Allelic Association Analyses: Estimation Recommendations

Abstract

We review the rich literature on the estimation of measures of inbreeding, relatedness and population structure, beginning with Sewall Wrights F-statistics and moving onto the descriptive statistics of Masatoshi Nei and Clark Cockerham. The current availability of genome-level single nucleotide variant data is allowing for sophisticated treatments of inferred identity by descent segments and inferred ancestral recombination graphs. Underlying such disparate methods is an emphasis of characterizing the descent status of alleles within and between individuals and populations and we have found allele-sharing statistics a convenient framework for examining the differences and similarities among different estimators. We have been able to resolve some long-standing reported differences among estimators, especially those involving the work of Nei. In the course of our algebraic and empirical treatment of descent measure estimation we have been able to formulate a set of five recommendations. Following the early work of Sewall Wright, we recommend 1. State that descent measures for pairs of alleles are relative to values in a reference set of allele pairs. With this view, we recommend 2. Use estimators that preserve descent measure rankings over different reference sets. Allele-sharing estimators satisfy this recommendation. Reducing genotypic data to allelic data has the benefit of reducing dimensionality, but we recommend 3. If genotypic data are available, avoid having to assume Hardy-Weinberg equilibrium by not reducing them to allelic data. Partly as a consequence of working with genotypic data, we recommend 4. Recognize that allele frequencies do not need to be estimated. Not estimating allele frequencies prevents the confounding of descent estimates for target pairs of alleles by the status of all pairs in a reference set. On the basis of both theoretical and empirical results, finally we recommend 5. Consider both inbreeding and kinship when estimating either one. It is difficult to envisage a natural population with relatedness but no inbreeding, or vice versa.