DNA Sequence Variants Drive Link Between Methylation and Gene Expression

The relationship between DNA methylation and gene expression is driven by sequence variants, according to a recent study conducted by researchers at deCODE Genetics, an Amgen subsidiary. The same variants are connected to human characteristics and a number of diseases. The study was published in the journal Nature Genetics.

Real-time DNA sequence analysis is made possible by a new technology called nanopore sequencing, which was created by ONT (Oxford Nanopore Technology). This technology 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 measurements, identify any chemical changes made to the nucleotides.

One such modification, known as DNA methylation, is believed to play a crucial role in determining which genes are active at any given time—a process commonly referred to as the regulation of gene expression by scientists in the field. Nanopore sequencing technology allows for direct measurement of DNA methylation while also providing longer DNA sequence reads compared to previous technologies.

Thanks to these advancements, measuring DNA methylation at all CpG sites in the human genome is now possible. Since the technology can read lengthy DNA sequences, it is also possible to measure DNA methylation on individual chromosomes belonging to each parent.

Researchers were able to examine correlations between the three sets of measurements on a haplotype level because they could link sequence variant alleles, CpG methylation, and gene expression to the corresponding parental chromosomes in the study. As the study demonstrated, sequence variants impact DNA methylation, and some of these variants have been connected to a number of diseases and other human characteristics.

The study's key finding is that sequence variants are responsible for the correlation between DNA methylation and gene expression, suggesting that these variants act as the driving force.

Most sequence variants connected to diseases are located in noncoding genome regions, or sections of the genome that do not encode proteins.  

As a result, it has been challenging to comprehend how noncoding sequence variants cause diseases. By examining the effects on DNA methylation, scientists demonstrated that many of these variants align with sequence variants previously linked to diseases. This finding enhances the understanding of how these variants contribute to disease progression.