2019 Fiscal Year Final Research Report
Disease-related genome analyses by long-read sequencers
| Project/Area Number |
17H01539
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | ロングリードシーケンス / CNV / リピート異常 / 染色体構造異常 / Chromothripsis |
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| Outline of Final Research Achievements |
To overcome the low genetic solution rates in the short-read NGS analysis of human rare diseases, we started using long read sequencers such as PacBio Sequel I and II as well as Oxford Nanopore PromethION for whole genome sequencing in unsolved cases who received short read exome sequencing with negative results. We could obtain >20-bp CNVs by using PBSV. We also developed Tandem-Genotypes (Genome Biol 2019) for detecting abnormal repeat regions and dnarrange (medRxiv 2020) for finding genome-wide SVs.
Using these tools, we could find a homozygous 12.4-kb deletion involving CLN6 in a PME family (J Hum Genet 2019), a 4.6-kb SAMD12 intronic repeat insertion in a BAFME family (J Hum Genet 2019), a (GGC)n repeat expansion in NOTCH2NLC in familial and sporadic NIID (Nat Genet 2019), and biallelic pathogenic repeat expansion in a CANVAS family (J Hum Genet 2020). We could utilize the long read sequencing in solving unsolved patients by short read sequencing.
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| Free Research Field |
ゲノム医学・人類遺伝学
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| Academic Significance and Societal Importance of the Research Achievements |
ショートリード次世代シーケンス（NGS）での遺伝性疾患の解析では、原因解明率が約30%程度に留まるため、新しい解析手法が期待されている。ロングリードNGSはその有力な候補である。本研究では、ロングリードNGSの新たな解析手法を開発し、その具体的な使用法と具体的な成果を論文に発表している。例えばTandem-Genotypesでロングリード全ゲノムシーケンスデータからリピート伸長を見出した神経核内封入体は、ロングリードNGSの使用法を明示し世界的にも注目され、疾患解明におけるロングリードNGS研究を推進する大きな契機となると考える。
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