Monozygotic (MZ) twins are an ideal model for scientific research since many of the confounding factors associated with most human studies, such as DNA sequence and environment, can be eliminated. Although MZ twins are genetically identical, they typically display some level of phenotypic discordance. With the emergence of the study of epigenetics, scientists have hypothesized that differences in epigenetic marks may account for some phenotypic discordance in MZ twins. Comparative analysis of the epigenomes of MZ twins discordant for disease, including cancer, obesity, and diabetes, has led to the identification of epigenetic modifications, including changes in DNA methylation, histone marks, and differences in microRNA expression, that may contribute to the disease phenotype. Following identification of these changes, researchers are working to elucidate both the cause and the potential mechanism by which these modifications may lead to disease. Understanding how epigenetic modifications drive changes in phenotype using MZ twin studies may serve as a powerful tool in identifying new experimental opportunities in health and disease.
Keywords
Monozygotic twin Dizygotic twin Classical twin model Case co-twin model Twin discordance Heritability Cancer Diabetes Obesity Psychiatric disorders
List of Abbreviations
AD
Alzheimer’s disease
AML
Acute myeloid leukemia
ART
Assisted reproductive technology
BPA
Bisphenol A
BWS
Beckwith-Wiedemann syndrome
CNV
Copy number variation
CRF
Corticotrophin-releasing factor
CRISPR
Clustered regularly interspaced short palindromic repeat
Over the last century, the study of twins has been a powerful tool for evaluating the role of genetics and environment in determining phenotype. While identical twins share a genome, they typically display some level of phenotypic discordance for many traits and diseases. These differences in phenotype are often attributed to differential exposure to environmental factors such as smoking, UV rays, nutrition, toxins, and activity level (Fig. 1). While it has been demonstrated that these factors may induce changes in the genome of identical twins, leading to phenotypic discordance, evidence indicates that they may also induce changes in the epigenome. Changes in the epigenome may be responsible for some MZ twin discordance since epigenetic mechanisms are important regulators of gene expression. As discussed in this chapter, differences in epigenetic marks have been attributed to discordant phenotype in MZ twins in many diseases, including cancer, diabetes, and obesity.
Identical twins with phenotypic discordance due to environmental exposure. Although MZ twins share an identical DNA sequence, differential exposure to environmental factors over time can contribute to phenotypic discordance as seen in this pair of identical twins with varying amounts of UV exposure (Reprinted with permission from “Factors contributing to the facial aging of identical twins” by B Guyuron, DJ Rowe et al., 2009, Plast Reconstr Surg, 123(4), p. 1322. Copyright (2009) Wolters Kluwer Health, Inc)
Twinning
There are two main types of twins, dizygotic (DZ) or monozygotic (MZ) . DZ twins, also known as fraternal twins, are the result of a double ovulation event leading to two ova fertilized by two different sperm. DZ twins share approximately half their genome (similar to non-twin siblings), but share an in utero environment. MZ twins, or identical twins, develop from a single oocyte fertilized by a single sperm that splits into two ova, leading to a shared DNA sequence and shared in utero environment. DZ twinning is believed to be a heritable maternal dominant trait, while MZ twinning is typically viewed as a random process (Wong et al. 2005; Shur 2009).
Twins occur in approximately 1 in 80 births (Hall 2003). DZ twins are more common than MZ twins, accounting for 70% of twin pregnancies. While the MZ twinning event is rare, it is relatively constant at 3.5–4 per 1000 births across all human populations (Hall 2003). Western and East Asian countries have seen an increase in twinning rates since the 1970s with the advent of assisted reproductive technology (ART) procedures (Tagliani-Ribeiro et al. 2011).
There are four distinct twin types based on the timing of the splitting of the zygote, which determines whether the twins will share a chorion, including the placenta, and amniotic sac (Fig. 2) (Singh et al. 2002). Type one twins occur when the zygote splits between days 1 and 3 post-fertilization and results in a separate chorion and amniotic sac (18–36%). Type two twins split at the early blastocyst stage (days 4–8) and result in two separate amniotic sacs and a shared chorion (80%). Type three twins split between days 8 and 12 and result in a shared chorion and amniotic sac (2–4%). Type four split results in conjoined twins (2.5%). It is unknown if the timing of the zygote split contributes to phenotypic variation between twins, but a study by Kaminsky et al. found that twins that shared a placenta actually had more variable epigenomic profiles compared to twins that did not (Kaminsky et al. 2009).
Twin types defined by the stage at which the egg divides. Type one (18–36%) results from abnormal splitting of the embryonic cells at the two-cell stage (days 1–3), resulting in two separate chorionic and amniotic sacs. Type two (80%) results from a split in the inner cell mass (ICM) of the early blastocyst (days 4–8) resulting in one chorion and two amniotic sacs. A type three (2–4%) split occurs at the late blastocyst (days 8–12) resulting in one chorion and one amniotic sac. Type four (2.5%) split occurs after day 12 and results in incomplete division and conjoined twins (Reprinted with permission from “Epigenetics as the Underlying Mechanism for Monozygotic Twins Discordance” by Tara L. Hogenson, 2013, Medical Epigenetics, 1, p. 4. Key: ICM Inner Cell Mass)
Twin Models
The two most popular twin models for scientific research include the classical twin model and the case co-twin model. The classical twin model compares MZ and DZ twins to estimate the contribution of genetics and environment to the variation of a complex trait within the general population, also known as heritability (H2). The estimation of heritability is based on the assumption that while both MZ and DZ twins share a similar prenatal and postnatal environment, MZ twins share all of their genetic material while DZ twins share half. Therefore, the heritability of a trait can be estimated as twice the difference between MZ and DZ twin concordance rates, also known as Falconer’s formula (Boomsma et al. 2002). In this formula, r(MZ) is the MZ twin correlation rate and r(DZ) is the DZ twin correlation rate; H2 = 2(r(MZ) − r(DZ)).
One of the most well-known examples using the classical twin model is the Minnesota Study of Twins Reared Apart performed by a University of Minnesota psychologist, Dr. Bouchard (Bouchard et al. 1981). Dr. Bouchard performed a longitudinal assessment of MZ and DZ twins reared apart and compared them to twins reared together. Surprisingly, the twins reared apart had a nearly identical correlation of traits versus those reared together, indicating the strong effect of genetics over environment. Dr. Bouchard’s study garnered national interest in the use of the twin model. As a result, the classical twin model has been used to study the heritability of several traits and diseases (Table 1).
Table 1
Heritability of several complex traits and diseases from twin studies. MZ probandwise concordance (Reprinted with permission from “Epigenetics as the Underlying Mechanism for Monozygotic Twins Discordance” by Tara L. Hogenson, 2013, Medical Epigenetics, 1, p. 5)
The case co-twin model involves the evaluation of MZ twins discordant for a trait or disease through comparison of their epigenomes and genomes. The goal is to identify variants between the twins that may contribute to discordance, with the unaffected twin serving as the control. The case co-twin design is the most popular method for epigenetic studies and will be the model used for the majority of papers reviewed in this chapter.
Types of Epigenetic Differences in Identical Twins
Through epigenetic mechanisms, cells with the same DNA sequence can express unique phenotypes through suppression or induction of gene expression. There are several well-known epigenetic mechanisms, including DNA methylation, chromatin remodeling, and microRNA expression. Looking at these epigenetic marks, several studies have identified epigenetic differences in identical twins.
DNA methylation consists of adding an additional methyl group at cytosine residues on CpG dinucleotides in mammals. Addition of methyl groups to CpG dinucleotides interferes with binding of transcription factors to initiate chromatin compaction and gene silencing (Bird 2002; Wong et al. 2010). This type of modification is typically considered permanent through inheritance during cell division.
Several studies have demonstrated that MZ twins display a greater level of concordance in methylation compared to DZ twins or unrelated individuals (Fraga et al. 2005; Boks et al. 2009; Kaminsky et al. 2009). Fraga et al. studied the DNA methylation levels in 80 MZ and DZ twins and found an extremely high correlation of epigenetic modifications between identical twins (66%) (Fraga et al. 2005). In addition, several studies show that DNA methylation patterns are strongly influenced by the environment (Fraga et al. 2005; Bjornsson et al. 2008; Wong et al. 2010). The same study by Fraga et al. found that as MZ twins are exposed to different environmental factors over time, their DNA methylation patterns diverge significantly (Fig. 3) (Fraga et al. 2005). This indicates the methylome is both heritable and regulated by environmental factors.
Chromosome 3 methylation in 3-year-old twins vs. 50-year-old twins. Chromosomal regions of MZ twins were compared using genomic hybridization. The 3-year-old twins have a very similar distribution of DNA methylation indicated by the presence of the yellow color. A comparison of 50-year-old twins shows abundant changes in the pattern of DNA methylation as shown by the presence of green and red signals, which indicate hypermethylation and hypomethylation events (Reprinted with permission from “Epigenetic differences arise during the lifetime of monozygotic twins.” by M.F. Fraga, E. Ballestar et al., 2005, Proc Natl Acad Sci U.S.A., 102 (30), p. 10607. Copyright (2005) National Academy of Sciences, USA)
Chromatin remodeling includes the regulation of gene expression through the posttranscriptional modification of core histone residues. These modifications influence the level of chromatin compaction, leading to either induction of gene expression or repression. Well-characterized histone modifications include acetylation, methylation, phosphorylation, ubiquitination, and ADP-ribosylation, among others (Vaquero et al. 2003).
The most common method for studying chromatin differences in MZ twins includes measuring specific histone modification levels in promoter regions of a gene of interest. Fraga et al. studied global acetylation levels of histones H3 and H4 in MZ twins and discovered that while the twins were epigenetically indistinguishable in early age, 35% of MZ twins showed a significant difference over time (Fraga et al. 2005). This suggests that the epigenomes in twins may diverge with age and may lead to discordance.
MicroRNAs (miRNAs) are small noncoding posttranscriptional regulating RNAs that play a key role in control of gene expression in eukaryotic organisms (Meda et al. 2011). miRNAs are typically 22 nucleotides long and suppress translation through binding to complementary mRNA species. Once bound to target mRNA, miRNAs interfere with translation through inhibition or degradation (Almeida et al. 2011).
Differential expression of miRNAs may have an effect on discordant phenotypes in identical twins. One study looking at lymphoblastoid cell lines of MZ twins discordant for autism found differential expression of the brain-specific miRNAs to the gene targets ID3 and PLK2(Sarachana et al. 2010). Both ID3 and PLK2 have been identified as genes of interest in autism (Durand et al. 2007; Zhang et al. 2008). Dysregulation of expression of these miRNAs may contribute to the development of autism in the affected twin.
Epigenetic Modification
The epigenome is highly dynamic, unlike DNA sequence, and undergoes constant fluctuation in response to external factors that promote or suppress gene expression. Several factors may induce changes in the epigenome including chemical exposure, dietary intake, and social interactions (Fig. 4). Also, some changes may be stochastic in nature.
Environmental factors induce changes in epigenome. Several environmental factors have been shown to cause changes in the epigenome, including chemical exposures, dietary intake, and social interactions. These factors modify the epigenome through epigenetic mechanisms, including changes in miRNA expression, DNA methylation, and histone modification. These modifications result in changes in gene expression and may lead to disease onset. Key: BPA Bisphenol A
Chemical exposure associated with smoking has been demonstrated to change the epigenome through DNA methylation modification and altered miRNA expression (Enokida et al. 2006; Marsit et al. 2007; Wong et al. 2009; Momi et al. 2014). Nicotine itself is associated with the expression of DNA methyltransferase 1 (Satta et al. 2008). Breitling et al. conducted a genome-wide screen for differentially methylated CpG sites associated with smoking (Breitling et al. 2011). They found lower DNA methylation on the promoter of F2RL3, leading to increased expression. F2RL3 encodes for the protein PAR4, which is involved in platelet activation and regulation of cardiovascular function, such as inflammation (Leger et al. 2006). Smoking has previously been associated with lowered platelet aggregation, making PAR4 a potential drug target for cardiovascular disease treatment in smokers.
Dietary exposure to certain chemicals, such as the endocrine disruptor bisphenol A (BPA), can also modify the epigenome. BPA interferes with the function of the endocrine system by blocking or mimicking the actions of hormones. It is commonly found in many household products, including food and beverage containers (Skinner et al. 2011). Using a mouse model that measures methylation changes in the epigenome, Dolinoy et al. found that maternal dietary exposure to BPA caused both a decrease and increase in CpG methylation at certain loci in the genome of the offspring, leading to a change in phenotype (Dolinoy et al. 2007a). Other dietary factors shown to modify the methylome include intake of folate, riboflavin, cobalamin, pyridoxine, methionine, and choline (Niculescu and Zeisel 2002).
Social interactions also play a role in modification of the epigenome (Weaver et al. 2004; Mueller and Bale 2008). In a study by Mueller et al., the authors found that adult male mice exposed to prenatal stress during the first week of pregnancy showed a reduction in DNA methylation of the promoter region of the corticotrophin-releasing factor (CRF) gene, leading to CRF overexpression (Mueller and Bale 2008). The same change was not observed in female mice. CRF is involved in the stress response pathway and overexpression is associated with an increased stress response. These mice were also found to have an increase in promoter methylation of the NR3C1 gene, which encodes the glucocorticoid receptor, leading to lower expression. Decreased expression of the glucocorticoid receptor is associated with depressive-like and anxiety-like phenotypes (Weinstock 2008).
Stochastic errors may also contribute to epigenetic variation. During cell division, DNA methylation marks are inherited in a semiconservative manner. Epigenetic modifications show a considerably low fidelity of transmission from maternal to daughter chromatids, where the error rate for the transmission is 1 × 103 per base compared to the 1 × 106 error rate for DNA replication (Ushijima et al. 2003). This low fidelity is associated with a high rate of random epigenetic errors, which may be a contributing factor to discordance in MZ twins.
Mechanisms for Epigenetic Discordance
Exactly how a change in the epigenome leads to a change in phenotype is not always clear, yet several twin studies have identified a potential mechanism for discordance. These include errors during genomic imprinting, miRNA inactivation, and genomic errors in molecules that act as epigenetic modifiers. Researchers are currently working to expand our knowledge of these processes, and MZ twin models may serve as an important tool in this field of research.
Imprinted genes are a well-known epigenetic mark. Genomic imprinting is a process that involves repression of a maternal or paternal allele through epigenetic modifications. Inappropriate imprinting is associated with several diseases including Silver-Russell syndrome, Beckwith-Wiedemann syndrome, Angelman syndrome, and Prader-Willi syndrome (Skinner et al. 2011). Beckwith-Wiedemann syndrome (BWS) is often discordant in MZ twins (Petronis 2006; Shur 2009). BWS is caused by a loss of DNA methylation in imprinted genes in the 11p15.5 region, which codes for genes IGF2, H19, KCNQ1OT1, and CDKN1C. MZ twins discordant for BWS usually show imprinting defects at the KCNQ1OT1 gene on the maternal allele, leading to biallelic expression and congenital overgrowth syndrome. It is uncertain why one twin may have normal allelic expression of KCNQ1OT1 while the other inherits biallelic expression, but some researchers speculate that this discordance may be because of the twinning event itself due to the high frequency of this error in MZ twins (Shur 2009; Bliek et al. 2009). Interestingly, one study found the site of umbilical cord insertion into the placenta of monochorionic twins is positively associated with methylation of IGF2/H19 (Loke et al. 2013).
X-inactivation by miRNA is a critical regulator of gene expression. During embryonic development in females, the miRNA Xist coats one X chromosome and inhibits expression of a majority of the genetic sequence, leading to dosage compensation. X-inactivation is generally considered random in females with 50% of cells expressing the paternal haplotype and 50% expressing the maternal haplotype. However, there are some instances in which X-inactivation is not random, also known as X-inactivation skewing. X-inactivation skewing in female MZ twins has been shown to play a role in discordant disease phenotypes among twin pairs, including fragile X syndrome, color blindness, Duchenne muscular dystrophy, and hemophilia B (Gringras and Chen 2001). Using methylation analysis in MZ female twins discordant for hemophilia A, Bennett et al. demonstrated that the affected twin showed nonrandom X-inactivation with only the paternal allele active in her cells, leading to discordance (Bennett et al. 2008).
Epigenetic molecules, such as DNA methyltransferases, play a critical role in regulating the marks associated with expression of the epigenome. Genomic errors in epigenetic molecules may attribute to phenotypic discordance between MZ twins. One study focused on 3-year-old MZ twins discordant for MLL-associated acute myeloid leukemia (AML) in order to identify mutations driving the disease (Zhu et al. 2014). Fluorescence in situ hybridization analysis indicated the affected twin had a chromosomal translocation in the MLL gene, disrupting its function. By comparing the genomic sequence of the leukemia cells of the affected twin to the peripheral blood mononuclear cells from the unaffected twin, the researchers discovered a biallelic mutation in SETD2 (encodes for a histone H3K36 methyltransferase) in the twin with leukemia. In addition, Zhu and colleagues observed a high frequency of SETD2 mutations in patients with MLL-rearranged leukemia, leading to a global loss of H3K36me3 (Zhu et al. 2014). Loss of H3K36me3 is associated with progression of leukemia through enhancement of the stemness of leukemia stem cells.
Epigenetic-Associated Twin Discordance and Disease
MZ twin studies have been useful in determining the role that both genetics and environment play in disease. MZ twins discordant for disease serve as a valuable tool for the identification of factors that contribute to disease onset. Several studies of MZ twins discordant for complex disease were able to identify an epigenetic mechanism that may contribute to phenotypic discordance between twins. Next is a brief review of those studies.
Cancer
Cancer has a high discordance rate between MZ twins, indicating a strong environmental component to the disease. Changes in DNA methylation patterns are one of the most common epigenetic alterations identified in cancer (Dolinoy et al. 2007b). In one study evaluating MZ twins discordant for childhood leukemia, BRCA1 showed constitutive promoter hypermethylation (12%) in all cells of the affected twin but not the healthy twin (3%), leading to the inactivation of the tumor suppressor gene (Galetzka et al. 2012). The authors hypothesized this epigenetic error most likely occurred during epigenetic reprogramming following fertilization, when genome-wide demethylation in the early embryo erase most germline methylation patterns, followed by reestablishment of those patterns.
In order to evaluate epigenetic changes associated with cancer over time, Roos et al. analyzed epigenome-wide DNA methylation profiles in 41 pairs of MZ twins discordant for several cancers using blood samples collected up to 5 years before diagnosis (Roos et al. 2016). The authors identified one novel significant pan-cancer signal, SASH1, and three loci suggestive of cancer, CO11A2, AXL, and LINC00340. These methylation signatures were detectable up to 5 years before diagnosis. In a similar study, Heyn et al. examined DNA methylation patterns of MZ twins discordant for breast cancer (Heyn et al. 2013). They discovered the docking protein, DOK7, was shown to have increased promoter methylation years before cancer diagnosis, making it a potential biomarker for early detection.
Diabetes
MZ twins show an approximate 50% concordance rate for type I diabetes (TID), indicating that both genetic and environmental factors play a role in onset (Redondo et al. 2001). In order to identify differential epigenetic marks, Raykan et al. studied DNA methylation levels in a specific subset of immune cells in 15 MZ twins discordant for T1D (Rakyan et al. 2011). They identified 132 differentially methylated CpG sites in genes known to be associated with T1D or the immune response, including the HLA gene, HLA-DQB1. The authors confirmed their findings by performing a longitudinal study measuring DNA methylation differences before and after clinical diagnosis, suggesting that T1D-associated methylation differences arise early in the development of disease.
Similar to T1D, MZ twins show a concordance rate of approximately 50% for type 2 diabetes (T2D) (Poulsen et al. 1999). In a study by Ribel-Madsen et al., the authors collected biopsies of skeletal muscle and adipose tissue from 5 pairs of twins discordant for T2D and measured DNA methylation levels of 26,850 CpG sites in the promoters of 14,279 genes (Ribel-Madsen et al. 2012). Of the genes analyzed, they discovered a number of known T2D-related genes differentially methylated between the discordant twins, including PGC-1α and HNF4α. These findings demonstrate the potential role of epigenetic changes in disease onset of T2D.
Obesity
MZ twins show a high concordance rate for obesity (74%) compared to DZ twins (32%), indicating a strong genetic component for the disease (Maes et al. 1997). However, it has been demonstrated that diet and exercise have an impact on epigenetic modification and several studies indicate that epigenetics plays a role in obesity (Brons et al. 2010; Whitelaw et al. 2010; Jacobsen et al. 2012; Barres et al. 2012; Nitert et al. 2012; Dick et al. 2014; Desai et al. 2015). A study by Dalgaard et al. looked at identical mice bearing a mutation in Trim28, a multi-domain protein that supports heterochromatin deposition and gene silencing. This mutation does not allow the TRIM28-ZFP57 complex to form, leading to a change in the epigenetic state of IGN1and lowered expression (Dalgaard et al. 2016). A reduced level of IGN1 is associated with obesity. The authors also analyzed the adipose tissue samples of MZ twins with discordant body mass index and discovered lowered TRIM28 and IGN1 levels in the obese twin. This indicates a distinct epigenetic mechanism for discordance between MZ twins. The cause of this epigenetic switch is unclear, though the authors propose it may be due to diet, hormone, temperature, or parental effects.
Psychiatric Disorders
Many epidemiology studies have revealed a long list of environmental factors that may contribute to psychiatric disease onset, including stress, mental and physical abuse, and drug abuse (Oh and Petronis 2008). A study by Petronis et al. looking at the role of epigenetics in schizophrenia (SZ) compared the epigenetic profile of a pair of discordant and concordant MZ twins (Oh and Petronis 2008). Bisulfite sequencing of the DRD2 gene showed the epigenetic profile of the affected discordant twin was more similar to the affected concordant twins than the profile of their unaffected co-twin (Petronis et al. 2003). This was one of the first indications that epigenetic modification of a gene associated with SZ may play a role in disease onset (Fig. 5).
Epigenetics of MZ twins discordant for complex disease. In this model, both twins inherit an epigenetic predisposition to psychosis. Differential exposure to various factors, including differences in development, environment, hormones, and stochastic events, may cause changes in DNA methylation (represented by the red circles on the DNA helix) leading to either hypomethylation (shown here) or hypermethylation of promoter regions of genes related to disease. In one twin, these changes may result in onset or relapse of psychosis through overexpression of disease-related genes, while the other twin is unaffected (Reprinted with permission from “Phenotypic differences in genetically identical organisms: the epigenetic perspective.” by Albert H.C. Wong, Irving I. Gottesman, and Arturas Petronis; 2005, Hum Mol Genet, 14 (suppl_1), p. R15. Copyright (2005) Oxford University Press)
In a more recent study, Fisher and colleagues studied methylation variation in MZ twins discordant for childhood psychotic symptoms from the ages of 5 to 10 years (Fisher et al. 2015). MZ twins showed a higher concordance rate (43%) compared to DZ twins (22%) for childhood psychotic symptoms, indicating both a strong genetic and environmental component (Polanczyk et al. 2010). The authors discovered one region that was highly differentially methylated at age 10 in the promoter regulatory region of the protein coding gene C50RF42. This same CpG site was found to be significantly hypomethylated in post-mortem SZ patients. The protein coded by this gene is largely uncharacterized, but appears to be important in neural development. Differential methylation of this gene may in part explain discordant phenotypes between MZ twins and may be detectable at an early age.
Future Implications for Disease and Medicine
While epigenetics may play a role in MZ twin discordance, it is important to note there are several well-known genetic mechanisms that have been shown to cause discordance. These include differences in the in utero environment, somatic mosaicism, and de novo mutations. In rare cases, twins may not inherit identical genomes. This could be caused by asymmetric distribution of mitochondria, chromosomal abnormalities, point mutations, copy number variations (CNVs), and single nucleotide polymorphisms (SNPs) (Kato et al. 2005).
In addition, there are several limitations to studying epigenetics, even in MZ twins. Epigenetic marks are both cell and tissue specific. This specificity makes it difficult to study tissues that are not easy to sample. Most studies, including twin studies, evaluate peripheral blood cells, but a blood sample may include a mixture of cells with several different profiles. Because of this, it is critical to analyze the blood sample for cellular subtypes before analysis. If possible, a single cell technology is the best approach when studying epigenetics.
Another important caveat of epigenomic studies is that the epigenome is constantly changing. According to Levesque et al., the human methylome consists of at least three types (Levesque et al. 2014). The first type includes stable DNA methylation sites which are required for cellular identity. The second is highly variable (even in MZ twins) and responsive to external signals, but are stable for a short period of time. The third are highly variable and respond to external signals throughout life. It is important the researcher be aware of which type of methylation site they are evaluating in order for the data to be relevant.
The ability to detect epigenomic differences in MZ twins makes them a powerful tool for studying disease. As demonstrated in this chapter, epigenomic modifications between MZ twins have been identified across a wide range of phenotypes. While some of these methylation changes may be biomarkers for disease, others may be involved in disease susceptibility or disease onset. Discerning the effect of these marks will be critical in understanding the disease process. Current advances in targeted genome editing using zinc finger nucleases (ZFNs), clustered regularly interspaced short palindromic repeats (CRISPRs), and transcription activator-like effector nucleases (TALENs) allow for targeted epigenetic editing and are promising tools for studying the effect of specific epigenetic modifications. Identification of epigenetic marks associated with disease may be an important step for the discovery of key targets for future drug therapies.
Dictionary of Terms
Monozygotic Twins – Also known as identical twins, develop from a single oocyte fertilized by a single sperm that splits into two ova, leading to a shared DNA sequence.
Dizygotic Twins – Also known as fraternal twins, are the result of a double ovulation event leading to two ova fertilized by two different sperm.
Heritability – An estimation of the contribution of genetics and environment to the variation of a complex trait within the general population.
Classical Twin Model – The estimation of the heritability of a trait through comparison of the concordance rates between monozygotic and dizygotic twins.
Case Co-Twin Model – The evaluation of monozygotic twins discordant for a trait through comparison of the epigenome and genome in order to identify variants that may contribute to phenotype.
Key Facts on the Study of Identical Twins
The famous scientist Sir Francis Galton, cousin of Charles Darwin, is considered by many to be the first scientist to propose the twin model for the study of human trait and disease in 1874.
By most accounts, the first study using the twin method was by Jablonski in 1922, studying hereditary refraction of the human eye in twins.
The famous Minnesota Study of Twins Reared Apart by Dr. Bouchard was inspired by the “Jim Twins,” who were separated at birth and reunited at the age of 39.
Despite being raised apart, the “Jim Twins” were given the same name by their adoptive parents, both married women named Linda, had a son named James, and a dog named Toy.
Twin registries are available worldwide with up to 150,000 pairs of registered twins.
Summary Points
Identical twins are an ideal experimental model for epigenetic studies since they share a genome and similar prenatal and postnatal environment, eliminating many of the confounding factors associated with most human studies.
There are four characterized identical twin types based on the timing of the splitting of the zygote, which determines if the twins will share a chorion, placenta, and amnion.
The two most popular models for twin studies include the classical twin model and the co-case twin model.
Several environmental factors shown to have an impact on the epigenome include smoking, diet, and social interactions.
Scientists have discovered several differences in epigenetic marks in identical twins including modifications in DNA methylation, histone marks, and miRNA expression.
Epigenetic mechanisms for discordance in monozygotic twins include differences in genomic imprinting, X-inactivation, or genomic mutations in epigenetic modifiers.
Changes in the epigenome may account for disease discordance in monozygotic twins for several complex diseases, including cancer, diabetes, obesity, and psychiatric disorders.
Researchers are working to identify both the cause and the potential mechanism by which modifications in the epigenome may lead to the disease phenotype using twin studies.
Unraveling the mechanism by which epigenetic modifications induce a change in phenotype may serve as a valuable tool in identifying new pathways for prevention and treatment of disease.
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