Genetic Variants & Disease Risk Insights

The relationship between DNA methylation and genetic variants is driven by sequence variants, according to a recent study conducted by researchers at deCODE Genetics, an Amgen subsidiary. The same variations are connected to human characteristics and a number of diseases.

The study was published today in the scholarly journal Nature Genetics under the heading: Sequence variations determine the relationship between CpG methylation and gene expression.

Real-time DNA sequence analysis is made possible by a new technology called nanopore sequencing, which was created by ONT (Oxford Nanopore Technology). This method pulls DNA molecules through minuscule protein pores, allowing real-time electric current measurements to determine which nucleotides in the DNA have made it through. This makes it feasible to read the DNA’s nucleotide sequence and, using the same measures, identify any chemical changes made to the nucleotides.

One such alteration is known as DNA methylation, and scientists in the field often refer to it as “regulation of gene expression” since it is believed to play a significant role in selecting which genes are used at any particular moment. Direct measurement of DNA methylation is now possible because to nanopore sequencing technology, which also produces longer reads of DNA sequences than previous methods could. The measurement of DNA methylation at all CpG sites in the human genome is now achievable thanks to these advancements, and since the technology can read lengthy DNA sequences, it is also possible to assess DNA methylation on individual chromosomes belonging to each parent.

By tagging CpG methylation, gene expression, and sequence variant alleles to parental chromosomes in the study, the researchers were able to look at correlations between the three sets of measurements at the haplotype level. The study demonstrates that sequence variants impact DNA methylation and that certain of these variants are associated with a variety of diseases and other characteristics of humans. Crucially, the work demonstrates that sequence variants are responsible for the relationship between DNA methylation and gene expression, suggesting that these variants constitute the driving force.

Most sequence variants connected to diseases are located on non-coding genomic regions, or sections of the genome that do not encode proteins. It has proven challenging to comprehend how noncoding sequence variations cause diseases as a result. We can now better understand how these variants contribute to the development of diseases because the scientists were able to demonstrate that many of them correlate to sequence variants that had previously been linked to disease by examining the impact on DNA methylation.

For more information: The correlation between CpG methylation and gene expression is driven by sequence variants, Nature Genetics, https://doi.org/10.1038/s41588-024-01851-2