The absorption of ultraviolet (UV) radiation is the first step in a chain of events which can induce DNA damage associated with cancer and aging, yet the sequence dependence of UV absorption remains to be investigated. Here, we present a systematic study of UV absorption spectra of DNA based on all-electron Hartree–Fock calculations. We analyze all possible sequences up to four base pairs, as well as longer randomized sequences and genomic nullomers—motifs which are missing in a given genome. We observe a pronounced sequence dependence: cytosine- and guanine-rich motifs exhibit significantly enhanced absorption, whereas adenine–thymine-rich sequences absorb less in the mid-UV range. Most genomes are biased toward adenine–thymine-rich sequences which leads to decreased absorption of UV radiation by the sun. In addition, we introduce a computational framework enabling spectral calculations of large DNA and RNA fragments, opening the door to large-scale optical analyses.