Long Read Sequencing Industry: Global Long Read Sequencing Revolutionizes Genomics Research
Emergence of Third Generation Long Read Sequencing Industry Technologies
The first generation Sanger sequencing dominated from 1977 until the mid-2000s and facilitated the sequencing of the human genome. However, Sanger sequencing had limitations in read lengths attainable.
The development of next-generation sequencing (NGS) technologies in the mid-2000s, like Illumina sequencing, helped overcome this limitation by massively parallelizing the sequencing process. Global Long Read Sequencing While NGS greatly increased sequencing throughput and reduced costs, it still produced relatively short reads, averaging only 150 base pairs. Such short reads make it difficult to sequence complex genomic regions with repeats or structural variants. To address this short read limitation, a new class of sequencing platforms termed “third-generation” or “long-read” sequencing has emerged since 2012. These platforms like Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) are able to generate reads that are 10-100x longer than short-read NGS technologies.
Resolving Repetitive Regions and Structural Variation
One of the major advantages of long read sequencing is the ability to resolve complex repetitive genomic regions that are difficult or impossible to sequence and assemble with short reads. Tandem and interspersed repeats make up a significant portion of mammalian genomes, including over 50% of the human genome. However, short reads cannot reliably span repeat units or distinguish closely related repeats from each other. This has hampered complete assembly of mammalian genomes. In contrast, long reads of 10-100 kb generated by PacBio or 50-500 kb reads from ONT can routinely span repetitive elements, resolving their structures and orientations. This has enabled production of reference-grade whole genome assemblies for diverse species like the gorilla, loblolly pine and rice. Long reads are also indispensable for characterizing structural variations like inversions, translocations, and complex genomic rearrangements which often involve repeats. Many disease-causing variations lie in difficult to sequence regions that long reads can help explore.
Applications in Metagenomics and Isolate Long Read Sequencing Industry
Another active application area for long read sequencing is environmental and microbial metagenomics. Metagenomic studies seek to characterize the collective genomes of microbial communities directly from environmental samples without culturing individual species. However, short read metagenomics has limitations as sequences cannot be confidently assigned to species or assembled into genomes. Third generation sequencing has transformed this field by enabling assembly of near complete genomes from mixed microbial communities. This has provided unprecedented insights into the genetic diversity, metabolic potential and ecosystem functions of various microbiomes. Long reads have also accelerated microbial isolate sequencing by rapidly obtaining finished-quality reference genomes from cultured isolates, bypassing the need for laborious gap-filling with additional sequencing. This enables more targeted studies on physiology and pathways of novel microbes. Overall, long reads are helping revolutionize our understanding of microbial dark matter in various ecosystems.
Clinical Applications in Human Genomics
The ability to resolve complex structural variation is driving growing applications of long reads in clinical genomics. Long read whole genome sequencing has an advantage over short read exome sequencing in detecting all types of disease-causing variants including those in non-coding and repetitive regions. This improves diagnostic yield, especially for genetic disorders originating from structural variants. Long reads are frequently analyzed in parallel with exome orgenome sequencing in clinical labs to validate or resolve variants of unknown significance. Several diagnostic testing labs have now started offering long read based tests for diseases like autism, epilepsy, mitochondrial disorders and cancers. Pharmaceutical companies are using long reads for studying genomic biomarkers, pharmacogenomic effects and structural differences between cancer subtypes. As DNA sequencing becomes more integrated into precision medicine, long reads will play an increasing role by providing a complete view of genomic variation in patient samples.
Technical Advances and Remaining Challenges
While significant progress has been made in read lengths and throughput, long read sequencing still faces several technical challenges. Early platforms had relatively high error rates >10-15% requiring extensive post-correction. Continuous advances by manufacturers have steadily brought error rates down. However, sequencing homopolymer regions and coding repeats remains difficult. Another issue is shorter read lengths and lower throughput from nanopore sequencers compared to PacBio. Third generation platforms also require relatively high input DNA amounts limiting applications involving precious clinical samples. Ensuring high accuracy and longer reads from portable, affordable sequencers applicable to point-of-care settings remains an active area of development.
Adoption has also been slowed by higher reagent and instrument costs compared to short read NGS. However, reduced prices, improved yields and expanded applications are improving access. As technologies mature further, long read sequencing is set to transform human genome analysis and our understanding of genomic complexity across all fields of biological research.
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Money Singh is a seasoned content writer with over four years of experience in the market research sector. Her expertise spans various industries, including food and beverages, biotechnology, chemical and materials, defense and aerospace, consumer goods, etc. (https://www.linkedin.com/in/money-singh-590844163)
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