FamLink2 - A comprehensive tool for likelihood computations in pedigrees analyses involving linked DNA markers accounting for genotype uncertainties

Artikel i vetenskaplig tidskrift, 2025

There is an increasing demand for software that can handle an arbitrary number of linked markers in forensic genetics; primarily with application to inference of relationships and direct matching but also in applications such as ancestry inference and mixture interpretation. With the emergence of sequencing technologies, denser sets of SNP markers are generated and analyzed. Additionally, sequence data of low quality and quantity DNA generate uncertainty about the underlying true genotype. We provide an efficient implementation of a general model for pedigree likelihood computations with genetic marker data using a three-layered approach. The top and first layer is the population model where allele frequencies and population substructure are accounted for. The second layer is the inheritance model which efficiently handles linked markers using an IBD model. The third and bottom layer is the observational level where we model the likelihood of the true genotype given underlying reads as well as parameters for errors.
We exemplify the utility of our implementation as well as provide validation according to guidelines established by the ISFG using a combination of two published SNP panels. We demonstrate that computations are feasible for panels encompassing 10,000 markers and we argue that, due to the properties of the underlying algorithm, extending the number of markers will result in a linear increase in computation time. In addition we study the impact of parameters used in our model and suggest some guidelines pertaining to their values. The results demonstrate that a probabilistic model for low coverage sequence read data is needed instead of relying on an a threshold based genotype and applying our general model for inference of relationships on a real case can be superior, i.e. higher information content, to other methods relying on either fixed genotypes with low quality sequence data or simple pair wise relationship tests.
In summary, the implementation, FamLink2 (freely available at https://famlink.se
), can jointly handle genetic linkage, genotype uncertainty and population substructure for an arbitrary pedigree with data for any number of individuals. Whereas the current study will focus on calculations disregarding mutations, FamLink2 has the ability to model mutations for certain built-in pedigrees.