The ghost in our genes: legal and ethical implications of epigenetics.

Author:Rothstein, Mark A.
 
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Abstract: Epigenetics is one of the most scientifically important, and legally and ethically significant, cutting-edge subjects of scientific discovery. Epigenetics link environmental and genetic influences on the traits and characteristics of an individual, and new discoveries reveal that a large range of environmental, dietary, behavioral, and medical experiences can significantly affect the future development and health of an individual and their offspring. This article describes and analyzes the ethical and legal implications of these new scientific findings.

THE GHOST IN OUR GENES: LEGAL AND ETHICAL IMPLICATIONS OF EPIGENETICS

"At the heart of this new field [of epigenetics] is a simple but contentious idea--that genes have a 'memory.' That the lives of your grandparents--the air they breathed, the food they ate, even the things they saw--can directly affect you, decades later, despite your never experiencing these things yourself." BBC, Ghost in Your Genes.

TABLE OF CONTENTS I. INTRODUCTION II. BACKGROUND A. Description of Epigenetics B. The Roles of Epigenetic Programming in Normal Cells C. Examples of Abnormal Epigenetic Effects 1. Cancer 2. Adult Onset Diseases 3. Transgenerational Effects of Endocrine Disrupting Chemicals 4. Ionizing Radiation 5. Smoking and Air Pollution 6. Diet 7. In Vitro Fertilization 8. Aging 9. Maternal Behavior D. Unique Aspects of Epigenetic Changes E. Questions Remaining to be Answered in Epigenetics Research III. LEGAL IMPLICATIONS A. Regulatory Applications 1. Environmental Regulation 2. Food and Drug Regulation 3. Occupational Safety and Health Regulation B. Litigation Applications C. Discrimination in Employment Against Fertile Women D. Other Forms of Discrimination IV. ETHICAL IMPLICATIONS A. Environmental Justice B. Privacy and Confidentiality C. Equitable Access to Health Care D. Intergenerational Equity E. Eugenics V. CONCLUSION I. INTRODUCTION

Following completion of the sequencing of the human genome in 2003, the functional analysis of the human genetic code seemed to be a relatively straightforward task. In fact, notwithstanding the enormous progress in understanding the genetic basis of diseases and other traits made possible by the Human Genome Project, full understanding of human genetic processes has turned out to be far more complex than initially expected. Perhaps the most important of these complexities is epigenetics, which plays a major role in the expression of human genetic traits. From cancer to environmental toxicity to maternal behavioral effects to in vitro fertilization risks, epigenetic effects play an important, previously under-appreciated role in the interaction of nature and nurture to determine human traits.

Epigenetic changes are alterations in the chemical modification of DNA that do not involve modifying the actual DNA sequence, which is the genetic information coding for the various inherited traits and predispositions in humans and other organisms. Although epigenetic effects do not change the genetic code per se, they leave "marks" on the DNA sequence, which in turn affect whether, when, and how specific segments of the genetic code are turned on or "expressed." Accordingly, the genetic code has been compared to the hardware of a computer, whereas epigenetic information has been compared to computer software that controls the operation of the hardware. (1) Further, the factors that affect the epigenetic information may be analogized as parameters for operating the software.

There is growing awareness of the importance of epigenetics from both a health and policy perspective. (2) This is due in large part to the realization that the epigenome is highly sensitive and responsive to environmental influences, including toxic exposures, dietary factors, and behavioral impacts. While the nature and importance of at least some epigenetic changes are well-established, many of the implications and mechanisms of epigenetics remain uncertain or speculative. Although the term epigenetics has been used for decades, most of the progress and insights in understanding epigenetics has occurred in the past decade, and much remains to be understood. Several major scientific undertakings have recently focused efforts on epigenetic research, and significant new developments in this field are occurring on a continual basis. It is clear that epigenetics is an enormously important and generally under-appreciated mediator between the environment and genetics, and epigenetics is already presenting important regulatory, legal, and ethical issues.

This article provides an initial exploration of the legal and ethical implications of the rapidly emerging science of epigenetics. Part II defines epigenetics, summarizes the characteristics of epigenetic mechanisms, and describes the current state of research in this emerging field. Some examples of effects that can result from aberrations in epigenetics are also discussed. Part III explores legal issues raised by epigenetic data, including both regulatory and litigation applications. Part IV addresses the ethical implications of epigenetics. Part V concludes by noting the conceptual and practical challenges in societal responses to epigenetics.

  1. BACKGROUND

    1. Description of Epigenetics

      The term "epigenetics" was first introduced in 1942 by Conrad Waddington to describe the interactions of genes with their environment, which bring the phenotype into being,s Today, epigeneties refers to modifications of the genome that do not involve a change of DNA sequence (i.e., the A's, C's, G's and T's that code information in DNA). (4 Until recently, most genetic variation was believed to be caused by mutations that change the DNA sequence, thus resulting in altered gene products with different properties affecting the development of phenotypic traits, such as eye color, metabolism, and disease susceptibility. (5) While epigenetic changes can result in changes in the expression of these same traits, they do so not by changing the form or function of gene products, but by altering the timing and quantity of their production in tissues at key points in time. (6) Changes in determining which genes are expressed and their degree of expression can have dramatic effects on the development and characteristics of an organism.

      Some epigenetic changes involve chemical alterations to the DNA molecule itself, most commonly the addition of a methyl group to cytosine bases (the "C's") to form methyl-cytosine, (7) which makes the DNA molecule in that region less likely to be expressed. This binding predominantly occurs at sites where a C precedes a guanine ("G") base to form what is referred to as a CpG site. (8) In somatic cells, approximately 70 percent of the over 28 million CpG units in the human genome are normally methylated, helping to suppress expression of many genes. (9) CpG sites often are clustered upstream of many mammalian genes to form CpG islands. These upstream regions are often the "promoter" region of a gene, where the binding of a specific molecule (the "promoter protein") that recognizes the promoter sequence will cause the gene to be expressed.

      When the CpG islands are relatively unmethylated, that region of the chromosome is in an "open" configuration that permits increased accessibility to the gene promoter. (10) In contrast, binding of a methyl group to a cytosine base makes the DNA strand less available to be expressed. If enough of the cytosine bases in a CpG island upstream of a gene are methylated ("hypermethylation"), these epigenetic changes will turn off the gene. There is thus an inverse relationship between DNA methylation and gene expression. (11) Methylation is responsible for the normal suppression of many genes in somatic cells. (12)

      Other epigenetic changes involve chemical alterations to the proteins that bind with DNA to form chromosomes, including methylation or acetylation of histone proteins that bind with DNA and affect the higher-order structure of chromosomes and the nucleus. (13) For example, the acetylation of historic proteins signals an open configuration of the chromosomal region that promotes expression, whereas deacetylation causes the chromosome to become more compacted and inactive. (14) The third and most recently discovered type of epigenetic effect is RNA interference, which involves RNA molecules produced from DNA binding back to the DNA at specific sites to turn off gene expression. (15) Although the various types of epigenetic changes have generally been studied separately until recently, "[i]t is becoming clear that significant crosstalk exists between different epigenetic pathways." (16) Each epigenetic change is referred to as a "mark," and the total set of epigenetic marks in an organism is referred to as the epigenome.

      An important aspect of epigenetic changes is that they are durable, have a propensity to spread, and can even be transmitted from one generation to the next. Some epigenetic alterations, in particular DNA methylation changes, are inheritable both from a progenitor cell to its progeny cells through the process of mitosis (cell division), and from a progenitor organism to its progeny organisms through the process of meiosis (sexual reproduction). (17) Thus, for example, when the DNA strand copies itself when a cell divides, the methyl groups on the parent DNA strand are copied onto the new daughter DNA strand. A growing body of evidence exists in animals, plants, and humans that epigenetic effects induced by many types of stimuli and interventions-including nutrition, endocrine disrupting chemicals, maternal care, and maternal stress-can be inherited transgenerationally and affect subsequent generations. (18)

      Another important aspect of epigenetic effects is that they are sensitive to the stage of development, at which epigenetic patterns are subject to reconfiguration or "reprogramming." (19) The age at which an organism is exposed to...

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