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Exp Mol Med. 2017;49(7):e356.

Findings of a 1303 Korean whole-exome sequencing study.

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제1저자 곽수헌, 채지수 · 교신저자 박경수, 김종일

PMID 28706299 PMC5565953 DOI 10.1038/emm.2017.142 IF 17.5 내분비대사내과
소속 (10)
  1. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
  2. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
  3. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  4. Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
  5. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
  6. Green Cross Genome, Yongin, Korea.
  7. Korean Hemophilia Foundation, Seoul, Korea.
  8. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
  9. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
  10. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.

Abstract

Ethnically specific data on genetic variation are crucial for understanding human biology and for clinical interpretation of variant pathogenicity. We analyzed data obtained by deep sequencing 1303 Korean whole exomes; the data were generated by three independent whole exome sequencing projects (named the KOEX study). The primary focus of this study was to comprehensively analyze the variant statistics, investigate secondary findings that may have clinical actionability, and identify loci that should be cautiously interpreted for pathogenicity. A total of 495 729 unique variants were identified at exonic regions, including 169 380 nonsynonymous variants and 4356 frameshift insertion/deletions. Among these, 76 607 were novel coding variants. On average, each individual had 7136 nonsynonymous single-nucleotide variants and 74 frameshift insertion/deletions. We classified 13 pathogenic and 13 likely pathogenic variants in 56 genes that may have clinical actionability according to the guidelines of the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology. The carrier frequency of these 26 variants was 2.46% (95% confidence interval 1.73-3.46). To identify loci that require cautious interpretation in clinical sequencing, we identified 18 genes that are prone to sequencing errors, and 671 genes that are highly polymorphic and carry excess nonsynonymous variants. The catalog of identified variants, its annotation and frequency information are publicly available (http://koex.snu.ac.kr). These findings should be useful resources for investigating ethnically specific characteristics in human health and disease.

Figures

Figure 1
Figure 1 Population stratification and principle component analyses. The merged data of 1303 Korean participants and the 1000 Genomes Project were investigated (a) for population structure analysis using the ADMIXTURE and (b) for principal component analysis. The Korean participants of our study clustered with East Asians and were separated from other populations. ACB, African Caribbeans in Barbados; AFR, African; AMR, American; ASW, Americans of African Ancestry in SW USA; BEB, Bengali from Bangladesh; CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah Residents (CEPH) with Northern and Western Ancestry, USA; CHB, Han Chinese in Beijing, China; CHS, Southern Han Chinese; CLM, Colombians from Medellin, Colombia; EAS, East Asian; ESN, Esan in Nigeria; EUR, European; FIN, Finnish in Finland; GBR, British in England and Scotland, UK; GIH, Gujarati Indian from Houston, Texas, USA; GWD, Gambian in Western Divisions in the Gambia; IBS, Iberian Population in Spain; ITU, Indian Telugu from the UK; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Ho Chi Minh City, Vietnam; KOR, Korean; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; MXL, Mexican Ancestry from Los Angeles, USA; PEL, Peruvians from Lima, Peru; PJL, Punjabi from Lahore, Pakistan; PUR, Puerto Ricans from Puerto Rico; SAS, South Asian; STU, Sri Lankan Tamil from the UK; TSI, Toscani in Italy; YRI, Yoruba in Ibadan, Nigeria.
Figure 2
Figure 2 Evidence attributes for the 26 P or LP variants in 56 ACMG genes. Individual evidence attributes of the 26 variants classified as P or LP are shown. Exonic functions of the variants are shown on the right. Classification was based on the ACMG guidelines (Calls) or determined using the ClinVar database. ACMG, American College of Medical Genetics and Genomics.
Figure 3
Figure 3 Characterization of highly misinterpretable loci. (a) Example of a sequencing error prone gene, MUC6, showing excess coverage (gray) and imbalanced allelic fraction (blue) of VQSR filtered variants. (b) Distribution of variants with significant deviation from HWE (green), indicating sequencing error prone loci. (c–f) The frequency distribution of genes according to the burden of nonsynonymous variants and their cutoff values for highly polymorphic genes. The cutoff values for (c) excess number of entire nonsynonymous variants was 1.88, (d) excess rate of entire nonsynonymous variants was 0.78 × 10−3, (e) excess number of rare nonsynonymous variants was 0.064 and (f) excess rate of rare nonsynonymous variants was 0.027 × 10−3. The dashed line indicates the cut-off value for each category. The Venn diagrams show how the highly polymorphic genes in Koreans overlap with the 1000 Genomes Project (1KGP). VQSR, Variant Quality Score Recalibration.

그림 출처: PubMed Central 공개 논문 (PMC5565953)

Conflict of interest statement

The authors declare no conflict of interest.

그 밖의 정보
출판 형태
Journal Article
저널
Experimental & molecular medicine · eISSN 2092-6413
전자 출판
2017-07-14
MeSH
Asian People / genetics · Data Interpretation, Statistical · Exome / genetics · Female · Frameshift Mutation · Genetic Loci · Genetic Variation* · High-Throughput Nucleotide Sequencing · Humans · Male · Polymorphism, Single Nucleotide · Republic of Korea · Exome Sequencing*
참고문헌
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