Monozygotic twins, or identical twins, originate from a single fertilized egg that splits early in development, making them near-perfect genetic copies. This shared DNA suggests that if one twin inherits a disease predisposition, the other should express the condition. However, studies of twin pairs where one sibling develops a heritable disease while the other remains healthy show this assumption is inaccurate. This paradox highlights that genetic identity is not the sole determinant of disease expression, pointing instead to molecular and developmental forces that drive individual health outcomes.
The Accumulation of Epigenetic Differences
The most significant factor causing divergence in identical twins is the accumulation of differences in the epigenome. The epigenome is a layer of molecular “marks” that controls how genes are read without changing the underlying DNA sequence. This mechanism involves chemical modifications, such as DNA methylation and histone acetylation, which act as switches to turn genes on or off. DNA methylation, for example, often silences a gene by adding a methyl group to the DNA strand, preventing the genetic information from being transcribed.
While identical twins begin life with nearly indistinguishable epigenetic profiles, these regulatory patterns begin to drift apart immediately after birth. This phenomenon, known as “epigenetic drift,” involves changes in the location and density of these chemical tags over time, increasing differences in gene expression as the twins age. Older twins, especially those who have lived apart or experienced different lifestyles, show marked differences in their methylation and acetylation patterns. These changes in gene regulation can ultimately determine whether a disease-associated gene remains silent or becomes active, causing disease discordance.
Post-Zygotic Somatic Mutations
Identical twins are not truly 100% genetically identical due to events occurring after fertilization. The cell division process that builds the embryo is imperfect, leading to changes in the DNA sequence in some cells after the zygote splits. These alterations are called post-zygotic somatic mutations, which are variations in the genetic code that arise randomly during development and are not present in every cell.
These somatic mutations include single nucleotide variants (SNVs), small insertions or deletions, or larger structural rearrangements like Copy Number Variations (CNVs). If a mutation occurs very early in development, it may be present in a large proportion of one twin’s cells—a state known as mosaicism—affecting a specific organ or function. For example, an early-stage CNV deletion in a gene predisposing an individual to schizophrenia may be present in one twin but absent in the other, directly causing disease discordance.
The Impact of Unique Environmental Triggers
The environment plays a powerful role in activating the epigenetic machinery, serving as the external force that steers the twins’ molecular paths toward divergence. “Environment” is broadly defined to include diet, exercise, exposure to toxins, infectious agents, and differences in the shared maternal blood supply within the womb. These non-shared environmental exposures act as triggers that initiate the distinct epigenetic changes observed between the twins.
For instance, one twin might have greater exposure to a carcinogen, such as smoking, which is strongly linked to changes in DNA methylation patterns. Similarly, differences in nutrient availability in the uterus, especially if they shared a placenta, can lead to measurable differences in their DNA methylation profiles at birth. These differing biochemical environments push the twins’ gene expression profiles onto separate trajectories, resulting in a disease expressed by only one sibling.
Randomness in X Chromosome Inactivation
In female identical twins, a unique developmental mechanism involving the X chromosome can lead to disease discordance. Females possess two X chromosomes, but one X chromosome is randomly silenced, or inactivated, in every cell early in embryonic development to achieve equal gene dosage with males. This process, known as X chromosome inactivation (XCI), creates a mosaic pattern where some cells use the maternal X and others use the paternal X.
XCI is usually random, resulting in a roughly 50:50 distribution of active maternal and paternal X chromosomes, but sometimes the process becomes “skewed.” If one twin randomly inactivates the X chromosome carrying the healthy version of an X-linked gene (e.g., for hemophilia) in a high percentage of her cells, she may express the disease. Conversely, the unaffected twin may have a pattern that favors the inactivation of the X chromosome carrying the disease-causing allele, protecting her from the condition. This random, early developmental event can be the reason for discordance in X-linked traits between genetically identical female siblings.