-based behavioral genetic research methods such as twin, family and adoption studies are used. [1] Moreover, the identification of genes under environmental influence can be completed through genome-wide association studies. [3] Research on cases of gene-environment interplay allow for a deeper understanding of the nuances surrounding nature versus nurture debates. Environmental factors can cause deviations from expected gene expression, which ultimately impact cellular processes, such as cell signaling. They can also affect the likelihood of disease. By identifying environmental effects on cellular processes, scientists can gain a better understanding of the mechanisms behind diseases and gain insights into treating them. [4]

Types

Some of the different types of gene-environment interplay. Adapted from Jaffee and Price, Psychiatry, 2008 and Flowers, Froelicher & Aouizerat, European Journal of Cardiovascular Nursing, 2012 Gene-evironment interplay flow chart.png
Some of the different types of gene-environment interplay. Adapted from Jaffee and Price, Psychiatry, 2008 and Flowers, Froelicher & Aouizerat, European Journal of Cardiovascular Nursing, 2012

Gene-environment interactions (GxE)

Gene–environment interaction occurs when genetic factors and environmental factors interact to produce an outcome that cannot be explained by either factor alone. [6] For example, a study found that individuals carrying the genetic variant 5-HTT (the short copy) that encodes the serotonin transporter were at a higher risk of developing depression when exposed to adverse childhood experiences, whereas those with other genotypes (long copy) were less affected by childhood maltreatment. However, there is a caveat as these stressful events may also be caused by an individual's predisposition for getting into these situations. [7]

Gene-environment correlation (rGE)

Gene–environment correlations describe how different environmental exposures are statistically linked to genes. [8] These correlations can emerge through multiple different mechanisms, both causal and non-causal. [9] In regard to causal mechanisms, there are three common types of gene-environment correlations: [9]

Passive

The childhood environment of an individual may be correlated with their inherited genes, since an individual's parents may have selected for their childhood environment. [5] This type of correlation is considered "passive" since the child's environment is being determined by parental decisions rather than by the child's own decisions. For example, parents who have high openness-to-experience, which is a moderately heritable personality trait, are more likely to provide their children with musical training. [10] Consequently, a correlation has also been documented between children with more openness-to-experience and their likelihood of receiving musical training as young children.

Evocative

This type of gene-environment correlation can emerge when an individual's genetics causes others to alter their environment. [5] For instance, one study on children in middle childhood found that a child's innate desire for autonomy partially determined the degree of maternal control evoked. [11]

Active

This occurs when individuals seek out environments that are compatible with their genetic predispositions. [5] For example, a person with a genetic predisposition for athleticism may be more inclined to choose sports-related activities and environments.[Citation needed]

Epigenetics

Epigenetics focuses on cellular changes in gene expression that do not involve changes in genetic code. [12] Epigenetic changes can be a result of cellular mechanisms or environmental factors. One instance of an environment impacting gene expression is DNA methylation as a result of smoking during pregnancy. [13] Another environmental exposure that can trigger epigenetic changes is heavy metals like arsenic. This is done through the disturbance of histone acetylation and DNA methylation which is correlated with increased rates of cancer, autoimmune diseases, and neurological disorders. [14]

Environmental factors

Pollutants

Epigenetic modifications can affect gene activity independently of DNA sequence modifications. [15] Air pollution exposure has been associated with decreased DNA methylation levels which is a process crucial for gene regulation. The effects of air pollution can be seen in the prenatal environment as methylation changed in response to the presence of NO2 and NOx ,which are forms of air pollution. When exposed to air pollution, there was a decline in intrauterine growth. While the mechanism is not fully understood, it could involve the formation of reactive oxygen species, leading to oxidative stress and cellular signaling cascade or increased fetal cortisol levels. [16] A consequence of altered DNA methylation is hydroxymethylation, which replaces the methyl group with a hydroxyl group. Hydroxymethylation potentially could disrupt gene expression patterns and contribute to disease development, such as lung cancer. [17] Additionally, exposure to pollutants can exacerbate inflammatory conditions like asthma by inducing inflammation in the airways. This leads to increased cytokine expression and immune cell recruitment. [16] Certain pollutants, such as endocrine-disrupting chemicals (EDC), interfere with hormone signaling pathways and gene expression related to hormone regulation. A certain type of EDC, bisphenol A has been linked to changes in gene expression in reproductive tissues and developmental pathways. [18]

Schematic representation of epigenetic histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011 Histone modifications.png
Schematic representation of epigenetic histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011

Malnutrition

Nutrition plays a crucial role in shaping gene expression, which can ultimately impact an individual's phenotype. Fetal malnutrition, for example, has been associated with decreased level DNA methylation, particularly on genes like IGF2, which is involved in insulin metabolism. [19] The alteration in DNA methylation patterns can elevate the risk of developing metabolic disorders and type II diabetes mellitus. [20] Furthermore, prenatal malnutrition can lead to differential DNA methylation of genes related to growth, development, and metabolism. These epigenetic changes increase the likelihood of adverse phenotypes such as obesity and high cholesterol later in life. [21] Malnutrition can also significantly impact gene expression in the small intestine, leading to alterations in nutrient transporters, digestive enzymes, barrier function, immune responses, and metabolic adaptation. [22] Socioeconomic factors such as poverty and minority status may exacerbate the effects of malnutrition. Research indicates that individuals that reside in impoverished communities or those who belong to marginalized racial and ethnic groups may encounter limited access to nutritious food options. [23]

Exercise

Physical activity induces epigenetic modifications of specific genes, altering their expression profiles. For example, exercise has been linked to increased methylation of the ASC gene, which typically decreases with age. Methylation can compact a gene, decreasing the amount of protein produced from the gene and the ASC gene stimulates cytokine production. Thus, the expression of inflammatory cytokines decreases. This suppression can help prevent the development of chronic inflammation and associated age-related diseases due to excess inflammatory cytokines. [24] However, these epigenetic modifications depend on the intensity and type of exercise and are reversible with the cessation of physical activity. [25] Research shows that exercise for more than six months can have an effect on telomere length. Elongation at the ends of chromosomes helps to maintain chromosomal stability and induces epigenetic modifications of specific genes. [26]

Prenatal environment

The maternal environment can have epigenetic effects on the developing fetus. For instance, alcohol consumed during pregnancy can cross from maternal blood to the placenta and into the fetal environment of the amniotic cavity, where it can induce epigenetic modifications on fetal DNA. [27] Mouse embryo cultures show that alcohol exposure during fetal development can contribute to changes in DNA methylation of genes involved in development, metabolism, and organization of DNA during brain development. [28] These alcohol-induced changes in DNA methylation during pregnancy contribute to the distinct set of traits seen in Fetal Alcohol Spectrum Disorder (FASD). [28] Other instances of prenatal environment impact on fetal epigenetic state include maternal folic acid, stress, and tobacco smoking during pregnancy. [29] [30] [31]

Early life stress

Early life stress encompasses parental absence, abuse, and lack of bonding. These stressors during early childhood are associated with epigenetic modifications of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which mediates the stress response. Using a rat model of maternal care, research has shown that reduced care between mother and offspring is associated with down regulation of glucocorticoid receptors (GR) in the hypothalamus. [32] GRs play a critical role in the HPA axis by aiding in the restoration of normal physiological state after stress exposure. Down regulation of GRs expression occurs through histone modifications and DNA methylation of the GR gene, resulting in dysregulation of the stress response, including prolonged inflammation and cellular damage. [33] Additionally, numerous studies have linked early life stress with later-life psychiatric disorders, including anxiety and depression, through epigenetic modulation of genes involved in the HPA axis. [34] Socioeconomic disparities, discrimination, and cultural factors prevalent within minority communities can contribute to heightened levels of stress and adversity, impacting gene expression and health outcomes. [35]

Studies

Adoption and twin studies

Adoption and twin studies are used to investigate the complex interplay between genes and the environment. These studies typically involve the comparison of identical (monozygotic) and fraternal (dizygotic) twins to determine the extent to which genetic factors and environmental influences contribute to variations in traits or behaviors. These studies have contributed to studies of behavior, personality, and psychiatric illnesses. [36] For example, a Finnish adoption study on schizophrenia revealed that a healthy environment can mitigate the effects of genetics in adopted individuals born to schizophrenic mothers. [37] Criminal and antisocial behavior have also been found to be influenced by both genetic and environmental factors through these types of studies. [38] [39]

Animal models

Animal models provide a controlled and manipulable environment in which researchers can investigate the complex interactions between genes and environmental factors, shedding light on various biological and behavioral outcomes. For example, one study has demonstrated the utility of mouse models in understanding gene-environment interactions in schizophrenia due to the genetic similarities. [40]

Research on moths and butterflies has shown that environmental factors like bright sunlight influences their color vision. In environments with more light, they develop more of different opsins which allow them to detect light and discern colors. Butterflies depend on color vision to find the correct flowers for their diet and their preferred habitat. [41]

Medical Conditions

Gene-environment interplay has been found to play a part in the majority of diseases. For instance, gene-environment interactions have a prevalent role in mental health disorders; specifically, evidence has found a link to alcohol dependence, [39] schizophrenia, [42] and psychosis. [43] The link to alcohol dependence is potentially influenced by a dopamine receptor gene (DRD2) as individuals with the TaqI allele may have interactions involving this allele and alcohol dependence. [39] This interaction is more prevalent when the individual is experiencing higher stress levels. The impacts on psychosis originate from a single nucleotide polymorphism (SNP), in the AKT1 gene. This causes its carriers who regularly use cannabis to be more susceptible to developing psychosis. Additionally, individuals who are homozygous for this particular AKT1 mutation and use cannabis daily are at an increased risk for developing psychotic disorders. [43] For schizophrenia, genome-wide by environment interaction studies (GWEIS) and genome-wide association studies (GWAS) are used to determine the loci at environmental factors used in the determination of GxE. [43] Evidence also supports that gene-environment interplay is connected to cardiovascular and metabolic conditions. [4] These include roles in obesity, [3] pulmonary disease, [44] and diabetes. [45] The rise in the incidence of type II diabetes is suggested to be linked to interactions between diet and the FTO andKCNQ1 genes. Mutations within the KCNQ1 gene affects a pathway that leads to a decrease in insulin secretion due to a decline in pancreatic β cells, but within mice fed a high fat diet enhanced the dysfunction within the pancreatic β cells. [45]

Related Research Articles

A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and genotype of its mother. In genetics, maternal effects occur when an organism shows the phenotype expected from the genotype of the mother, irrespective of its own genotype, often due to the mother supplying messenger RNA or proteins to the egg. Maternal effects can also be caused by the maternal environment independent of genotype, sometimes controlling the size, sex, or behaviour of the offspring. These adaptive maternal effects lead to phenotypes of offspring that increase their fitness. Further, it introduces the concept of phenotypic plasticity, an important evolutionary concept. It has been proposed that maternal effects are important for the evolution of adaptive responses to environmental heterogeneity.

Schizophrenia is a neurodevelopmental disorder with no precise or single cause. Schizophrenia is thought to arise from multiple mechanisms and complex gene–environment interactions with vulnerability factors. Risk factors of schizophrenia have been identified and include genetic factors, environmental factors such as experiences in life and exposures in a person's environment, and also the function of a person's brain at it develops. The interactions of these risk factors are intricate, as numerous and diverse medical insults from conception to adulthood can be involved. Many theories have been proposed including the combination of genetic and environmental factors may lead to deficits in the neural circuits that affect sensory input and cognitive functions.

Metabolic imprinting refers to the long-term physiological and metabolic effects that an offspring's prenatal and postnatal environments have on them. Perinatal nutrition has been identified as a significant factor in determining an offspring's likelihood of it being predisposed to developing cardiovascular disease, obesity, and type 2 diabetes amongst other conditions.

Prenatal stress is exposure of an expectant mother to psychosocial or physical stress, which can be caused by daily life events or by environmental hardships. This psychosocial or physical stress that the expectant mother is experiencing has an effect on the fetus. According to the Developmental Origins of Health and Disease (DOHaD), a wide range of environmental factors a woman may experience during the perinatal period can contribute to biological impacts and changes in the fetus that then causes health risks later in the child's life.

Nutriepigenomics is the study of food nutrients and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation and lactation are linked to non-communicable diseases, such as obesity, cardiovascular disease, diabetes, hypertension, and cancer. If metabolic disturbances occur during critical time windows of development, the resulting epigenetic alterations can lead to permanent changes in tissue and organ structure or function and predispose individuals to disease.

<span class="mw-page-title-main">Transgenerational epigenetic inheritance</span> Epigenetic transmission without DNA primary structure alteration

Transgenerational epigenetic inheritance is the transmission of epigenetic markers and modifications from one generation to multiple subsequent generations without altering the primary structure of DNA. Thus, the regulation of genes via epigenetic mechanisms can be heritable; the amount of transcripts and proteins produced can be altered by inherited epigenetic changes. In order for epigenetic marks to be heritable, however, they must occur in the gametes in animals, but since plants lack a definitive germline and can propagate, epigenetic marks in any tissue can be heritable.

Developmental origins of health and disease (DOHaD) is an approach to medical research factors that can lead to the development of human diseases during early life development. These factors include the role of prenatal and perinatal exposure to environmental factors, such as undernutrition, stress, environmental chemical, etc. This approach includes an emphasis on epigenetic causes of adult chronic non-communicable diseases. As well as physical human disease, the psychopathology of the foetus can also be predicted by epigenetic factors.

Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal and human behavior. It seeks to explain how nurture shapes nature, where nature refers to biological heredity and nurture refers to virtually everything that occurs during the life-span. Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health.

The epigenetics of schizophrenia is the study of how inherited epigenetic changes are regulated and modified by the environment and external factors and how these changes influence the onset and development of, and vulnerability to, schizophrenia. Epigenetics concerns the heritability of those changes, too. Schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. Although schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding; epigenetics offers a new avenue for research, understanding, and treatment.

Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.

The fetal origins hypothesis proposes that the period of gestation has significant impacts on the developmental health and wellbeing outcomes for an individual ranging from infancy to adulthood. The effects of fetal origin are marked by three characteristics: latency, wherein effects may not be apparent until much later in life; persistency, whereby conditions resulting from a fetal effect continue to exist for a given individual; and genetic programming, which describes the 'switching on' of a specific gene due to prenatal environment. Research in the areas of economics, epidemiology, and epigenetics offer support for the hypothesis.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

<span class="mw-page-title-main">Frances Champagne</span> Psychologist

Frances A. Champagne is a Canadian psychologist and University Professor of Psychology at the University of Texas at Austin known for her research in the fields of molecular neuroscience, maternal behavior, and epigenetics. Research in the Champagne lab explores the developmental plasticity that occurs in response to environmental experiences. She is known for her work on the epigenetic transmission of maternal behavior. Frances Champagne's research has revealed how natural variations in maternal behavior can shape the behavioral development of offspring through epigenetic changes in gene expression in a brain region specific manner. She won the NIH Director's New Innovator Award in 2007 and the Frank A. Beach Young Investigator Award in Behavioral Neuroendocrinology in 2009. She has been described as the "bee's knees of neuroscience". She serves on the Committee on Fostering Healthy Mental, Emotional, and Behavioral Development Among Children and Youth in the United States.

Epigenetic effects of smoking concerns how epigenetics contributes to the deleterious effects of smoking. Cigarette smoking has been found to affect global epigenetic regulation of transcription across tissue types. Studies have shown differences in epigenetic markers like DNA methylation, histone modifications and miRNA expression between smokers and non-smokers. Similar differences exist in children whose mothers smoked during pregnancy. These epigenetic effects are thought to be linked to many of negative health effects associated with smoking.

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

Fetal programming, also known as prenatal programming, is the theory that environmental cues experienced during fetal development play a seminal role in determining health trajectories across the lifespan.

Sleep epigenetics is the field of how epigenetics affects sleep.

Environmental epigenetics is a branch of epigenetics that studies the influence of external environmental factors on the gene expression of a developing embryo. The way that genes are expressed may be passed down from parent to offspring through epigenetic modifications, although environmental influences do not alter the genome itself.

Nutritional epigenetics is a science that studies the effects of nutrition on gene expression and chromatin accessibility. It is a subcategory of nutritional genomics that focuses on the effects of bioactive food components on epigenetic events.

In Environmental epigenetics, Exposure to certain materials or chemicals can cause an epigenetic reaction. The epigenetic causing substances cause issues like altered DNA methylation, CpG islands, chromatin, along with other transcription factors. Environmental epigenetics aims to relate such environmental triggers or substances to phenotypic variation. Numerrous studies have demonstrated how exposure to environmental pollutants, such as heavy metals, pesticides, and air pollutants, can induce epigenetic changes in various organisms. For example, research has shown that exposure to pollutants like biphenol A (BPA) and polycyclic acromatic hydrocarbons (PAHs) can lead to DNA methylation changes and histone modifications in plants, animals, and humans.

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