Zachary A. Kaminsky Discusses Novel Genomic Technology & Epigenetics
Emerging Research Front Commentary, August 2010
|
Article: DNA methylation profiles in monozygotic and dizygotic twins
Authors: Kaminsky, ZA, et al. |
Zachary A. Kaminsky talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front paper in the field of Molecular Biology & Genetics.
Why do you think your paper is highly
cited?
I believe the paper is highly cited because it represents a coming together of novel genomic technology and the emerging field of epigenetics to address difficult questions in human biology, making us take a hard look at the molecular factors underlying twin discordance and the inheritance of phenotypic traits. The paper is the first of its kind to employ the use of microarrays to investigate DNA methylation differences between twins on a genomic scale.
Furthermore, the study design uses a comparison of monozygotic and same-sex dizygotic twins, which is traditionally taken as an elegant and intuitive system with which to study heritability, as the degree of genetic heterogeneity is well defined and the differential environmental influences between the siblings are believed to be at a minimum. The results of this study support the tenets of the epigenetic theory of complex disease and point to epigenetic factors as the future place to search for disease risk.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This paper is the first of its kind to look at epigenetic differences in monozygotic and dizygotic twins on a genome-wide scale. The findings identify DNA methylation differences in identical twins, which offers an alternative to environmental factors as the substrate of phenotypic differences in genetically identical organisms.
Additionally, a larger degree of similarity in monozygotic as compared to dizygotic twins suggests that there is an inherited component controlling DNA methylation. Comparing genetically identical to non-identical animals suggested that genetic factors could not account for the observed levels of difference, leading to the conclusion that the epigenetic factors themselves may be inherited. If supported in future research, this finding impacts our understanding of the inheritance of phenotypic traits.
Would you summarize the significance of your paper
in layman's terms?
Figure 1:
"An artistic representation of the finding that DNA
methylation varies between monozygotic twins..."
View larger image & complete description in tab
below.
Complex non-Mendelian diseases often exhibit a discordance of monozygotic twins and inherited predisposition. Twin discordance means that one twin will often be affected by a disease while the other will not, despite sharing the identical DNA sequence. The traditional interpretation for this is that the twins had a non-shared experience of an environmental factor conferring disease risk.
Complex diseases often appear to be inherited such that the diseases tend to run in families. Comparing identical to fraternal twins in complex diseases have suggested an inherited component to disease and fueled the search for genetic factors for incurring risk. Despite considerable effort from the scientific community over the past 30 years, few consistent environmental factors or genetic variants have been identified to account for twin discordance and the inherited risk to disease.
The current study uses a genome wide approach to investigate DNA methylation, a modification to the DNA that can alter the amounts of protein made by the genes and that, if misregulated, can result in disease. The first finding shows that DNA methylation differences exist between identical twins on a genomic scale and provides a molecular substrate beyond the traditional view of non-shared environmental influence to account for observations of twin discordance in complex disease.
Using the same methodology to compare identical to fraternal twins, the study finds evidence that DNA methylation signatures may be passed from the parent generation to their children. This finding has particular significance to human health and disease because it suggests that any changes to a parent's epigenetic profile have the potential to be passed to their children.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
At the time we began this study, the use of epigenomic microarray technology was in its infancy such that our laboratory had to develop a technique with which to measure genome wide DNA methylation. Optimization of the technique was a learning process with many setbacks along the way; however, we ultimately developed a robust method and useful tool for addressing our hypotheses in a novel and genomic manner.
The study of epigenetic factors themselves, such as DNA methylation offers many challenges. As epigenetic patterns can vary by tissue type, it became very important to match the levels of cellular heterogeneity in our peripheral white blood cell samples in order to avoid confounding the results.
Additionally, depending on the time of twinning, twins may share placental connections that allow for a sharing of hematopoietic stem cells. Such cases are called monochorionic twinnings and could result in twins appearing more epigenetically similar and confounding our study design. We therefore confined our blood-based heritability studies to dichorionic monozygotic twins where twinning occurs earlier. This type of twinning occurs less frequently than monochorionic twinning, and thus limited the number of twins we could include in our study.
Where do you see your research leading in the
future?
The findings of this study suggest that epigenetic factors may be passed from the parent to offspring generations; however, this particular study design does not address whether such patterns continue to be propagated transgenerationally—that is, beyond a single parent-to-child transfer. Future studies using animal models and well phenotypically characterized families may help us to address the issue of transgenerational epigenetic inheritance.
Furthermore, the findings in this study suggest that epigenetic factors such as DNA methylation may underlie some of the complex traits observed in non-Mendelian disease that have not been explained by genetic and environmental influence. Future research should be focused on searching for epigenetic differences in complex diseases.
Do you foresee any social or political
implications for your research?
Previously, it was believed that the DNA sequence alone was the substrate conferring inheritance of traits from parent to offspring generations. As the DNA sequence is robust to change or mutation, this interpretation afforded us a particular freedom to affect our own health as we saw fit without the fear of deleterious consequences for our children.
The epigenetic code is far less robust to change from the environment and is known to be affected by environmental factors ranging from diet to pesticides, while the potential for many other modifiers remain to be elucidated. If the results of our study are replicated and the mechanisms of epigenetic inheritance are further elucidated, it suggests that the degree of any one individual's exposure to epigenetic modifying agents could affect the health of our children and possibly subsequent generations.
This realization confers an additional sense of responsibility to us as
individuals and to society to ensure that we are making the best health
decisions for our children as well as ourselves.
Zachary A. Kaminsky, Ph.D.
Instructor
Department of Psychiatry
School of Medicine
Johns Hopkins University
Baltimore, MD, USA
Figure 1:
Figure 1: An artistic representation of the finding that DNA methylation varies between monozygotic twins. Depicted above are two genetically identical monozygotic twins that display differential patterns of DNA methylation. The twins are standing in front of a volcano plot, showing the relative fold change of DNA methylation (x axis) as a function of the significance of the finding (y axis) for each of the ~12000 loci interrogated on the epigenomic microarray platform used.
© Zachary A. Kaminsky. Used with permission.
KEYWORDS: DNA METHYLATION PROFILES, MONOZYGOTIC, DIZYGOTIC, TWINS, EPIGENETIC DIFFERENCES, GENE, DISCORDANT, GENOME, ASSOCIATION.