**1. Introduction**

The major histocompatibility complex (MHC) genomic region consists of a large group of evolutionary-related genes involved functionally with the innate and adaptive immune systems in jawed vertebrates [1]. In humans, the MHC is located on the short arm of chromo‐ some 6, band p21.3, and the MHC class I and class II genomic regions encode the highly polymorphic gene complex classified as the human leukocyte antigen (HLA) complex [2, 3]. The HLA class I and class II molecules expressed by the MHC play important roles in restricted

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cellular interactions and tissue histocompatibility due to cellular discrimination of "self" and "nonself" that require an essential knowledge of the effects of HLA allele matched and mismatched donors in transplantation medicine [4] and transfusion therapy [5]. While the HLA class I molecules are expressed by all nucleated cells to present processed peptides of intracellular origin to CD8+ cytotoxic T cells and serve as ligands for natural killer cells, the class II molecules are expressed by antigen-presenting cells such as B cells, dendritic cells, or macrophages to present exogenous peptides to CD4+ helper T cells of the immune system [6]. In addition, the classical HLA class I genes, HLA-A, HLA-B, and HLA-C, and the classical HLA class II genes, HLA-DR, HLA-DQ, and HLA-DP are distinguished by their extraordinary polymorphisms, whereas the nonclassical HLA class I genes, HLA-E, HLA-F, and HLA-G, are distinguished by their tissue-specific expression and limited polymorphism [2, 3, 7].

The highly polymorphic HLA genomic region is critically involved in the rejection and graftversus-host disease (GVHD) of hematopoietic stem cell transplants [8, 9], the pathogenesis of numerous autoimmune diseases [10–13], and infectious diseases [14]. Apart from regulating immunity, the MHC genes may have a role in reproduction and social behavior, such as pregnancy maintenance, mate selection, and kin recognition [15]. The MHC genomic region also appears to influence drug adverse reactions [16, 17], CNS development and plasticity [18– 22], neurological cell interactions [23, 24], synaptic function and behavior [25, 26], cerebral hemispheric specialization [27], and neurological and psychiatric disorders [28–32]. Hence, the MHC is one of the most biomedically important genomic regions that warrant special attention for genetic investigation.

In general, the study of the diversity and polymorphic variation of the MHC genomic region has been focused more on humans than any other species and animal population [1] largely because of the high cost and limited throughput of the first generation Sanger sequencing method [33, 34]. However, this is now changing because the next-generation sequencing (NGS) technologies are becoming the method of choice for lower-cost, high-throughput genotyping of MHC genes that are composed of highly homologous multiple loci such as those found in the macaque primate species [35]. Thus, the NGS technologies are expected to perform precise MHC genotyping in human and model animals that already have a collection of MHC allele references, and to facilitate MHC genotyping of wild animals that as yet have no MHC allele references. In addition, the NGS technologies are likely to replace traditional genotyping methods such as subcloning, Sanger sequencing, and previously developed PCR-based MHC typing methods (PCR-RFLP, PCR-SSP, and so on) in the near future. Recently, many articles concerning the development of NGS technologies for precise MHC genotyping and genotyp‐ ing data of MHC genes using the new NGS technologies have been published on the investi‐ gations of human and nonhuman MHC polymorphisms in various fields of study such as medical science, evolutionary biology, ecology, and population genetics.

In this chapter, we provide a short review of the current HLA polymorphism information and the use of PCR-based NGS for MHC genotyping in human and nonhuman species, particularly for the Filipino crab-eating macaque MHC (*Mafa*) class I (Mafa-A, -B, -E, -F, and -I) and class II loci (Mafa-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1).
