The human genome contains billions of DNA letters arranged into chromosomes. Understanding its intricate organization and how variations contribute to health and disease presents a significant challenge. Optical Genome Mapping (OGM) has emerged as a powerful new technology designed to analyze large-scale structural variations across the entire genome. This approach offers a unique “big picture” view, complementing existing methods that focus on smaller details.
What Optical Genome Mapping Is
Optical Genome Mapping is an imaging technology that evaluates the fluorescent labeling patterns of individual DNA molecules to assess genome-wide structural variants. It visualizes and analyzes large-scale structural changes in DNA, rather than reading individual DNA bases. It maps the physical location of DNA segments along chromosomes, offering a macroscopic view of the genome. Unlike traditional sequencing methods that focus on microscopic details, OGM converts DNA into a “barcode” whose profile can resolve copy number and structural variations without needing sequence-level data.
OGM can detect structural variants as small as 500 base pairs, a resolution that surpasses conventional cytogenetic approaches. This allows for an unbiased assessment of the entire genome. The technology relies on a specialized extraction protocol to isolate ultra-high molecular weight DNA molecules, ranging from approximately 150 kilobases to megabases in size.
How Optical Genome Mapping Works
The process of optical genome mapping begins with the isolation of intact, ultra-high molecular weight DNA molecules from a sample, such as blood, bone marrow, cultured cells, or tissue biopsies. These long DNA molecules, often exceeding 300 kilobases, are then labeled with fluorescent tags at specific DNA sequence motifs.
Following labeling, the tagged DNA molecules are loaded onto a silicon chip containing hundreds of thousands of parallel nanochannels. Electrophoresis guides the DNA into these nanochannels, ensuring that each channel accommodates only a single linearized DNA molecule, preventing tangling or folding. High-resolution cameras then image these stretched DNA molecules. The captured images are converted into digital representations of the unique label patterns. Specialized software then analyzes and compares these patterns to a reference genome, identifying structural variations.
Key Applications of Optical Genome Mapping
Optical Genome Mapping offers advantages in detecting large structural variants, including deletions, duplications, inversions, and translocations, which are often missed by other genomic methods. Its ability to identify these large-scale changes makes it useful in diagnosing rare genetic disorders. For instance, OGM has successfully identified disease-causing variants in previously undiagnosed cases, such as a mosaic deletion of 90 kilobase pairs on the X chromosome that was missed by multiple sequencing-based methods. It can also perform fine karyotyping, copy number analysis, and breakpoint analysis for microdeletion syndromes.
In cancer research, OGM is applied to identify chromosomal abnormalities that contribute to tumor development and progression. It can reveal novel gene fusions and complex rearrangements that impact cancer treatment strategies, some of which are difficult to detect with traditional methods. The technology also contributes to understanding genomic diversity in population studies by providing a comprehensive view of large structural variations across different individuals.
Optical Genome Mapping Alongside Other Genomic Techniques
Optical Genome Mapping complements other established genomic analysis tools rather than replacing them, offering a unique perspective on large-scale genomic architecture. Traditional cytogenetic methods like karyotyping, while capable of detecting large chromosomal aberrations, have limited resolution and are labor-intensive. Fluorescence in situ hybridization (FISH) offers targeted analysis but requires prior knowledge of the specific genomic region of interest, meaning it can miss unknown variants. Chromosomal microarrays (CMA) provide high-resolution detection of copy number variations across the genome, but they do not detect balanced rearrangements, which involve changes in chromosome structure without a gain or loss of DNA material.
Next-generation sequencing (NGS) excels at identifying small-scale genetic variants, such as single nucleotide polymorphisms and small insertions or deletions, offering base-level resolution. However, NGS struggles with detecting large copy number and structural variants, especially in repetitive regions of the genome, where it can be difficult to accurately align short-read sequences. OGM fills this gap by directly observing structural variations ranging from 500 base pairs up to megabase lengths, including balanced rearrangements that NGS often misses. A comprehensive understanding of the genome often requires a combination of these technologies, with OGM providing a high-resolution view of large-scale architecture that enhances the insights gained from other methods.