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

Candace S Y Chan; Ioannis Mouratidis; Austin Montgomery; Georgios Christos Tsiatsianis; Nikol Chantzi; Martin Hemberg; Nadav Ahituv; Ilias Georgakopoulos-Soares

doi:10.1016/j.csbj.2024.12.026

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

Comput Struct Biotechnol J. 2024 Dec 25:30:1-11. doi: 10.1016/j.csbj.2024.12.026. eCollection 2025.

Authors

Candace S Y Chan^{1

2

3}, Ioannis Mouratidis³, Austin Montgomery³, Georgios Christos Tsiatsianis³, Nikol Chantzi³, Martin Hemberg⁴, Nadav Ahituv^{1

2}, Ilias Georgakopoulos-Soares³

Affiliations

¹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
³ Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
⁴ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.

Abstract

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.

Keywords: CpG Islands; Nullomers; Pathogenicity.