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 north-west European origin, and a person from China1–4. 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 (27.8× 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 clades5,6, 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.

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

“…Another commonly used approach is to apply quality filters that are aimed at selectively removing errors. Every whole-genome sequence reported so far has used filtering to some extent: the most commonly used filters being those that remove sequences with a too-low coverage depth, discard variants with a low-confidence score or eliminate variants located within a cluster of variants 3,7,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] . Surprisingly, there is little consensus with respect to which filters should be used and at which threshold they should be applied.…”

“…As a result, each reported study developed its own heterogeneous set of filters and applied them at various (suboptimal) thresholds. For instance, in the case of the coverage depth filter, thresholds removing sequences with a coverage depth <4×, <10× or <11× were applied 6,10,11,16,17,23,24 . Additionally, it has not been assessed to which extent filters discard true variants, and how each filter can be optimized in terms of sensitivity and specificity.…”

The pursuit of genome-wide association studies: where are we now?

“…So far, seven human diploid genomes have been fully sequenced, and some important insights have been gained from these resequencing studies. [145][146][147][148][149][150][151] The most prominent finding from these studies is that, besides SNPs, other genetic variants are also abundant in the human genome. These studies found that in addition to the 3-4 million SNPs, several hundred-thousand of short indels (for example, sizes defined as 3 and 16 bp or less in the Bentley et al 147 and Wang et al 148 study, respectively) are also present in each individual human genome.…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…As such, the remaining several hundred thousands of indels in the range of several nucleotides to tens of nucleotides, which were identified in the recent whole genome resequencing experiments, do not currently have their own category. [27][28][29][30][31][32][33] For example, Wang et al (2008) 29 found B140 000 indels within 1-3 bp in the Han Chinese YH genome, and B400 000 indels defined from 1 to 16 bp were also detected in the African NA18507 genome by Bentley et al (2008). 30 Perhaps a new category such as 'short indels' needs to be created to fit them in, and those indels between 100 bp to 1 kb should probably be renamed as 'intermediate indels' (Figures 1c and d).…”

“…2 However, the richness of genetic variations in the human genome has recently been further corroborated by the several whole genome resequencing studies, revealing plenty of new SNPs, indels, CNVs and other structural variations. [27][28][29][30][31][32][33] The technological developments have facilitated and accelerated the process of identifying genetic variations, especially with the arrival of next generation sequencing technologies, which have made whole genome resequencing and the 1000 Genomes Project feasible. [53][54][55] In recent years, many studies have been done to directly examine the associations of CNVs with complex diseases using SNP genotyping arrays.…”