Women and men share the vast majority of their biology. However, they do not always develop the same diseases at the same frequency, experience the same symptoms or respond to treatments in exactly the same way.

These differences are well known in medicine. Autoimmune diseases are more common in women, while the prevalence and progression of cardiovascular, metabolic and neurological conditions can also differ between sexes. Responses to certain medicines, including their effectiveness and potential adverse effects, may vary as well.

But why does this happen?

A landmark study published in Science helped answer this question by analysing how biological sex influences gene activity across the human body. The research found that sex-associated differences in gene expression are present in almost every tissue studied, providing an important scientific foundation for a more personalised and representative approach to medicine.

The research was conducted by the international Genotype-Tissue Expression Consortium, known as GTEx. The team from the Institut de Recerca Sant Pau involved in the project was led by Dr José Manuel Soria, Head of the Genomics of Complex Diseases Unit at the Institut de Recerca Sant Pau and Scientific Director of BASE4 Biosciences.

The same DNA does not always produce the same biological activity

Most cells in the human body contain essentially the same DNA. However, a liver cell behaves very differently from a brain, muscle or heart cell.

This is because cells do not use every gene at the same time or at the same intensity. Some genes are more active in particular tissues, while others remain relatively silent.

This process is known as gene expression.

Gene expression can be understood as the way our cells read and use the instructions contained in DNA. By analysing RNA, the molecules produced when genes are activated, scientists can observe which biological processes are more or less active in a particular tissue.

The complete set of RNA molecules found in a cell or tissue is called the transcriptome.

While our genome remains relatively stable throughout life, the transcriptome is dynamic. It can change according to the tissue being studied, a person’s age, biological sex, health status, hormones, environmental exposure and other factors.

In simple terms, DNA tells us which instructions are available. RNA helps us understand which of those instructions the body is actually using.

What did the researchers study?

The researchers analysed gene expression across 44 types of healthy human tissue from 838 individuals.

The tissues included samples from organs and systems such as the brain, heart, liver, lungs, skin, thyroid, skeletal muscle, adipose tissue and blood.

The objective was to determine whether genes were expressed differently in females and males and whether those differences changed depending on the tissue being studied.

This large-scale approach was essential. Looking only at blood, for example, does not necessarily reveal what is happening in the liver, brain or cardiovascular system. Each tissue has its own biological function and its own pattern of gene activity.

Sex-associated differences were found throughout the body

The study found that approximately 37% of the genes analysed showed sex-associated differences in expression in at least one tissue.

This does not mean that female and male biology are completely different.

In fact, the researchers emphasised that most of our biology is shared and that the individual differences observed were generally small. There was also substantial overlap between female and male gene-expression patterns.

However, even relatively small differences can become biologically relevant when they appear across many genes, tissues and molecular pathways at the same time.

The study therefore presents a more nuanced picture. Women and men largely share the same genetic instructions, but some of those instructions may be activated at different levels or in different biological contexts.

The differences depend on the tissue

One of the most important conclusions was that these differences were highly tissue-specific.

A gene could show different activity between females and males in adipose tissue, for example, but show little or no difference in the liver or blood.

Only a very small number of genes showed consistent sex-associated differences across all the tissues studied. Most differences appeared only in certain organs or biological systems.

This is important because human diseases are rarely caused by a single gene acting in isolation. They often involve multiple genes, pathways, cell types and tissues interacting with one another.

It also means that conclusions drawn from a single type of biological sample may not fully represent what is happening elsewhere in the body.

Blood is extremely valuable because it is accessible and contains a large amount of biological information. Nevertheless, interpreting that information properly requires models capable of relating blood-based signals to the tissues and biological systems they may represent.

Why does this matter for medicine?

The study identified sex-associated gene-expression patterns involving a wide range of biological functions, including metabolism, immune activity, body-fat distribution, blood-sugar regulation, cancer biology and the processing of medicines.

This may help explain why some diseases affect women and men differently.

Biological sex can influence:

The risk of developing certain diseases.

The age at which a condition appears.

The way symptoms present.

The speed at which a disease progresses.

The biological response to a treatment.

The likelihood of experiencing particular adverse effects.

Traditionally, many biomedical analyses have combined female and male participants into a single population. Although this can be useful, it can also hide biological signals that are stronger or only visible in one sex.

The researchers found several relationships between genetic regulation and complex human traits that became visible only when female and male data were examined separately.

These findings do not mean that every woman or every man will respond in the same way. Biological sex is one important variable among many, including age, genetics, lifestyle, clinical history and environmental exposure.

Nevertheless, the study shows that sex should not simply be treated as a demographic detail. It can be a meaningful biological factor that affects how genes function across the body.

The contribution led by Dr José Manuel Soria

The study was an international collaboration involving researchers from multiple institutions within the GTEx Consortium.

The Sant Pau research team participating in the project was led by Dr José Manuel Soria, Head of the Genomics of Complex Diseases Unit at the Institut de Recerca Sant Pau and currently Scientific Director of BASE4 Biosciences. Dr Soria was a co-author of the publication alongside Ángel Martínez-Pérez, co-founder of BASE4 Biosciences.

Dr Soria highlighted the potential importance of the findings for personalised medicine. Understanding which genetic and molecular mechanisms behave differently between women and men could support better models for predicting disease risk and treatment response.

It is important to describe this contribution accurately: the overall international study was led by Barbara E. Stranger and other principal researchers, while Dr Soria led the participating research team from the Institut de Recerca Sant Pau.

From population averages to individual biology

This study provides an extensive map of sex-associated gene-expression differences across healthy human tissues.

However, it does not provide a diagnostic test, recommend different treatments or predict how a particular individual will respond to a medicine.

Its value is foundational.

The research shows why medicine should move beyond universal averages. A biological reference created without considering sex or tissue context may overlook important differences between individuals.

At the same time, sex alone is not sufficient to explain someone’s health. Two people of the same sex can have very different genetics, lifestyles, clinical histories and biological states.

The future of precision medicine will therefore require the integration of multiple dimensions:

Biological sex.

Genetic variation.

Gene expression.

Tissue-specific activity.

Clinical and lifestyle information.

Changes occurring over time.

This integrated approach can help us move from broad population-level associations towards a more complete understanding of individual biology.

How this scientific foundation connects with BASE4 Biosciences

The study reflects one of the scientific principles behind BASE4 Biosciences: human biology cannot always be understood through a single, universal model.

At BASE4, we combine genetic, transcriptomic and clinical information to build a more contextual view of an individual’s health. Our technology studies biological signals found in blood and uses computational models to interpret how they may relate to different tissues, biological pathways and health systems.

A central part of this approach is the development of sex-specific biological models.

Rather than assuming that the same molecular reference should be applied identically to everyone, BASE4 aims to account for the fact that female and male biology can regulate genes and biological pathways differently.

The goal is not to divide people into two simplistic categories. It is to add an important layer of biological context while also considering age, genetics, lifestyle, clinical data and the individual’s current molecular state.

This study does not directly validate BASE4’s technology or products. However, it provides strong scientific evidence for several principles on which our platform is built:

Biological sex can influence gene expression throughout the body.

These effects can vary significantly between tissues.

Blood alone does not directly represent every organ or biological system.

Molecular information becomes more valuable when interpreted in its biological and clinical context.

Sex-aware analysis may reveal signals that remain hidden when all individuals are evaluated using the same reference.

BASE4 builds on these principles by creating computational models designed to interpret human biology in a more personalised, tissue-aware and sex-specific way.

Towards a more complete model of human health

The main message of the study is not that female and male biology are fundamentally separate.

Most human biology is shared.

The study instead demonstrates that biological sex can subtly influence how genes are used across different tissues. Individually, many of these differences are small. Together, they may help explain meaningful differences in disease risk, biological function and treatment response.

Recognising this complexity is essential for developing a more precise form of medicine.

The genome provides the biological instructions. The transcriptome shows how those instructions are being used. By combining this information with tissue context, biological sex and clinical data, we can begin to build a more complete and individualised understanding of human health.

That is the direction in which biomedical science is moving, and the scientific vision that BASE4 Biosciences is working to translate into real-world applications.

Scientific reference

Oliva M, Muñoz-Aguirre M, Kim-Hellmuth S, et al. The impact of sex on gene expression across human tissues. Science. 2020;369(6509). doi:10.1126/science.aba3066.