The topography of nullomer-emerging mutations and their relevance to human disease

Nullomers are short DNA sequences (11–18 base pairs) that are absent from a genome; however, they can emerge due to mutations. Here, we characterize all possible putative human nullomer-emerging single base pair mutations, population variants and disease-causing mutations. We find that the primary determinants of nullomer emergence in the human genome are the presence of CpG dinucleotides and methylated cytosines. Putative nullomer-emerging mutations are enriched at specific genomic elements, including transcription start and end sites, splice sites and transcription factor binding sites. We also observe that putative nullomer-emerging mutations are more frequent in highly conserved regions and show preferential location at nucleosomes. Among repeat elements, Alu repeats exhibit pronounced enrichment for putative nullomer-emerging mutations at specific positions. Finally, we find that disease-associated pathogenic mutations are significantly more likely to cause emergence of nullomers than their benign counterparts.