Uppsala University Department of Information Technology

Technical Report 2019-008

An Empirical Evaluation of Genotype Imputation of Ancient DNA

Kristiina Ausmees, Federico Sanchez-Quinto, Mattias Jakobsson, and Carl Nettelblad

October 2019

With capabilities of sequencing ancient DNA to high coverage often limited by sample quality or cost, imputation of missing genotypes presents a possibility to increase power of inference as well as cost-effectiveness in analysis of ancient data. However, the high degree of uncertainty often associated with ancient DNA poses several methodological challenges, and performance of imputation methods in this context has not been fully explored. To gain further insights, we performed a systematic evaluation of imputation of ancient data using BEAGLE 4.0 and reference data from phase 3 of the 1000 Genomes project, investigating the effects of coverage, phased reference and study sample size. Making use of five ancient samples with high-coverage data available, we evaluated imputed data with respect to accuracy, reference bias and genetic affinities as captured by PCA. We obtained genotype concordance levels of over 99% for data with 1x coverage, and similar levels of accuracy and reference bias at levels as low as 0.75x. Our findings suggest that using imputed data can be a realistic option for various population genetic analyses even for data in coverage ranges below 1x. We also show that a large and varied phased reference set as well as the inclusion of low- to moderate-coverage ancient samples can increase imputation performance, particularly for rare alleles. In-depth analysis of imputed data with respect to genetic variants and allele frequencies gave further insight into the nature of errors arising during imputation, and can provide practical guidelines for post-processing and validation prior to downstream analysis.

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Uppsala Universitet