An explorer arrives at an island in search of buried treasure. With only fragments of an old map, he navigates by matching distinct features like a lake or rock. But in a dense forest, where everything looks the same, his map becomes useless. Even with a full map, his narrow telescope won’t help him see the whole island. He needs both a complete map and a bird’s‑eye view.

Our genetic landscape is much the same. Traditional sequencing provides high-resolution details of small regions, making it effective for detecting single nucleotide polymorphisms (SNPs) and small mutations. But because sequencing works by breaking DNA into short fragments, it struggles with larger structural variations like inversions and deletions, which require a continuous view of DNA to detect properly.

This challenge is the focus of a recent study published in the European Journal of Human Genetics, led by Karthik Bharadwaj, a scientist at CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, with Sofia Banu, a PhD student at CCMB, as the first author. Their research demonstrates how Optical Genome Mapping (OGM), combined with the telomere-to-telomere (T2T) CHM13 reference genome, is providing a more complete, end-to-end view of the genome, especially in regions that were previously difficult to map.

Unlike sequencing, OGM does not cut DNA into small pieces. Instead, it stretches ultra-long DNA molecules and labels them with fluorescent markers, allowing scientists to directly visualise large structural variations. Paired with the fully mapped T2T genome, this technique provides a gap-free view, particularly in highly repetitive regions like telomeres and centromeres, where sequencing often struggles. Banu explains, 

Our paper is about how we are bringing OGM and the T2T reference together to resolve clinical questions. This approach helps fill certain gaps in the field, particularly around structural variations which have been challenging to fully capture with older sequencing technologies.

The study tested this approach in clinical cases where standard genetic tests had failed. In one case, an inversion test returned negative results, leading to exome sequencing, which also found nothing. Exome sequencing focuses on analysing only protein-coding regions, which make up just a small portion of the genome.

“Genetic testing usually follows a stepwise approach, starting with targeted tests and escalating to broader sequencing when no answers are found. But even whole genome sequencing did not provide an answer. At that point, the real question became what is the cause of the disease,” describes Bharadwaj.

Targeted tests begin with single-gene sequencing or small gene panels, focusing on known disease-causing mutations. If these fail, broader approaches like exome sequencing or whole genome sequencing are used to search for answers.

This highlights why OGM is crucial. By providing a broad, continuous view of the genome, it allows researchers to see large structural variations that standard genetic testing often misses.

Ashwin Dalal, a scientist at the Centre for DNA Fingerprinting and Diagnostics (CDFD) in Hyderabad, predicts the long-term impact of this approach: ​“The T2T reference genome is likely to be used a lot more in the future. It is more reliable and can resolve genetic sequences that were previously a challenge, especially in repeat-rich regions like telomeres.”

This shift does not replace traditional sequencing, which remains essential for many aspects of genetic research. Instead, it complements existing methods, offering a broader, more connected perspective to fill in missing pieces of the genetic puzzle.

By combining a fully completed reference genome with a technique that captures the entire structure of DNA, researchers move beyond fragmented insights. They now have access to a complete map and a bird’s‑eye view of the genome, ensuring that no critical genetic variant remains hidden.

Just as the explorer finally acquires a full map and an aerial view of the island, genetic researchers now have the tools to navigate the genome with unprecedented clarity. The combination is reshaping the way we study genetic disorders, opening a new era in genetic diagnostics and research.