Scientists Solve One of Genomics’ Biggest Challenges by Using HiFi Sequencing to Distinguish Highly Similar Paralogous Genes
PacBio (NASDAQ: PACB) has announced a breakthrough study published in Nature Communications showcasing a new method for analyzing complex genomic regions. The research introduces Paraphase, an informatics tool that, when combined with HiFi long-read sequencing, enables high-precision variant detection in 316 previously inaccessible segmental duplication regions.
The study, led by researchers from PacBio, GeneDx, and a global genomics consortium, successfully analyzed 160 long segmental duplication regions, including 9 medically-relevant genes. Key findings include the discovery of 7 new de novo single nucleotide variants and 4 de novo gene conversion events in 36 trios, as well as comprehensive copy number variability analysis across populations.
The research demonstrates Paraphase's ability to analyze complex gene families like CYP21A2/CYP21A1P, which are associated with conditions such as congenital adrenal hyperplasia, spinal muscular atrophy, and red-green color blindness. The technology overcomes traditional sequencing limitations by phasing haplotypes across paralogous gene families, offering improved accuracy in genetic variation detection.
PacBio (NASDAQ: PACB) ha annunciato uno studio innovativo pubblicato su Nature Communications che presenta un nuovo metodo per analizzare regioni genomiche complesse. La ricerca introduce Paraphase, uno strumento informatico che, quando combinato con il sequenziamento HiFi a lettura lunga, consente di rilevare varianti con alta precisione in 316 regioni di duplicazione segmentale precedentemente inaccessibili.
Lo studio, guidato da ricercatori di PacBio, GeneDx e un consorzio globale di genomica, ha analizzato con successo 160 regioni di duplicazione segmentale lunghe, comprese 9 geni di rilevanza medica. I principali risultati includono la scoperta di 7 nuove varianti di nucleotidi singoli de novo e 4 eventi di conversione genica de novo in 36 triadi, oltre a un'analisi completa della variabilità del numero di copie tra le popolazioni.
La ricerca dimostra la capacità di Paraphase di analizzare famiglie geniche complesse come CYP21A2/CYP21A1P, associate a condizioni come l'iperplasia surrenalica congenita, l'atrofia muscolare spinale e il daltonismo rosso-verde. La tecnologia supera i limiti del sequenziamento tradizionale attraverso la fase di haplotipi tra famiglie geniche paraloghe, offrendo una maggiore accuratezza nella rilevazione delle variazioni genetiche.
PacBio (NASDAQ: PACB) ha anunciado un estudio innovador publicado en Nature Communications que presenta un nuevo método para analizar regiones genómicas complejas. La investigación introduce Paraphase, una herramienta informática que, cuando se combina con la secuenciación HiFi de lectura larga, permite la detección de variantes con alta precisión en 316 regiones de duplicación segmental previamente inaccesibles.
El estudio, liderado por investigadores de PacBio, GeneDx y un consorcio global de genómica, analizó con éxito 160 regiones de duplicación segmental largas, incluyendo 9 genes de relevancia médica. Los hallazgos clave incluyen el descubrimiento de 7 nuevas variantes de nucleótidos únicos de novo y 4 eventos de conversión génica de novo en 36 trios, así como un análisis completo de la variabilidad del número de copias entre poblaciones.
La investigación demuestra la capacidad de Paraphase para analizar familias de genes complejas como CYP21A2/CYP21A1P, que están asociadas con condiciones como la hiperplasia suprarrenal congénita, la atrofia muscular espinal y el daltonismo rojo-verde. La tecnología supera las limitaciones de la secuenciación tradicional al fasear haplotipos entre familias de genes paralojas, ofreciendo una mayor precisión en la detección de variaciones genéticas.
PacBio (NASDAQ: PACB)는 복잡한 유전체 영역을 분석하는 새로운 방법을 소개하는 혁신적인 연구를 Nature Communications에 발표했습니다. 이 연구는 Paraphase라는 정보 도구를 도입하며, HiFi 장기 읽기 시퀀싱과 결합할 경우, 316개의 이전에 접근할 수 없었던 세그먼트 중복 영역에서 고정밀 변이 탐지를 가능하게 합니다.
이 연구는 PacBio, GeneDx 및 글로벌 유전체 컨소시엄의 연구자들에 의해 주도되었으며, 9개의 의학적으로 중요한 유전자를 포함하여 160개의 긴 세그먼트 중복 영역을 성공적으로 분석했습니다. 주요 발견 사항으로는 36개의 삼중체에서 7개의 새로운 de novo 단일 뉴클레오타이드 변이와 4개의 de novo 유전자 전환 사건을 발견했으며, 인구 간 복제 수 변동성에 대한 포괄적인 분석이 포함됩니다.
이 연구는 Paraphase가 선천성 부신 과형성, 척수성 근위축증, 적녹색 색맹과 같은 질환과 관련된 CYP21A2/CYP21A1P와 같은 복잡한 유전자 가족을 분석할 수 있는 능력을 보여줍니다. 이 기술은 유사 유전자 가족 간의 해플로타입을 단계적으로 처리하여 전통적인 시퀀싱의 한계를 극복하고 유전적 변이 탐지의 정확성을 향상시킵니다.
PacBio (NASDAQ: PACB) a annoncé une étude révolutionnaire publiée dans Nature Communications présentant une nouvelle méthode pour analyser des régions génomiques complexes. La recherche introduit Paraphase, un outil informatique qui, lorsqu'il est combiné avec le séquençage HiFi à lecture longue, permet la détection de variantes avec une grande précision dans 316 régions de duplication segmentaire auparavant inaccessibles.
L'étude, dirigée par des chercheurs de PacBio, GeneDx et un consortium mondial de génomique, a réussi à analyser 160 régions de duplication segmentaire longues, y compris 9 gènes d'importance médicale. Les résultats clés incluent la découverte de 7 nouvelles variantes de nucléotides uniques de novo et 4 événements de conversion génique de novo dans 36 trios, ainsi qu'une analyse complète de la variabilité du nombre de copies au sein des populations.
La recherche démontre la capacité de Paraphase à analyser des familles de gènes complexes comme CYP21A2/CYP21A1P, qui sont associées à des conditions telles que l'hyperplasie surrénalienne congénitale, l'atrophie musculaire spinale et le daltonisme rouge-vert. La technologie surmonte les limitations du séquençage traditionnel en phasant les haplotypes à travers des familles de gènes paralogues, offrant une précision améliorée dans la détection des variations génétiques.
PacBio (NASDAQ: PACB) hat eine bahnbrechende Studie veröffentlicht, die in Nature Communications erscheint und eine neue Methode zur Analyse komplexer genomischer Regionen vorstellt. Die Forschung führt Paraphase ein, ein Informatik-Tool, das in Kombination mit HiFi-Langzeit-Sequenzierung eine hochpräzise Variantenerkennung in 316 zuvor unzugänglichen segmentalen Duplikationsregionen ermöglicht.
Die Studie, geleitet von Forschern von PacBio, GeneDx und einem globalen Genomik-Konsortium, hat erfolgreich 160 lange segmentale Duplikationsregionen analysiert, darunter 9 medizinisch relevante Gene. Zu den wichtigsten Ergebnissen gehört die Entdeckung von 7 neuen de novo Einzel-Nukleotid-Varianten und 4 de novo Genkonversionsereignissen in 36 Trios sowie eine umfassende Analyse der Variabilität der Kopienzahl in verschiedenen Populationen.
Die Forschung zeigt die Fähigkeit von Paraphase, komplexe Genfamilien wie CYP21A2/CYP21A1P zu analysieren, die mit Erkrankungen wie kongenitaler adrenaler Hyperplasie, spinaler Muskelatrophie und rot-grünem Farbblindheit assoziiert sind. Die Technologie überwindet die traditionellen Sequenzierungsbeschränkungen, indem sie Haplotypen über paraloge Genfamilien phasiert und so die Genauigkeit bei der Erkennung genetischer Variationen verbessert.
- Breakthrough in analyzing previously inaccessible genomic regions
- Successfully developed new tool (Paraphase) for improved genetic analysis
- Technology enables analysis of medically relevant genes linked to serious conditions
- Demonstrated superior accuracy compared to traditional sequencing methods
- None.
Insights
PacBio's publication in Nature Communications represents a significant technical breakthrough in genomic analysis. Their HiFi sequencing technology, paired with the new Paraphase informatics tool, has successfully analyzed 316 genes in segmental duplication regions that were previously inaccessible to conventional sequencing methods.
The technical achievement is remarkable - these paralogous genes (nearly identical copies) have long been the "dark matter" of genomics. The ability to distinguish between highly similar gene copies like SMN1/SMN2 (linked to spinal muscular atrophy) and CYP21A2 (associated with congenital adrenal hyperplasia) opens new research avenues previously blocked by technological limitations.
What separates this from incremental advances is the demonstration that PacBio's long-read approach can resolve complex genomic structures that short-read technologies fundamentally cannot address due to their inherent limitations. The identification of previously undetected de novo variants and gene conversion events showcases the technology's potential to reveal hidden genetic mechanisms.
The collaboration with GeneDx points toward potential clinical applications, suggesting a path from research discovery to diagnostic implementation. However, the transition from publication to clinical adoption typically requires additional validation studies and regulatory considerations.
For PacBio, this advances their competitive positioning in specialized sequencing applications where accuracy in complex regions is paramount. While immediate revenue impact may be modest, the technology enhancement strengthens their value proposition in the high-precision genomic analysis segment.
PacBio's Nature Communications study demonstrates a distinctive competitive advantage in one of sequencing's most challenging areas. By enabling accurate analysis of segmental duplications, PacBio addresses a persistent technological gap that has genomic research and diagnostic capabilities.
This advancement differentiates PacBio's platform in the crowded sequencing market. While competitors dominate in throughput and cost efficiency for straightforward genomic regions, PacBio now showcases superior capabilities in these complex regions containing medically relevant genes.
The technology's ability to phase haplotypes across paralogous gene families leverages the unique combination of read length and accuracy that defines PacBio's HiFi approach. This creates a technical moat in specialized applications where alternative technologies fundamentally fall short.
The collaboration with GeneDx, a clinical genomics provider, suggests potential commercialization pathways in diagnostic testing. Conditions like spinal muscular atrophy and congenital adrenal hyperplasia represent high-value diagnostic targets where improved accuracy could translate to better clinical outcomes.
For investors, this reinforces PacBio's technological leadership in accuracy-critical applications and suggests potential expansion into specialized clinical markets. While the direct revenue impact may develop gradually as research advances translate to clinical applications, this technological differentiation strengthens PacBio's competitive positioning in the precision genomics landscape.
MENLO PARK, Calif., March 17, 2025 (GLOBE NEWSWIRE) -- PacBio (NASDAQ: PACB), a leading provider of high-quality, highly accurate sequencing platforms, today announced a newly published study in Nature Communications unveiling a powerful new method for analyzing some of the most complex regions of the human genome. Led by researchers from PacBio, GeneDx, and a global consortium of genomics experts, the study utilizes Paraphase, an informatics tool that, when paired with HiFi long-read sequencing, allows for high-precision variant detection and copy number analysis in 316 previously inaccessible segmental duplication regions, including 9 challenging medically-relevant genes.
Segmental duplications (SDs) are highly similar, duplicated regions of the genome that have posed persistent challenges for genetic analysis. These regions contain hundreds of genes critical to human health—including those implicated in spinal muscular atrophy (SMN1/SMN2), congenital adrenal hyperplasia (CYP21A2), and red-green color blindness (OPN1LW/OPN1MW)—but their high sequence similarity makes accurate mapping and variant detection nearly impossible with short-read sequencing. Paraphase, combined with HiFi sequencing, overcomes these challenges by phasing haplotypes across paralogous gene families, providing a more complete and accurate view of genetic variation. This is enabled by the length and accuracy of reads from HiFi sequencing.
Study Reveals Previously Inaccessible Regions of the Genome
By applying Paraphase to 160 long (>10 kb) segmental duplication regions spanning 316 genes, the researchers revealed new insights into genetic variation across five ancestral populations.
Among the key findings:
- Newly Identified De Novo Variants in SDs in Parent-Offspring Trios: Analysis of 36 trios uncovered 7 previously undetected de novo single nucleotide variants (SNVs) and 4 de novo gene conversion events, two of which were non-allelic—a level of detail not possible with traditional sequencing approaches.
- Copy Number Variability Across Populations: The study profiled the copy number distributions of paralog groups across populations, showing high copy number variability in many gene families in SDs. It also provided a new approach for identifying false duplications in the reference genome.
- Gene Conversion Drives Sequence Similarity between Genes and Paralogs: The team identified 23 paralog groups with strikingly low genetic diversity between genes and paralogs, indicating that frequent gene conversion and/or unequal crossing-over may have played a role in preserving highly similar gene copies over time.
“For decades, sequencing technologies have struggled to provide reliable data on paralogous genes—some of the most medically relevant but hardest to analyze regions of the genome,” said Dr. Michael A. Eberle, Vice President of Bioinformatics at PacBio and senior author of the study. “With Paraphase and HiFi sequencing, we now have a scalable way to accurately genotype SD-encoded genes across diverse populations, filling in long-standing gaps in genomic research and improving our ability to identify disease-linked variants.”
The study also highlights how Paraphase can disentangle medically important gene families that have long required specialized, multi-step assays like MLPA and Sanger sequencing. For example, in the CYP21A2/CYP21A1P region—where mutations cause congenital adrenal hyperplasia—the researchers characterized a previously overlooked duplication allele carrying both a functional CYP21A2 copy and a CYP21A2(Q319X) pseudogene copy, which could have led to misclassification in standard tests.
“This study demonstrates that when we use HiFi sequencing we see a much richer and more complex picture of genetic variation,” said Dr. Xiao Chen, lead author of the study and principal scientist at PacBio. “Paraphase enables the precise resolution of genetic regions that have been largely inaccessible until now, providing new opportunities for disease research, population genetics, and potentially even clinical testing.”
“Long-read genome sequencing offers the ability to detect variants that are difficult to identify using other testing methods, particularly in regions with highly similar sequence,” said Dr. Paul Kruszka, MD, FACMG, Chief Medical Officer at GeneDx. “This work may enhance variant detection, resolve complex genomic regions, and provide more answers for patients and families, so we are encouraged by the prospect of the data.”
The full study, “Genome-wide profiling of highly similar paralogous genes using HiFi sequencing,” is now available in Nature Communications.
About PacBio
PacBio (NASDAQ: PACB) is a premier life science technology company that is designing, developing and manufacturing advanced sequencing solutions to help scientists and clinical researchers resolve genetically complex problems. Our products and technologies stem from two highly differentiated core technologies focused on accuracy, quality and completeness which include our HiFi long-read sequencing and our SBB® short-read sequencing technologies. Our products address solutions across a broad set of research applications including human germline sequencing, plant and animal sciences, infectious disease and microbiology, and oncology. For more information, please visit www.pacb.com and follow @PacBio.
PacBio products are provided for Research Use Only. Not for use in diagnostic procedures.
Forward Looking Statements
This press release may contain “forward-looking statements” within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the U.S. Private Securities Litigation Reform Act of 1995. All statements other than statements of historical fact are forward-looking statements, including statements relating to the uses, coverage, advantages, and benefits or expected benefits of using, PacBio products or technologies, including in connection with providing a scalable way to accurately genotype SD-encoded genes across diverse populations, fill in long-standing gaps in genomic research, and improve the ability to identify disease-linked variants; enabling precise resolution of genetic regions that were previously largely inaccessible; providing new opportunities for disease research, population genetics, and potential clinical testing; potentially detecting or enhancing the detection of variants difficult to identify using other methods, resolving complex genomic regions, and providing more answers for patients and families; and other future events. You should not place undue reliance on forward-looking statements because they are subject to assumptions, risks, and uncertainties and could cause actual outcomes and results to differ materially from currently anticipated results, including, the difficulty of generating discoveries in complicated areas of biology; potential performance, quality and regulatory issues; and third-party claims alleging infringement of patents and proprietary rights or seeking to invalidate PacBio's patents or proprietary rights. Additional factors that could materially affect actual results can be found in PacBio's most recent filings with the Securities and Exchange Commission, including PacBio's most recent reports on Forms 8-K, 10-K, and 10-Q, and include those listed under the caption "Risk Factors." These forward-looking statements are based on current expectations and speak only as of the date hereof; except as required by law, PacBio disclaims any obligation to revise or update these forward-looking statements to reflect events or circumstances in the future, even if new information becomes available.
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FAQ
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