The Genetic Mystery of Discordant Monozygotic Twins
In a striking case reported in 2025, a woman gave birth to monozygotic twins where Twin A was entirely healthy, while Twin B presented with multiple congenital conditions. This paradox challenges our understanding of genetic determinism. 1
Imagine two individuals, sharing not just the same family or the same birthday, but the very same set of DNA instructions. For monozygotic (MZ), or identical, twins, this genetic mirroring is a biological fact. They originate from a single fertilized egg that splits into two, creating lives with nearly identical genetic blueprints.
For decades, this perfect genetic correspondence led scientists and the public alike to assume their destinies—especially their health destinies—would be the same.
Yet, reality tells a different story. This is the fascinating puzzle of discordant monozygotic twins: individuals who are genetically identical but phenotypically distinct. Their existence challenges the simplistic notion of genetic determinism and opens a powerful window for scientific discovery, allowing researchers to isolate the profound roles played by epigenetic changes, postzygotic mutations, and unique environmental exposures in shaping who we are.
Monozygotic twins originate from a single fertilized egg with identical genetic material.
Discordant twins develop different traits, diseases, or conditions despite genetic identity.
These twins provide a unique natural experiment to study non-genetic influences.
Epigenetics, mutations, and environment all contribute to differences.
The discovery of discordant twins has propelled scientists beyond the genome to uncover the complex factors that intervene between DNA and destiny.
While MZ twins share the DNA sequence they inherit at conception, they do not necessarily share all the genetic changes that occur afterward. Postzygotic mutations happen after the egg has been fertilized, during the countless cell divisions that build an embryo.
If the twinning event occurs after one of these random mutations, it can be present in one twin but not the other 7 . Advanced whole-genome sequencing technologies are now revealing these subtle differences in the form of single-nucleotide variants (SNVs) and copy number variations (CNVs) that make each twin genetically unique at a fine level 3 8 .
Perhaps the most significant discovery in twin research is the role of epigenetics. Think of epigenetics as a layer of molecular "switches" that sit on top of your DNA, controlling which genes are active and which are silent without changing the underlying sequence.
These switches, which include DNA methylation and histone modifications, are influenced by a host of factors, from diet and stress to toxic exposures 4 .
MZ twins show remarkably similar epigenetic patterns when they are young, but as they age and accumulate different life experiences, their epigenetic profiles diverge 4 .
From the very beginning, MZ twins can experience different environments. They may have unequal placental sharing, leading to disparities in nutrient and oxygen delivery that can impact organ development 1 .
After birth, all the unique experiences—illnesses, friendships, traumas, diets—constitute their "non-shared environment," which continues to shape them through epigenetic mechanisms and direct physiological effects 5 6 .
Research has shown that even traits with high heritability, like those related to mental health, are significantly influenced by this unique environment 5 6 .
Single fertilized egg with identical DNA for both twins.
Random mutations occur after conception, potentially affecting only one twin if they happen after the egg splits 7 .
Differences in placental sharing, nutrient delivery, and positioning in the womb can create variations 1 .
As twins age, their epigenetic profiles diverge based on different experiences and environments 4 .
To understand how researchers unravel these mysteries, let's look at a specific ground-breaking experiment. A study published in 2018 used whole-genome sequencing (WGS) to investigate the genomic differences between monozygotic twins discordant for autism spectrum disorder (ASD) 8 .
The researchers recruited three pairs of MZ twins where one twin had ASD and the other did not. They then conducted a comprehensive scan of the entire genome for each individual, looking for three types of genetic variations: single-nucleotide variants (SNVs), small insertions/deletions (indels), and larger copy number variations (CNVs) 8 .
The key to their analysis was focusing on what they called "discordant variation in monozygotic twins" (DVMT)—mutations that were present only in the twin with ASD and completely absent in the unaffected co-twin.
of MZ twins discordant for ASD
sequencing for all individuals
of variations analyzed
"The researchers identified a total of 2,174 genes associated with the discordant variations across the twin pairs. A core group of 37 genes was particularly interesting, as they were covered by all three types of variations." 8
| Type of Genomic Variation | Number of Discordant Variations Identified | Number of Genes Affected |
|---|---|---|
| Single-Nucleotide Variants (SNVs) | 14,310 | 823 |
| Insertions/Deletions (Indels) | 2,425 | 557 |
| Copy Number Variations (CNVs) | 16,735 | 1,174 |
| Overlap Genes (in all 3 types) | 37 | 37 |
This study was pivotal because it demonstrated that even in "identical" twins, post-conception genetic mutations can contribute to neurodevelopmental disorders.
It provided researchers with a prioritized list of candidate genes and pathways, offering new directions for understanding the complex etiology of ASD 8 .
The 37 overlap genes represent high-priority candidates for further autism research, as they were affected by all three types of genetic variations.
The progress in this field is driven by a suite of sophisticated technologies that allow scientists to peer into the genome and epigenome with unprecedented clarity.
Sequences only the protein-coding regions of the genome (exomes). A cost-effective method to find coding variants linked to conditions like congenital scoliosis 2 .
Twin Recruitment
Sample Collection
Genomic Analysis
Data Interpretation
The insights gleaned from discordant twin pairs are not just academic; they have tangible implications for improving human health.
In medicine, twin studies help refine our understanding of disease risk. By controlling for genetics, researchers can identify true environmental risk factors and biomarkers for conditions from diabetes to psychiatric disorders .
For instance, studies of twins discordant for type 2 diabetes have revealed specific microRNAs and DNA methylation patterns associated with the disease, pointing to potential new diagnostic tools and therapeutic targets .
Furthermore, large-scale studies on MZ twin differences are beginning to identify genetic variants that influence an individual's sensitivity to their environment, which is a crucial step toward truly personalized medicine 5 .
Twin studies have helped identify environmental triggers for conditions like multiple sclerosis, rheumatoid arthritis, and certain cancers.
In the forensic sciences, the traditional method of DNA profiling (which uses short tandem repeats, or STRs) fails to distinguish between MZ twins, posing a challenge in criminal investigations or paternity disputes 7 .
Research into the genetic and epigenetic differences between twins is now providing solutions. Scientists are developing methods based on somatic mutations, DNA methylation marks, and even microbiome analysis to tell identical twins apart from biological samples, thereby upholding the principle of justice 7 .
Epigenetic clocks based on DNA methylation patterns can estimate the biological age of individuals and help distinguish between identical twins.
Identifying how genetic background interacts with environment to shape health outcomes
Understanding environmental triggers for conditions like depression, PTSD, and schizophrenia
Developing methods to distinguish between identical twins in legal contexts
"The study of discordant monozygotic twins is a powerful testament to the complexity of human biology."
It reveals that our selves are not written in our genes alone, but are dynamically sculpted through a lifetime of interactions—from the random molecular events in our earliest embryonic stages to the food we eat and the lives we lead. These twin pairs teach us that identity is more than a blueprint; it is a living, changing story of a unique individual.
By continuing to unravel the reasons why one twin develops a disease while the other remains healthy, science is moving closer to a future where we can not only predict illness but also proactively shape our environments to build healthier lives.
The story of identical but not the same twins is, ultimately, a story about all of us—a reminder of the beautiful and intricate interplay between the genetic hand we are dealt and the lives we play.