Genetics 101: How Our DNA Shapes Connective Tissue

Genetics, Epigenetics & More

When talkinga bout human health, traits and diseases, our DNA underlies it all. Your DNA, or genetic code, is responsible for the structure, function, and regulation of everything in your body. In this blog, I’m breaking down how genetics and epigenetics shape our connective tissue and the disorders that can arise from them.

What Are Genes?

Genes are instructions for making proteins and proteins make up our cells and tissue throughout our body. These proteins also play a role in forming, maintaining, and repairing tissues. For example, connective tissue genes provide the “instructions” for proteins like collagen, elastin, and other structural proteins that give tissues their strength and flexibility.

The central dogma of molecular biology is: DNA → RNA → Protein

This flow of information is how our bodies create proteins from our genetic code. While we all have the same genes, the variations in these genes make us unique. However, sometimes changes in these genetic codes can lead to genetic disorders, including those affecting connective tissues. Mutations in certain genes (such as COL5A1, TNXB, or ADAMTS2) can lead to connective tissue disorders, affecting the structure and function of our tissues.

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A Common Misconception:

❌ "I have the COL5A1 gene."
✅ Everyone has the COL5A1 gene. However, some people may have mutations in it.

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So, what Is a Mutation?

A mutation (or genetic variant) is simply a change in the DNA sequence. Not all mutations cause disease; in fact, many (if not most) are harmless - yes, even if they are in connective tissue genes. Mutations are classified as:

• Pathogenic Variant: A change that is known to cause a condition, such as certain COL5A1 mutations in classical Ehlers-Danlos syndrome (cEDS).

• Benign Variant: A change that has no known harmful effects.

• Variant of Uncertain Significance (VUS): A genetic change that we don’t yet know whether it causes disease or is harmless. Typically, this happens with rare mutations where the consequences are still unclear.

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How Do We Determine If a Mutation Is Pathogenic?

To determine if a mutation is harmful, scientists and clinicians rely on several methods:

• In silico analysis: Computer-based predictions of how a mutation affects protein function.

• Family studies: Checking if the mutation is inherited by other affected family members (and absent in people without symptoms).

• In vitro testing: Studying the mutation’s effect in cells.

• In vivo models: Using animal models to understand the mutation’s impact on a whole organism.

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What Is Inheritance?

Inheritance is the passing of genetic traits or conditions from parents to children.

Heritability refers to how much of a trait is influenced by genetics. Some traits, like eye color, are highly heritable.

In genetic disorders, there are two main types of inheritance patterns:

• Autosomal Dominant: One mutated copy of a gene can cause the disease. For example, Classical EDS (cEDS) or Vascular EDS (vEDS). If a parent has the mutation, there’s a 50% chance of passing it on to their children.

• Autosomal Recessive: Both copies of a gene must be mutated to cause disease. For example, Dermatosparaxis EDS (dEDS). If both parents are carriers, there’s a 25% chance of passing it on to their children.

Some conditions are also linked to sex chromosomes.

In diseases without clear genetic markers explaining all cases, it is hard to define exactly how it is inherited. Conditions like hypermobile EDS (hEDS), appear to follow an autosomal dominant inheritance pattern, but other genetic and epigenetic factors may influence the severity of the disorder.

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What Is Epigenetics?

Epigenetics refers to changes in gene expression without altering the underlying DNA sequence (genetic code). While every cell in your body carries the same DNA, epigenetics regulates which genes are active at any given time. This regulation is why different types of cells (e.g., eye cells vs. skin cells) can carry the same DNA but perform very different functions. (A great video explaining epigenetics can be found here.)

A common misconception:

❌ "Epigenetics turns genes on or off. Therefore, I can turn off my EDS through diet or supplements."
✅ Gene expression is regulated in complex ways that vary depending on the tissue, cell type, and developmental stage. It’s not as simple as turning genes on or off through diet or supplements.

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What Influences Epigenetics?

Epigenetic changes can be influenced by various factors:

• Methylation & histone modifications: Chemical tags that influence gene expression

• Environmental factors: Stress, diet, infections, and inflammation can alter gene expression

• Development & aging: As we age, gene expression can shift to accommodate changes in the body

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How Do Genetic Changes Affect Connective Tissue?

Genetic mutations in connective tissue genes result in the production of altered or defective proteins, which compromise the structure and function of tissues like skin, joints, and blood vessels. Some of the key proteins involved include:

• Collagen: Provides strength and structure to connective tissues.

• Elastin: Allows tissues to stretch and return to their original shape.

• Proteoglycans: Help organize collagen fibers and provide structure to the extracellular matrix.

• Enzymes: Assist in tissue remodeling and degradation

• Cell Signaling and Receptors: maintain structure and function, and respond to stimuli

Mutations in the genes encoding these proteins can lead to weaker, more fragile tissues and connective tissue disorders like EDS, Marfan Syndrome, Cutis Laxa and more.

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How Do Epigenetic Changes Influence Connective Tissue?

In connective tissue, epigenetic modifications can impact how genes responsible for structural proteins are expressed. These epigenetic changes are often triggered by environmental factors such as:

• Infections or post-viral syndromes

• Inflammation

• Injury

• Diet

• Stress

• Hormonal changes

Epigenetic changes can influence the integrity and strength of connective tissues, potentially altering the severity of conditions like EDS. For example, environmental stressors may exacerbate the symptoms of cEDS in individuals who already carry mutations in genes like COL5A1.

Research on epigenetics is rapidly growing, and scientists have discovered that these changes can sometimes be passed down to future generations, further complicating the inheritance and expression of certain conditions.

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Genetics & Epigenetics: Understanding Their Interplay

Genetics and epigenetics are interconnected. Here’s some ways that they influence each other:

• Mutations in Epigenetic Regulators: Some genes control DNA methylation or histone modification. Mutations in these genes can disrupt normal epigenetic patterns.

• Mutations Altering Epigenetic Marks: A mutation in a region where epigenetic modifications typically occur can lead to improper gene expression.

• Genetics Loads the Gun, Epigenetics Pulls the Trigger: A useful analogy to explain how genetic mutations make individuals susceptible to certain conditions, but epigenetic changes influence the severity of symptoms or how those conditions manifest.

Understanding the relationship between genetics and epigenetics helps explain why people with the same genetic mutation may experience different symptoms. This knowledge may also lead to new insights for treating and managing connective tissue disorders.

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