NGS: hunting mysterious ‘Dark Matter Genome’ towards rewriting the rules of human genetic diseases

Next generation sequencing (NGS) has revolutionised genomics research providing a wealth of genetic information of immense value to researchers. NGS technologies have been evolving over the last decade, leading to substantial improvement in understanding different biological systems from broader and deeper perspectives.

Contemporary advances in high throughput DNA sequencing technologies have ultimately enabled investigations into the entire genome and specific regions of interest, thus providing accurate in-depth genomic information and biological insight into unexpected DNA changes. In recent years, several NGS platforms with different sequencing chemistries have been developed that can perform sequencing of millions of smaller DNA fragments in parallel. With the advent of NGS technology, human genomes can now be systematically studied in their entirety at a much faster pace and cheaper cost. Sequencing of the human genome provides many benefits including more accurate diagnosis, prognosis and classification of diseases. It also offers attractive ways to identify ‘druggable’ casual mutations and other genetic variations, such as substitutions, insertions, deletions, inversions and translocation that could serve as an underlying cause for many human genetic diseases.

Deciphering the genetic information encoded by the human genome is paramount in biomedical research. Extensive investigation into genetic mutations that cause human diseases has uncovered that the disease-causing mutations occur within 1-2% of protein-coding DNA called ‘exons’. The remaining 98% of the genome constitutes ‘dark matter’ whose function remains unclear. Interpreting the effect of DNA changes within genomic dark matter is very difficult.

Recent advances in NGS technology have shed light on annotating genomic dark matter and assigning biological functions to many different regions of the human genome, such as promoters, enhancers, repressors, transcription factor binding sites and other regulatory elements. NGS technology has also accelerated the process of identifying disease-causing DNA abnormalities through genome-wide comprehensive scanning of non-coding mutations with regulatory benefits in the human genome. Detailed investigation of the types and genetic alterations that are related to human disease may lend insight into the interpretation of similar DNA abnormalities in other genetic disorders.

Thus, uncovering the non-protein coding DNA sequences with regulatory potential using NGS-based approaches could help us move forward in targeting the entire genome for clinical purposes. This article outlines the unmatched opportunities presented by NGS technologies to study genomic dark matter for better understanding of health and disease, opening doors for the development of novel treatments for human genetic disorders.

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