The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

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What is our study about?

Our DNA is 99.9% identical to any other person. Among this 0.1% different, we can see many types of genetic variants that explain the differences between two people, from the eye color to the predisposition to certain diseases. Among these genetic variants, we are interested in genomic inversions.

Genomic inversions are segments of DNA that run in the opposite direction to a reference genome. They can differ in size, capturing from a gene’s fragment to a chromosome’s portion. Inversions play important roles in the predisposition to complex diseases in humans since they encapsulate multiple genes and change their expression. Although they can predispose to some diseases, inversions that do not affect essential genes are very common in humans.

Genomic inversion in a chromosome's portion

It is well understood that DNA methylation, the addition of a methyl group in a CpG DNA site, is very associated with gene expression. However, there are no studies investigating whether genomic inversions produce changes in DNA methylation that consequently modulate gene expression. Besides, DNA methylation can be, at the same time, altered by environmental exposures. In this paper, we evaluated the changes in DNA methylation according to the inversion state (inverted or non-inverted) and the role of environmental exposures on these modulations.

How did we do?

To this end, we used methylation and genetic data from 1,009 children from the Human Early Life Exposome (HELIX) project. We selected the three most common and biggest inversions at 8p23.1, 16p11.2, and 17q21.31 and we compared the methylation at the inversion region between inverted homozygous (I/I), non-inverted homozygous (NI/NI), and heterozygous (NI/I) individuals. For the inclusion of the role of environmental exposures, we evaluated the interaction between the inversion and each exposure (64 in total) on DNA methylation.

What did we find?

We found that the three inversions have distinctive methylation patterns in blood across the inverted regions depending on the inversion genotype (I/I, NI/NI, NI/I). We also observed that the most differentially methylated CpG sites were mapped in genes differentially expressed by the inversion. This means that DNA methylation plays as a mediator between inversion and gene expression.

We also found that several methylation effects of inversions are modifiable by numerous environmental exposures, especially metals, diet, phenols, and organochlorines. Therefore, inversions are common genetic variants that seem to be important contributors to gene-environment interactions.

3D representation of the specific DNA Methylation pattern for the inverted and the non-inverted allele

What still needs to be done?

  • We performed our analyses in blood, but it would be interesting to see the effects on other tissues, particularly for those genes that were differentially methylated but did not have a clear function in the blood.
  • Only the three most common inversions were evaluated because we did not have enough CpG sites for evaluating others, but it should be nice to extend the analysis to other inversions.
  • Our data were children between 6 and 11 years old. It would be appealing to validate this study in adult populations and study the association with diseases.
  • Finally, we showed numerous inversion-exposure interactions, but they should be validated one by one in future studies.

For more details about this work, please refer to our paper (https://doi.org/10.1038/s42003-022-03380-2) published in nature communications.

Photo credits: Pau Bosch Castro

Natalia Carreras Gallo

PhD Student, ISGlobal