Nullomers: really a matter of natural selection?

Area of Science:

• Genomics
• Evolutionary Biology
• Bioinformatics

Background:

• Nullomers are short DNA sequences absent in human and other species' genomes.
• Previous assumptions suggested nullomers result from natural selection against deleterious sequences.
• This led to envisioning nullomer applications in drug target identification, pesticide development, environmental monitoring, and forensics.

Purpose of the Study:

• To investigate the evolutionary mechanisms behind the formation of nullomers.
• To determine whether natural selection or mutation is the primary driver of nullomer occurrence.

Main Methods:

• Analysis of nullomer sequences across different species, including humans, chimpanzees, cows, dogs, and mice.
• Examination of sequence variations, particularly single nucleotide differences, within nullomer populations.
• Comparative genomic analysis to identify patterns consistent with mutational processes.

Main Results:

• The hypermutability of CpG dinucleotides is identified as the primary cause for short sequence motifs becoming nullomers.
• Natural selection is unlikely to be the main driver of nullomer formation.
• Many human nullomers differ by only one nucleotide, supporting a mutational origin.
• Observed nullomer patterns in other species are consistent with those in humans.

Conclusions:

• The generation of nullomers is predominantly driven by mutation, specifically CpG hypermutability, rather than natural selection.
• The findings cast doubt on the utility of nullomers in various envisioned applications, such as drug discovery and forensics, which relied on the assumption of selection-driven origins.