Completed Genetics & Molecular Biology Diabetes, Hormones & Metabolism

Somatic adaptation and sex differences in human endocrine development and disease

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £1.6M
Period Feb 2018 — Feb 2023

In plain English

AI plain-English summary

A single genetic mutation in the SAMD9 gene can cause a severe growth disorder—but in some patients, the body’s own cells spontaneously correct the mutation, masking the underlying cause and making diagnosis nearly impossible. This research tackles a fundamental gap in understanding how our bodies dynamically edit their own genomes during development. The team has already shown that this “somatic adaptation” can hide disease-causing mutations in adrenal and growth disorders. They now want to know how widespread this phenomenon is across human disease. Separately, they are mapping how sex chromosomes and sex hormones shape the development of the adrenal gland, brain, and genital tubercle—and how losing an X chromosome (as in Turner syndrome) disrupts these processes. If successful, this work could change how clinicians diagnose and manage endocrine disorders. Instead of relying on a single genetic test, doctors might need to track how a patient’s genome changes over time. It could also link sex differences in development to common conditions like early-onset hypertension, stress responses, and neurodevelopmental disorders. This is fundamental science, but it has direct implications for personalised medicine—for example, tailoring treatments for adrenal or reproductive disorders based on a patient’s dynamic genetic profile rather than a static DNA sequence.

View original technical description
Our work focusses on new genetic mechanisms affecting human adrenal and reproductive function. We have recently described a multisystem growth restriction disorder caused by gain-of-function of SAMD9, where somatic adaptation can modify phenotype and mask detection of the genotype. In parallel, we developed a transcriptomic atlas of human adrenal and gonad development, mapping out sex-specific effects of organogenesis. We now plan to develop these insights to address several related fundamental questions: 1) How extensive is SAMD9 variability in endocrine and growth phenotypes and does dynamic somatic adaptation play a wider role in human disease mechanisms; 2) What are the dynamic roles of sex chromosomes and sex hormones in development (focussing on brain, adrenal gland and genital tubercle), and how does genetic variability of the X-chromosome contribute to phenotype in Turner syndrome (45,X); 3) Can we apply these concepts to discover new genetic mechanisms underlying adrenal and reproductive disorders. This work would provide novel disease models and approaches to analysis, could link the dynamics of development and sex-differences to common conditions (e.g. neurodevelopment, stress, early-onset hypertension), and would continue to elucidate the causes of human adrenal and reproductive disorders, with important implications for personalised management and development of new therapies.

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Researchers

John Achermann (EPMC Awardee)

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Original classification

Senior Research Fellowship Clinical Renewal

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