Epigenetics, and human biology and health responses to modernization in the Samoan archipelago.

Understanding human biological and disease risk responses to the changing environmental conditions from economic modernization and globalization has been a key area for biological anthropology and human biology research for the last thirty years (Baker et al 1986, Leonard et al 2009). These more recent studies are built on the long-standing concern for how biological and behavioral phenotypes are a product of the combined actions of genetic factors and environmental exposures through the lifespan. As molecular biology, genetics of development, genetic epidemiology and population genetics have made progress our more simple models have had to integrate the increased knowledge of how genetic and environment factors work together to form the range of phenotypes and health conditions of interest to human population biologists (Laland et al 2010). The impact of structural genetic variation, i.e., the usually understood coding region or exon, on human phenotypes and health has been less easy to decode, although there are key successes including 1) sickle cell and other hemoglobin variants and malaria (Richer and Chudley 2005), 2) lactase persistence in relation to dairy products consumption (Jarvela et al 2009) and 3) the start of unraveling the genetics of the variety of human adaptations to high altitude hypoxia (Beall et al 2010). The rapid changes in contemporary ways of life, especially dietary intake, physical activity patterns, changes in natural selection from infectious disease mortality and the psychosocial stressors present unique challenges for research on the interplay of genetic factors and environmental exposures. The essence of gene by environment interaction, as Ellen Demerath discusses in this issue, lies in the alterations in the way the structural genetic variants express their amino acids, protein products and ultimately, measurable phenotypes, in response to variation in environmental exposures, conditioned on the complexities of development stage, age and sex. The observation of phenotypes changing in different environments is a classic one in human biology and biological anthropology including century-old studies growth and development changes in migrants to higher resource societies (Boas 1912), regardless of the current understanding of the biological mechanisms. More recently and currently, studies continue to find gene-by-environment interactions in the rising context of non-communicable diseases (NCDs), such as obesity, diabetes and hypertension in relation to the excess energy balance stemming from the global nutrition transitions (Hunter 2005, Baylin et al 2012). The new challenge for molecular biologists is to document how the environment embodies its effects on gene transcription and translation, on the level and rate of amino acids produced and then on phenotypes (Attar 2012, Meissner 2012). The principles of epigenetic processes and how these are regulated has become crucially important because of the limited success provided by the last ten years of genome-wide association studies (GWAS) (Feinberg 2007, Manolio et al 2009). The first generation of GWAS proceeded on the common disease and common genetic variant assumption, i.e. that the common diseases of public health interest, NCDs such as obesity and diabetes, non-rare cancers, and neuropsychiatric conditions such as depression, would be influenced by non-rare, or common, risk alleles at SNPs generally defined as q > 0.05 in frequency. Although GWAS have identified hundreds of common variants associated with complex traits, they explain only a small fraction of phenotypic variance (Stranger et al 2011). Thus the contribution of allelic variants at the exon or exons, i.e., the structural genes, to phenotypic variation or disease risk is much smaller than optimistically hoped at the start of the genomic era. The key insight of the epigenetic perspective is that the regulation of gene expression at structural genes or exons, happens in other adjacent or distant genomic regions. The greatest degree of progress in unraveling epigenetic process has been made in DNA methylation. The addition of a methyl group to the five position of the cytosine pyrimidine ring or the number six nitrogen of the adenine purine ring. DNA methylation, particularly in CG-rich promoter sequences (CpG islands) has been shown to modify gene expression in a heritable manner (Hunter 2005, Feinberg 2007). As one of the most accessible biomarkers of epigenetic modification, DNA methylation has been widely studied in cancer and other human diseases but only recently has research begun to characterize epigenetic variation in normal tissues and at critical developmental time points, such as fetal development where major epigenetic reprogramming occurs. The level of DNA methylation at specific gene regulatory sites, as well as throughout the whole genome, is currently under study by many groups, as excitement builds about the ability to disentangle how well-measured environmental exposures lead to increased or decreased DNA methylation and contribute to transcription and translation processes of specific exons (Rakyan et al 2011). For us the questions are, ‘what is the importance of these new research areas and findings for our focus on the biology and health profiles of societies in transition’?, and ‘what are the policy consequences of such anthropological, biological and epidemiologic research for societies experiencing diverse forms of political and economic change’? A related set of epigenetic questions applied to health and biology of ethnic and minority groups in high income nations has been presented and discussed by Kuzawa and Sweet (2009). They emphasized in a very creative manner how health disparities stemming from poverty and discrimination are embodied in biology and disease risk through epigenetic mechanisms. Influenced by all these innovations this paper presents some preliminary results on gene by environment expression and epigenetics from my 35-year long research on modernizing Samoans. Lastly, I offer some brief ideas about how societies may intellectually contextualize public health prevention and medical treatment efforts given this perspective.