Computational statistical methods for genotyping biallelic DNA markers from pooled experiments

Sammanfattning: The information conveyed by genetic markers such as Single Nucleotide Polymorphisms (SNPs) has been widely used in biomedical research for studying human diseases, but also increasingly in agriculture by plant and animal breeders for selection purposes. Specific identified markers can act as a genetic signature that is correlated to certain characteristics in a living organism, e.g. a sensitivity to a disease or high-yield traits. Capturing these signatures with sufficient statistical power often requires large volumes of data, with thousands of samples to analyze and possibly millions of genetic markers to screen. Establishing statistical significance for effects from genetic variations is especially delicate when they occur at low frequencies.The production cost of such marker genotype data is thereforea critical part of the analysis. Despite recent technological advances, the production cost can still be prohibitive and genotype imputation strategies have been developed for addressing this issue. The genotype imputation methods have been widely investigated on human data and to a smaller extent on crop and animal species. In the case where only few reference genomes are available for imputation purposes, such as for non-model organisms, the imputation results can be less accurate. Group testing strategies, also called pooling strategies, can be well-suited for complementing imputation in large populations and decreasing the number of genotyping tests required compared to the single testing of every individual. Pooling is especially efficient for genotyping the low-frequency variants. However, because of the particular nature of genotype data and because of the limitations inherent to the genotype testing techniques, decoding pooled genotypes into unique data resolutions is a challenge. Overall, the decoding problem with pooled genotypes can be described as as an inference problem in Missing Not At Random data with nonmonotone missingness patterns.Specific inference methods such as variations of the Expectation-Maximization algorithm can be used for resolving the pooled data into estimates of the genotype probabilities for every individual. However, the non-randomness of the undecoded data impacts the outcomes of the inference process. This impact is propagated to imputation if the inferred genotype probabilities are to be devised as input into classical imputation methods for genotypes. In this work, we propose a study of the specific characteristics of a pooling scheme on genotype data, as well as how it affects the results of imputation methods such as tree-based haplotype clustering or coalescent models.