June 7, 2024  |  General

Powered by PacBio: Selected publications from May 2024

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PacBio HiFi sequencing technology continues to be the tool of choice for genomics professionals working at the forefront of discovery, enabling them to pursue new avenues of exploration across diverse domains of biology.

In this edition of our Powered by PacBio blog series, we highlight scientific papers from the month of May 2024. These compelling publications highlight the power of PacBio sequencing to help understand rare disease, reveal mysteries around thyrotropin resistance, identify novel isoforms, and more.
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Understanding rare and undiagnosed disease  Fiber-Seq  Kinnex  Iso-Seq method

Understanding rare and undiagnosed disease

Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing

In this paper, researchers from 35 institutions led by Radboud Netherlands, Germany, Spain, Belgium, Italy, UK, Egypt, Canada, France, Finland, Solve-RD consortium use HiFi sequencing (10-fold coverage) to identify disease-causing genetic variants in previously extensively studied (short-read exome & WGS) but undiagnosed rare disease families:

Findings included:

  • Hi-Fi long-read genome sequencing was conducted for a unique cohort of 293 individuals from 114 previously studied rare disease families, and causal genetic variants were identified in 13% of the families.
  • 4% of families with novel candidate disease-causing SVs (most variants affecting already established disease genes). Authors noted that “Confirmation of the pathogenic nature of these variants may broaden the known phenotypic spectrum of the affected genes or establish new inheritance patterns.”; and one “de novo deletion suggests a potential novel neurodevelopmental disease gene.”
  • In a subcohort, a de novo missense variant in TUBA1A (described as a cause of lissencephaly 3) was identified in one patient diagnosed with Aicardi syndrome: “Clinical reassessment of the patient’s phenotype confirmed the new findings.”
  • “Clinical interpretation of variants was hampered by the large number of identified “rare” SV. Large catalogues of identified variants from long-read sequencing of both affected and unaffected individuals will therefore be of critical importance to improve variant interpretation in such cases”. Solve-RD is sharing “the full dataset, including expert-curated pedigree and phenotype information. In addition, we also share a frequency call set of high-quality SVs of the unrelated individuals as a resource for other researchers.”


In rare disease research, “our results demonstrate the added value of HiFi long-read genome sequencing in undiagnosed rare diseases.”



STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179

In this paper, researchers from U of MI, U of Chicago, UW, U of Miami, Nagoya U Japan, U Brussels Belgium, and Brotman Baty WA present their work employing Fiber-Seq to “identify a new variation type causing Mendelian disease by altering the non-coding regulatory network in thyroid cells — solving a hidden cause linked for 20 years” (from accompanying News & Views):

Key findings:

  • Resistance to thyrotropin (RTSH) describes conditions with reduced sensitivity to TSH, linked to a locus on chromosome 15q but genetic basis has remained elusive.
  • The study showed that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features.
  • Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants’ thyrocytes.”


“This finding broadens our current knowledge of genetic defects altering pituitary–thyroid feedback regulation.”



Systematic evaluation of single-cell RNA-seq analyses performance based on long-read sequencing platforms

In this paper, a team of scientists from China performed both PacBio Kinnex & ONT “with 10x genomics scRNA-seq and compared them to the benchmark NGS using exact the same cDNA libraries of different sample sizes”:

Key takeaways:

  • Long-read scRNA-seq “accurately captures all cell types”, “generated more consistent gene expression profiles compared with NGS”, “performed better than NGS in cell annotation with a small cell sampling size”, and “more cell type-specific molecules could be identified in a larger cell sample size.”
  • “PacBio identified a greater amount of cell type specific genes and isoforms” and “could specify more allele-specific transcripts.”
  • “PacBio demonstrates superior performance in discovering novel transcripts” and “novel isoforms identified using PacBio data were more accurate.”


“The higher sequencing quality of PacBio outperforms ONT in accuracy of novel transcripts identification and allele-specific gene/isoform expression.”


Iso-Seq method

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms 

In a previous preprint now formally published in the journal Science, researchers from UCLA, UPenn, CHoP, U of TN, St Jude, SUNY, and China used the Iso-Seq method to establish an isoform-resolved cell atlas of the developing human cortex, showing that “the number and complexity of isoforms per gene were strongly predictive of disease.” Leveraging this resource, they “reprioritized thousands of rare de novo risk variants associated with autism spectrum disorders (ASDs), intellectual disability, and neurodevelopmental disorders (NDDs).


Ready to kickstart breakthroughs of your own?

These recent publications exemplify the versatility and power of PacBio sequencing. From tackling challenges associated with Mendelian disease to helping provide better understanding of the underlying biology of undiagnosed rare disease, PacBio technology is enabling scientific pioneers to make transformative breakthroughs like never before.

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