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Human monozygotic (MZ) twins occur in about 1 in 250 live births. Since they
are derived from a single zygote, they are considered genetically identical.
However, discordance is well known for many phenotypic traits and diseases.
This discordance is typically attributed to differences in placenta, amniotic
sac and vascularization of separate cell masses or even mosaicism in their
genetic and cytogenetic composition. Epigenetic factors that influence expression
of genes represent another potential difference that could explain phenotypic
discordance between MZ twins. There are 2 major classes of epigenetic alterations
of genes: methylations of cytosine at cytosine-guanine (CpG) dinucleotides
and acetylations and methylations of DNA bound histones. Cytosine methylation
at regions of gene promoters rich in CpG dinulceotides usually silences genes,
whereas histone acetylation is frequently associated with activation of genes.
Fraga et al studied epigenetic patterns related to both global and locus-specific
DNA methylation and histone H3 and H4 acetylation in 80 Caucasian twins ranging
in age from 3 - 74 years. First, they documented the twins were true MZ twins
by microsatellite analysis. Next they showed that over 80% of female twins
had the same X-chromosome methylation pattern making subsequent epigenetic
differences between these twins unlikely to be explained by differential X
inactivation. Next, they measured 5-methylcytosine (5mC) genomic content and
acetylation of histones H3 and H4. Two thirds of twin pairs had almost identical
5mC genomic content and acetylation levels, while the other third was discordant
for these results. Most interesting was that the youngest twins were epigenetically
more similar to each other, while the oldest twin pairs were more distinct
from one another. Methylation fingerprinting confirmed this finding revealing
greater differences in twins who were older, had spent less of their lifetimes
together or had different health/disease histories. Further analysis of DNA
sequences revealed that the differential methylation involved both Alu repetitive
DNA and single-copy genes.
Finally, the authors examined the effects of differential epigenetic alteration
on gene expression. They subjected lymphocyte RNA from the 2 most distinctive
twin pairs (3- and 50-year old twin pairs) to microarray analysis in which
expression of a large number of genes was determined. The expression profiles
of the 3-year old twins were almost identical, whereas the profiles of the
50-year old twins were quite different. To a limited extent they also observed
epigenetic differences in cells from the mouth, intra-abdominal fat and muscle
biopsies.
The authors concluded that patterns of epigenetic modification of twin pairs
diverge as they age and as their lifestyles become distinct reflecting accumulated
exposure to a wide range of internal and external factors including environmental
factors. They referred to the phenomenon as “epigenetic drift”.
In an accompanying editorial, Martin generally agreed with the authors conclusions,
although cautioned that some of the observed differences could be explained
by shifts in the cellular heterogeneity known to occur in human tissues with
aging.
Fraga
MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the
lifetime of monozygotic twins. Proc Natl Acad Sci. 2005; 102:10604
- 10609.
Martin GM. Epigenetic drift in aging identical twins. Proc Natl Acad Sci. 2005;102:10413 - 10414.
Editor’s Comment: We struggle in clinical
genetics to explain how equivalent mutations can lead to different disease
phenotypes in different families and even within single families. Epigenetic
drift could help to explain this difference; although this is probably more
likely in genetic diseases that affect older children and adults more so
than infants. It is clear that we must begin to consider epigenetics as an
important factor in genetic disease.
William A. Horton, M.D.
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Current GGH - Vol. 24 No. 1
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