Efficiency and power as a function of sequence coverage, SNP array density, and imputation.
High coverage whole genome sequencing provides near complete information about genetic variation. However, other technologies can be more efficient in some settings by (a) reducing redundant coverage within samples and (b) exploiting patterns of genetic variation across samples. To characterize as many samples as possible, many genetic studies therefore employ lower coverage sequencing or SNP array genotyping coupled to statistical imputation. To compare these approaches individually and in conjunction, we developed a statistical framework to estimate genotypes jointly from sequence reads, array intensities, and imputation. In European samples, we find similar sensitivity (89%) and specificity (99.6%) from imputation with either 1× sequencing or 1 M SNP arrays. Sensitivity is increased, particularly for low-frequency polymorphisms (MAF < 5%), when low coverage sequence reads are added to dense genome-wide SNP arrays--the converse, however, is not true. At sites where sequence reads and array intensities produce different sample genotypes, joint analysis reduces genotype errors and identifies novel error modes. Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Jason
J
Flannick
Joshua M
JM
Korn
Pierre
P
Fontanillas
George B
GB
Grant
Eric
E
Banks
Mark A
MA
Depristo
David
D
Altshuler
D000465:Algorithms; D016000:Cluster Analysis; D030541:Databases, Genetic; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*; D044465:White People