Ī link with HIV infection may explain a large number of mutations in the sequence of the Omicron variant. This is not entirely unexpected - at times, viruses within the body acquire and swap segments of genetic material from each other, and this is one common means of mutation. One origin hypothesis is that various mutations in the Omicron variant, comprising a 9- nucleotide sequence, may have been acquired from another coronavirus (known as HCoV-229E), responsible for the common cold.

Omicron did not evolve from any other variant but instead on a distinct track diverging in perhaps mid-2020. As of 6 January 2022, the variant has been confirmed in 149 countries. The first known cases outside of South Africa were two people who travelled on 11 November: one who flew from South Africa to Hong Kong via Qatar, and another who travelled from Egypt to Belgium via Turkey. The first known samples were collected in Johannesburg, South Africa on 8 November.

Omicron was first detected on 22 November 2021 in laboratories in Botswana and South Africa based on samples collected on 11–16 November. On 26 November 2021, WHO designated B.1.1.529 as a variant of concern and named it 'Omicron', after the fifteenth letter in the Greek alphabet. Mutation data from WHO, structure from PDB: 6VYB. In this trimeric structure, two monomers (gray and light blue) have their receptor-binding domains in the 'down' conformation while one (dark blue) is in the 'up' or 'open' conformation. Illustration of the locations of the Omicron mutations in the spike protein, top view (left) and side view (right), showing amino acid substitutions (yellow), deletions (red), and insertions (green).