ReviewTwins for epigenetic studies of human aging and development
Highlights
► Summarize newest development in making use of twins in epigenetic studies on human aging. ► Introduce new extension of the classical twin design to studying molecular phenotypes. ► Propose novel approaches for finding loci under epigenetic regulation in human aging. ► Associate changes in the observed epigenetic phenotypes with environmental variables.
Introduction
The human life expectancy experienced a remarkable increase during the last century with an unprecedented gain in the developed world (Christensen et al., 2009) and similar improvement has been observed or expected in the developing countries. At the same time, researches have shown even larger improvement in health expectancy than in lifespan (Jeune and Brønnum-Hansen, 2008, Robine, 2006). These phenomena suggest the important role of improving environment in determining individual health status and survival. Although social-economic development and consequently advances in biomedical technology together with improved healthcare and disease treatment can be considered in explaining these changes, studying the biological mechanism of how environmental attributes affect individual health is of central importance to public health. In the literature, recent studies have shown that the impact of environmental factors can be acquired via the epigenome or genome in epigenetics (Fraga et al., 2005, Wong et al., 2005, Poulsen et al., 2007, Szyf et al., 2008, Ling and Groop, 2009, Tan et al., 2010, Petronis, 2010), one of the current topics in cancer and complex disease studies drawing active research. Although the molecular evidences are interesting and current techniques such as those offered by Affymetrix and Illumina allow genome-wide epigenetic (DNA methylation) profiling, identifying and understanding the epigenetic patterns under a given genetic predisposition and environmental exposures impose new challenges to traditional epidemiology both in experimental design and in methodological issues.
Twins are of special interest for genetic studies due to their genetic similarity and rearing-environmental sharing. The last century witnessed successful uses of twins in exploring the genetic and environmental contributions to human diseases and other complex traits like, e.g. life span and aging. The twin design makes use of the unique genetic make-ups in twins and infers the genetic importance in human diseases or traits. By comparing phenotype correlation in identical or monozygotic (MZ) and fraternal or dizygotic (DZ) twin pairs, various genetic and environmental components can be assessed using the classical twin design. For example, the heritability for human lifespan was estimated about 25% using Danish twins (Herskind et al., 1996, Hjelmborg et al., 2006) meaning that about one quarter of the human life span variation can be accounted for by genetic factors. In our recent review (Tan et al., 2010), the use of twins in functional genomic studies of human complex diseases has been summarized and new approaches that expand the traditional twin design to molecular genetic studies proposed. Here, we emphasize the novel use of identical twins discordant in disease phenotypes in epigenetic studies which can be a powerful approach in linking disease with gene regulation patterns and environmental exposures. Likewise, the human aging phenotypes are complex phenotypes that can be affected by a large number of both genetic and environmental factors together with their interplay. With proper and efficient design, twins can offer remarkable opportunities for functional genomic studies of human aging and development. In this paper, we highlight the different twin study designs and application issues and summarize the newest development in making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process (Fig. 1).
Section snippets
New technology and new opportunities
Right at conception, the genomic DNA sequence is identically fixed. However, the functional profile of a gene is determined not only by its sequence but also by the way in which it is regulated by epigenetic mechanisms including DNA methylation, histone modification, different species of non-coding RNAs, etc. It is anticipated that, perhaps the most significant change in the 21st century genetics will be the shift from structural genomics, where genes are regarded as a static concept, to
Modern use of a classical design
Aging is a natural process that everyone must undergo at his or her own time and pace. Although genetics may initially determine how a person ages, environment could over time play a higher role than the genes during aging.
Environments especially early life events are important modifiers of the aging process (Szyf, 2012, Szyf, 2009, Murgatroyd and Spengler, 2011). Since the genetic mechanisms behind aging are not controllable, understanding how environmental factors retard or accelerate the
Monozygotic twins: a unique source
Alterations in gene expression due to global epigenetic changes triggered by genetic, environmental and stochastic effects accumulate over time (Fraga et al., 2005) and can have substantial impact on susceptibilities to aging-associated diseases and health status (Gronniger et al., 2010, Gilbert, 2009, Poulsen et al., 2007, Holliday, 2010, Bocklandt et al., 2011), adding new evidence that nature and nurture are, in fact, inextricably linked. Elucidating the complex interplay between gene and
DZ twins for QTL mapping
The fast development in high throughput SNP genotyping techniques using DNA microarray platforms, such as Illumina and Affymetrix, and more recently, the next generation sequencing technique, is revolutionizing the way we design and conduct genetic epidemiological studies of human complex traits or diseases. High resolution genome-wide scans enabled by the high density and informative SNP marker arrays makes it possible for researchers to map quantitative trait loci (QTL) that are responsible
Twins and noncoding RNAs
The central dogma of “DNA makes RNA makes protein” is being challenged by recent observations about the extent of noncoding RNA (ncRNA) transcription in the higher eukaryotes and the range of RNA-directed genetic and epigenetic phenomena (Esteller, 2011). The currently identified major species of ncRNAs include short micro-RNAs (miRNAs), small interfering RNA (siRNA), long intergenic ncRNAs (lincRNAs) (Mercer et al., 2009), and many other, as yet, unknown ncRNAs. Among them, miRNAs are a major
Concluding remarks
Most of the complex traits including diseases and aging phenotypes are caused by the interaction between genome and environment through the interface of epigenetics. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on epigenetic processes remains limited. With proper design and analytical approaches, twins can help us with identifying epigenetic marks and link them with
Acknowledgements
This work was jointly supported by the Novo Nordisk Foundation 2010 research grant (principle investigator: Qihua Tan) and the Region of Southern Denmark 2010 research grant (principle investigator: Qihua Tan), the EU Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 and NIH/NIA grant P01 AG08761.
References (62)
- et al.
A general test of association for quantitative traits in nuclear families
American Journal of Human Genetics
(2000) - et al.
Ageing populations: the challenges ahead
Lancet
(2009) - et al.
Twins. Novel uses to study complex traits and genetic diseases
Trends in Genetics
(2000) - et al.
The epigenetics of social adversity in early life: implications for mental health outcomes
Neurobiology of Disease
(2010) - et al.
Genetic inheritance of gene expression in human cell lines
American Journal of Human Genetics
(2004) Epigenetics and twins: three variations on the theme
Trends in Genetics
(2006)- et al.
A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test
American Journal of Human Genetics
(1998) - et al.
Maternal care, the epigenome and phenotypic differences in behavior
Reproductive Toxicology
(2007) The early life environment and the epigenome
Biochimica et Biophysica Acta
(2009)- et al.
Differential and correlation analyses of microarray gene expression data in the CEPH Utah families
Genomics
(2008)