A highly annotated whole-genome sequence of a Korean individual

Abstract

Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of northwest European origin, and a person from China. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8x coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.

Figure 1. Geographic map and Venn diagram of five sequenced genomes, indel distribution, and SNP-indel densities correlation

a, Geographic map showing the regions of ancestry of five sequenced genomes. MT type, mitochondrial haplogroup. b, The number of SNPs overlapping between five genomes. c, Correlation between SNP–indel densities on chromosome 6 (per 10-kb window). From top: SNP density, indel density, SNP–indel density (moving average of ten 10-kb windows), SNP density in a portion of chromosome 6, and indel density along the same portion of chromosome 6. The x axis represents the nucleotide position in Mb.

Figure 2. Representative examples of genomic variations in AK1

a, Homozygous deletion identified by targeted haploid sequencing (top) and diploid sequencing (bottom). Stretched sequencing pairs and a drop in sequencing coverage define the deletion in both panels. Chr, chromosome. b, Heterozygous deletion identified by targeted haploid sequencing (top) and confirmed by diploid sequencing (bottom). Stretched pairs confirm the deletion in the diploid sequence but complete coverage drop is not detected. c, Copy number gain is identified by CGH microarray (top) and confirmed by increased coverage for the corresponding genomic region by diploid sequencing (bottom). For all panels: blue, fold coverage; horizontal red lines, stretched sequence pairs; green, CNV region in the DGV; grey, gene; vertical red bars, homozygous SNPs; vertical black bars, heterozygous SNPs; and broken vertical grey lines define the boundaries of the structural variants.

Figure 3. Potential implications of AK1 variants and comparisons of non-synonymous SNPs among three sequenced genomes

a, Top, the numbers of non-synonymous SNPs (nsSNPs) and genes containing non-synonymous SNPs are compared between the Korean (AK1), Han Chinese (YH) and Yoruban (NA18507) genomes. Bottom, comparison of non-synonymous SNPs and genes containing non-synonymous SNPs in AK1 with those in the YH and Yoruban genomes. Common denotes shared by three genomes. Left axis: number of nsSNPs (blue) or genes containing nsSNPs (red); right axis: ratio (%) of the number of nsSNP genes to the number of nsSNPs (green). b, Seven-hundred-and-seventy-three SNPs potentially associated with clinical phenotypes derived from the database of human gene mutation data (HGMD), OMIM, SNPedia and other hypotheses. DM, diabetes mellitus; NIDDM, non-insulin-dependent diabetes mellitus; TB, tuberculosis. c, Genes affected by large homozygous and heterozygous chromosomal deletions.