From nonexistence to novel applications: Nullomers and related k-mer based concepts in bioinformatics

Underrepresented k-mer sequences, provide insights into evolutionary constraints, molecular mechanisms, and organismal fitness. Analysis of these sequences have broad applications across genomics and proteomics, such as in biomarker development, cancer diagnostics, phylogenetic analysis, synthetic biology and novel drug discovery. Absent sequences (nullomers and neomers) show promise for cancer detection and tissue-of-origin identification using nucleic acids derived from liquid biopsies, while quasi-primes serve as genomic fingerprints that offer potential for evolutionary studies for understanding trait evolution, and in metagenomics, as biomarkers of organismal presence. The chapter also discusses computational challenges associated with analyzing absent sequences and highlights available k-mer based resources and databases. With the continuous expansion of genomic and proteomic data, absent sequences present an innovative framework for addressing fundamental biological questions and advancing applications in basic and translational research.