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Epigenetic Forces May Blaze Divergent Heritable Paths From Same DNA

27 January 2009. The mystery of why one twin develops schizophrenia and the other one does not, even when they share all of the same genes, has persisted despite the search for environmental explanations. A new study, reported online in Nature Genetics on January 18, offers clues. Conducted by Art Petronis of the University of Toronto and the Centre for Addiction and Mental Health in Toronto, it found vast differences in gene regulation across the genome, even in monozygotic twins. Most strikingly, Petronis and colleagues report that these epigenetic differences may arise from a second molecular mechanism of heritability other than variations in the DNA sequence.

Epigenetic processes control gene activity without changing the genetic code. While the DNA sequence sets a stable “stage,” epigenetic processes correspond to a “play” in progress, according to Petronis (Petronis, 2004).

Recent findings suggest that epigenetic mechanisms play key roles in neural development, activity, and survival (see review by Tsankova et al., 2007; also see SRF related news story). At least one hypothesis has cast them as causal agents in schizophrenia, based in part on observations that methionine, an amino acid that alters gene expression, triggers psychotic symptoms in patients with schizophrenia (see SRF Current Hypothesis by Grayson and colleagues).

One epigenetic mechanism involves attaching methyl groups to DNA (see SRF related news story; for another epigenetic process, see SRF related news story on histone methylation). A genomewide scan last year by Petronis's group found abnormal DNA methylation patterns in frontal cortex tissue obtained from subjects with schizophrenia or bipolar disorder (see SRF related news story).

Previously, the Petronis lab found DNA methylation differences between single-egg co-twins and suggested that these might explain why about half will show discordance for schizophrenia (Petronis et al., 2003). The new study takes a more comprehensive look at cells’ epigenetic state. It examined DNA methylation at specific loci across the entire genome in 114 monozygotic and 80 dizygotic twins.

Led by first author Zachary Kaminsky, also of the Centre for Addiction and Mental Health and the University of Toronto, the researchers examined cheek, gut, and white blood cells. The gut cells came from non-inflamed tissue collected during biopsies for a study of inflammatory bowel disease. In an interview with SRF, Irving Gottesman of the University of Minnesota in Minneapolis, one of the study’s collaborators, said, “Ideally, we would have had brain tissue,” but that can be hard to obtain.

Kaminsky and colleagues used microarrays to explore the unmethylated genome on CpG islands, cytosine-and-guanine packed areas where methylation can silence genes. In all three kinds of tissue, they found DNA methylation differences between monozygotic co-twins. The greatest dissimilarities occurred in cheek cells of identical co-twins who resulted from a later, rather than early, splitting of the embryo. The researchers suggest that phenotypic similarities between genetically identical co-twins may reflect epigenetic factors that they share at the time the blastocyst divides.

Despite these differences between monozygotic siblings, their gene expression patterns looked more alike than those of dizygotic co-twins, although this finding turned out to be due entirely to the early-splitting group of same-egg twins. Since DNA sequence differences between identical twins rarely occur, Kaminsky and associates think it unlikely that their widespread epigenetic dissimilarities could follow from the genetic code; rather, they must reflect inherited gene regulation profiles. This counters the long-held “truth” that DNA sequence variations represent the sole means of passing heritable information between generations.

Marshalling additional support for that conclusion, Kaminsky and associates noted that, unlike the DNA sequence in a given individual, methylation patterns varied by tissue type. Furthermore, inbred mice, who share nearly identical genes, showed similar methylation profiles to outbred mice.

Just as DNA fingerprinting has reopened criminal cases, the discovery of this other kind of heritability, if replicated, may signal the need to revisit twin studies. According to Gottesman, who conducted many of the seminal heritability studies in mental illness, “Now that we have noticed these phenomena under the umbrella of epigenetics, it may be that we’ve overlooked some of the most important factors in the etiology of schizophrenia and other major mental disorders that have an important genetic component, as inferred from twin and ordinary family studies.”—Victoria L. Wilcox.

Kaminsky ZA, Tang T, Wang S-C, Ptak C, Oh GHT, Wong AHC, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet. 2009 Jan 18. Abstract

Q&A With Art Petronis. Questions by Hakon Heimer and Victoria Wilcox.

Q: To start off, could you summarize the most important findings and your conclusions from them?
A: The most important finding is that, although we still don’t have the final answer, we cannot exclude a possibility that epigenetics may be a secondary molecular substrate of heritability. Most, if not all, human diseases, including all psychiatric diseases, exhibit evidence for inherited predisposition. The most elegant way to estimate heritability is by comparison of concordance of monozygotic (MZ) and dizygotic (DZ) twins. In schizophrenia, the numbers are as follows: MZ twins exhibit 50 percent concordance, while DZ twins exhibit 15 percent concordance for schizophrenia, and the heritability is 70 percent. The traditional understanding is that DNA sequence is the molecular basis of heritability.

In our recent twin study, we compared the degree of epigenetic differences between MZ twins to the degree of epigenetic differences between DZ twins. We detected that MZ twins, despite their numerous epigenetic differences, are still more similar to each other in comparison to DZ twins. There could be several explanations for this. The null hypothesis is that the larger epigenetic differences in DZ twins are secondary; i.e., they are induced by DNA sequence differences in DZ twins. The alternative hypothesis is that those large epigenetic differences that we see in DZ twins represent vestiges of the inherited epigenetic profiles. MZ twins originate from a single zygote and, therefore, their epigenetic origin is the same (or very similar). DZ twins originate from two separate zygotes, the epigenetic profiles of which can be very different. Before continuing, it is necessary to explain the concept of epigenetic variation of the zygotes. In our earlier studies, we investigated the epigenetics of the germline, more specifically, sperm, and detected significant epigenetic differences across sperm cells from the same individual. Even short (about 500 nucleotide) stretches of DNA exhibited enough epigenetic variation to make each germ cell unique from the epigenetic point of view. We don’t know if oocytes exhibit such a significant degree of epigenetic variation, but it is likely to be similar to what we detected in the sperm. If germ cells are different epigenetically, zygotes will be different as well.

We performed a series of additional experiments looking at the possible effects of DNA sequence on DNA methylation and did not detect much evidence that the larger epigenetic differences in DZ twins are secondary. These findings favor—and I want to emphasize that they do not prove, but only favor—the alternative hypothesis that some of the epigenetic peculiarities in the zygotes are not completely erased; they survive all those numerous mitotic divisions experienced by an organism during development. If some of the inherited epigenetic factors play a role in phenotypic outcomes, we have a case of epigenetic heritability.

The ramifications of this finding may be quite interesting. Traditional genetic studies in complex diseases thus far could explain only a small fraction of heritability. Maybe a part of that heritability that we detect in phenomenological twin studies is actually due to epigenetic mechanisms.

Q: What questions remain about the methods and data that you want to follow up on?
A: Overall, this was a significant effort that required over 700 microarray experiments to test nearly 100 sets of MZ and DZ twins, but it was only a pilot study. First, the twin sample—when it is split into tissue categories (white blood cells, buccal epithelial cells, and gut cells)—brings only ~20 sets per MZ or DZ twin group. Second, we used the so-called CpG island microarrays, and we interrogated only 12,000 loci in the genome. So if we add up these 12,000 loci, it would only equal about 1 percent of the genome, which is merely a tiny fraction to interrogate. The next step should be a dedicated replication effort that would investigate a much larger twin sample and use more comprehensive microarrays; ideally, we would utilize whole genome tiling microarrays. In addition, it would be particularly interesting to investigate some complex phenotypes and try to identify links between phenotypic differences in MZ and DZ co-twins vs. epigenetic differences in such co-twins.

Q: Is anything known about the difference between methylation or epigenetics in general in the nervous system versus the tissue types that you sampled? How does that play into your thinking about this? And do you have any ideas for how to surmount the fact that you’re not looking directly at the nervous system if you start thinking about this in terms of your schizophrenia or bipolar disorder research?
A: You’re absolutely right; this is a limitation. However, we have to separate basic human epigenetic studies from those in human diseases. If we want to learn about the principles of epigenetic metastability, blood, gut, or buccal cells are sufficient. In human disease epigenetic studies, unfortunately, we often cannot acquire tissue from the disease site. This directly applies to psychiatric diseases where brain samples are available only postmortem. Still, it is important to note that the non-brain tissues may contain vestiges of epigenetic changes that were inherited or occurred before tissue differentiation in embryogenesis. In our earlier studies, we detected that, despite significant epigenetic differences across tissues, epigenetic profiles from different tissues of the same individuals exhibit some degrees of similarity. Another important aspect is that the non-brain tissues may help to address the cause-effect conundrum between epigenetic changes and disease. If epigenetic abnormalities are detected in the brains of schizophrenia patients, we cannot immediately know which of these changes caused or predisposed to schizophrenia and which ones were induced by the disease or disease-associated events (e.g., compensatory mechanisms of the brain, treatment with neuroleptics). Compared to the brain, the non-brain tissues should contain fewer secondary epigenetic changes.

Q: Is there any chance that variation in DNA sequence could contribute to the differences between the monozygotic co-twins?
A: Yes, the idea that monozygotic twins are not necessarily identical in their DNA sequences is not new. The most recent observation is actually that monozygotic twins may have some copy-number variation, and there was a paper published from Jan Dumanski’s lab in the American Journal of Human Genetics last year (
Bruder et al., 2008) showing that there are some loci in monozygotic twins that exhibit copy-number variation. There are some other studies over the last 15 years demonstrating that there are some somatic mutations—trinucleotide repeats and some single-nucleotide mutations—that can potentially make monozygotic twins different. All these observations are very interesting, and I believe many more insights are still to come when sequencing of the entire human genome will become less expensive. It is early to prognosticate what proportion of phenotypic differences will be explained by DNA sequence variation or epigenetic differences. At this point all we can say is that epigenetic differences in MZ twins by far exceed the DNA sequence ones.

Comments on News and Primary Papers
Comment by:  Shiva SinghRichard O'Reilly
Submitted 2 February 2009 Posted 3 February 2009

The methylation difference between twins is clearly...  Read more

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