k-mer-Based Genome-Wide Association Studies in Plants: Advances, Challenges, and Perspectives

Genome-wide association studies (GWAS) have allowed the discovery of marker–trait associations in crops over recent decades. However, their power is hampered by a number of limitations, with the key one among them being an overreliance on single-nucleotide polymorphisms (SNPs) as molecular markers. Indeed, SNPs represent only one type of genetic variation and are usually derived from alignment to a single genome assembly that may be poorly representative of the population under study. To overcome this, k-mer-based GWAS approaches have recently been developed. k-mer-based GWAS provide a universal way to assess variation due to SNPs, insertions/deletions, and structural variations without having to specifically detect and genotype these variants. In addition, k-mer-based analyses can be used in species that lack a reference genome. However, the use of k-mers for GWAS presents challenges such as data size and complexity, lack of standard tools, and potential detection of false associations. Nevertheless, efforts are being made to overcome these challenges and a general analysis workflow has started to emerge. We identify the priorities for k-mer-based GWAS in years to come, notably in the development of user-friendly programs for their analysis and approaches for linking significant k-mers to sequence variation.