The major histocompatibility complex (MHC) region encodes human leukocyte antigen (HLA) genes and is the most complex region in the human genome. The extensive polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known

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... es, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein coding human endogenous retrovirus genes. We revealed extensive allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Further, we showed that the transcriptome within the MHC region can be defined by 14 distinct co-expression clusters, with evidence of co-regulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.