Advances in MICA genotyping: characterization of 406 novel alleles and their frequencies in multiple populations

In 2020, we reported <i>MICA</i> allele frequencies from a cohort of over one million German individuals. This study identified <i>MICA*008</i> (42%), <i>MICA*002</i> (12%), and <i>MICA*009</i> (9%) as the most common <i>MICA</i> alleles at protein resolution. Additionally, we discovered novel alleles with a cumulative frequency of 0.3%. To reduce this fraction of unnamed sequences, we aimed to fully characterize the most frequent novel alleles using both long- and short-read sequencing. As a result, we submitted 603 sequences to the IPD-IMGT/HLA Database: 406 novel alleles and 197 sequence extensions and confirmations. Among the novel alleles, 199 encoded for distinct novel MICA proteins. Following the inclusion of these sequences into the IPD-IMGT/HLA Database, we genotyped 93,814 individuals from an independent cohort. In the German subset (n=48,618), our previous findings on <i>MICA</i> allele frequencies were confirmed. As anticipated, the cumulative frequency of novel alleles decreased significantly from 0.3% to 0.03%, reflecting the expanded reference database. The most frequent of the previously novel alleles were <i>MICA*107N</i> (0.02%), <i>MICA*141</i> (0.01%), <i>MICA*119</i> (0.01%), <i>MICA*089</i> (0.01%), and <i>MICA*247</i> (0.01%). While allele frequencies in other European and the South African White population were similar to those in Germany, greater variation was observed in the South African Black, non-indigenous Chilean, and Turkish populations. Notably, some of the novel alleles appeared to be population-specific; for example, <i>MICA*258</i> was exclusively identified in samples from the Black or Colored populations of South Africa. In conclusion, the extensive characterization of novel <i>MICA</i> alleles has substantially reduced the fraction of unknown sequences in <i>MICA</i> donor genotyping, which will support future biomedical and population genetic studies.