Unraveling the Genetic Pattern of HLA Tissue Types: Mechanisms, Models and Implication

As the genetic cornerstone of the immune system, the human leukocyte antigen (HLA) system plays a core role in immune recognition and immune response regulation. The genetic transmission of its tissue type strictly follows Mendel's genetic law, and it is transmitted from generation to generation through closely linked gene clusters on homologous chromosomes in the form of co-dominant alleles.

The HLA locus is located in the short arm 6p21.3 region of human chromosome 6, which contains classical HLA-I (HLA-A, -B, -C) and HLA-II (HLA-DR, -DQ, -DP) genes, showing a high degree of polymorphism-more than 8,000 alleles have been found at HLA-B locus alone, which makes it difficult for identical twins. Understanding the genetic model, recombination mechanism and clinical effect of the HLA gene is not only the key to analyzing the family aggregation of immune-related diseases but also provides a theoretical basis for the selection of relatives and donors in transplantation medicine.

In this paper, the inheritance law of HLA histotype is systematically explained, including Mendel's genetic model, gene recombination mechanism, haplotype variation and transmission deviation caused by special genetic phenomena.

Mendel Genetic Model of HLA Gene

The inheritance of the HLA gene follows Mendel's law, and its gene cluster located on chromosome 6 is transmitted in a co-dominant way. Parents pass a haplotype to their offspring so that the offspring can express their parents' HLA molecules at the same time. This genetic model not only creates individual immune diversity but also provides a theoretical basis for transplantation matching and disease correlation research.

Co-dominant Genetic Characteristics of Chromosome 6p21.3

The HLA gene family is located in the short arm 6p21.3 region of human chromosome 6, which constitutes the core of the major histocompatibility complex (MHC). As a typical co-dominant genetic system, each allele of the HLA gene can be expressed independently, so that individuals can express HLA molecules from both parents at the same time. This genetic characteristic provides a molecular basis for the immune system to recognize diverse antigens. Co-dominant expression means that in heterozygote individuals, HLA alleles on two homologous chromosomes both encode corresponding protein molecules and participate in antigen presentation.

This co-dominant genetic feature has important immunological significance:

• Firstly, heterozygote individuals can present a wider range of antigenic peptides and enhance the body's defense against pathogens.
• Secondly, in transplantation matching, the greater the difference of HLA heterozygosity between donors and recipients, the higher the risk of immune rejection. Studies have shown that individuals with HLA heterozygotes have stronger resistance to the disease progression of HIV infection, which may be related to the increased diversity of antigen presentation under heterozygosity.
• Co-dominant inheritance also makes HLA genotype directly determine phenotype, without inferring from explicit and implicit relationships, which provides a clear genetic marker for genotyping technology.

Linkage disequilibrium (LD) structure across CFB-SKIV2L-TNXB-FKBPL-NOTCH4 region and results of haplotype-based association study (Ye et al., 2016)

Integrity of Haplotype Transmission

HLA genes are transmitted in the form of closely linked Haplotype on chromosomes, that is, HLA genes on the same chromosome tend to be passed on to their offspring as a whole. This phenomenon stems from the high linkage imbalance of HLA gene clusters on chromosomes. Haplotype refers to the combination of alleles of HLA loci on a chromosome, such as HLA-A02: 01-HLA-B07: 02-HLA-C07: 02-HLA-DRB 115: 01 to form a complete haplotype. In the process of meiosis, HLA haplotypes are transmitted as a genetic unit, rather than separate individual genes, which ensures the cooperative expression of immune response-related genes.

When parents transmit haplotypes to their offspring, they follow Mendel's first law (separation phenomenon): both parents randomly transmit one haplotype to their offspring, so that the offspring can get two haplotypes from their parents. Assuming that the haplotypes of fathers are H1 and H2 and mothers are H3 and H4, the possible haplotype combinations of offspring are H1H3, H1H4, H2H3, and H2H4, and the probability of each combination is 25%. The integrity of haplotype transmission is of key significance in transplantation matching. The probability of HLA haplotype combination between siblings follows a specific law: 25% probability of complete coincidence (H1H3 vs H1H3), 50% semi-coincidence (H1H3 vs H1H4), and 25% total incompatibility (H1H3 vs H2H4).

Mendelian inheritance of HLA haplotypes demonstrated in a family study (Choo et al., 2007)

In family genetic analysis, high-resolution HLA typing techniques (such as NGS) can accurately track haplotype transmission and provide accurate data for genetic linkage analysis by virtue of high-throughput sequencing advantage. In contrast, the traditional serological typing technology (such as PCR-SSP) has obvious limitations. It relies on antigen-antibody reaction, and can't identify Null Allele, which easily leads to false non-conformity to genetic laws in family genetic analysis.

HLA Gene Recombination and Haplotype Variation

HLA gene recombination and haplotype variation are the key mechanisms to shape immune diversity. During meiosis, HLA gene clusters break the original haplotypes through cross-exchange and form new combinations. This genetic dynamic not only drives the evolution of population polymorphism but also brings challenges and opportunities for transplant matching and disease association research.

Frequency of Cross-exchange During Meiosis

Although HLA genes tend to be transmitted in haplotype form, the Crossing Over of homologous chromosomes during meiosis can lead to recombination within HLA gene clusters and break the original haplotype structure. The recombination rate of the HLA gene cluster is much higher than the average level of the human genome, which is an important mechanism for maintaining HLA polymorphism and population genetic diversity. Studies have shown that the overall recombination rate of HLA gene clusters is about 1-2 times/meiosis, which is equivalent to about 1 recombination per megabase (Mb) per generation, which is significantly higher than the genome average of 0.7 times/Mb.

The distribution of recombination events in the HLA gene cluster is not uniform, and there are many recombination hot spots. For example, the recombination rate between HLA-A and HLA-B is about 1%, while the recombination rate between HLA-B and HLA-C is lower (about 0.5%), and the recombination rate of HLA-II gene regions (such as between HLA-DR and HLA-DQ) is as high as 2%. The distribution of recombination hotspots may be related to chromatin structure and DNA sequence characteristics. For example, the intron region between HLA-A and HLA-B is rich in AT sequences, which may increase the probability of DNA double-strand breaks, thus promoting recombination.

Distribution of recombination in HLA region (Wang et al., 2019)

Functional Impact of Regrouping Spots

The spot of recombination between HLA-A and HLA-B (about 1% recombination rate) is of great genetic significance. First, the recombination in this region can produce new HLA-A and HLA-B allele combinations. For example, HLA-B07:02 originally linked with HLA-A02:01 may combine with HLA-A*11:01 through recombination to form a new haplotype. Secondly, this recombination may break the harmful linkage imbalance, such as separating disease-related alleles from protective alleles and thus be positively selected in evolution.

In the HLA-II gene region, the high recombination rate (about 2%) between HLA-DRB1 and HLA-DQB1 leads to a higher diversity of Class II haplotypes. This high recombination rate enables HLA-DR and HLA-DQ genes to evolve independently, forming more diverse antigen presentation combinations and enhancing the body's ability to cope with changeable pathogens.

Preimplantation genetic testing of β-thalassemia combined with HLA matching. There was one case in which the woman had a copy- neutral LOH at 6p21.31-p22.3 (Wang et al., 2019)

Effect of New Allele Formation on Genetic Stability

The synergistic effect of recombination events and gene mutation makes HLA genes constantly produce new alleles, which not only challenges genetic stability but also provides impetus for population evolution. The formation of new alleles is mainly through two mechanisms:

• One is the accumulation of single nucleotide polymorphism (SNP)
• The other is the exchange of sequence fragments caused by Gene Conversion.

For example, in the HLA-B*27 allele family, the generation of new alleles mostly comes from the point mutation of exon 2 and exon 3, while the diversity of HLA-DRB1 alleles depends more on the sequence recombination brought about by gene transformation.

The emergence of new alleles can have a significant impact on genetic stability, which is manifested as follows:

• First, in the parent-offspring HLA typing system, the emergence of new alleles may lead to the deviation of genetic laws, thus interfering with the results of paternity testing based on HLA typing.
• Secondly, in the process of organ transplantation donor-recipient matching, the traditional HLA typing technology has a blind spot for detecting new alleles, which may lead to the potential risk of immune rejection.

However, the formation of new alleles is of great significance to population evolution: they provide richer antigen-presenting molecules for the immune system and enhance the adaptability of species to new pathogens. In the course of human evolution, the high mutation rate and recombination rate of the HLA gene are considered an adaptive response to the rapid evolution of pathogens, and this genetic plasticity enables human beings to maintain their advantages in the struggle against pathogens.

Fnd values of haplotypes and allele frequencies (Alter et al., 2017)

Significance of Parental-child HLA Matching

HLA matching between parents and offspring is of great significance in clinical practice, and its genetic law provides a key basis for transplantation medicine and disease risk assessment. This matching relationship based on Mendelian inheritance not only determines the success or failure of related donor transplantation but also is closely related to the family aggregation of autoimmune diseases, which is an important link between genetics and clinical medicine.

Mendelian transmission of HLA haplotypes is an important reason for family aggregation of autoimmune diseases, and high-risk haplotypes transmitted from parents to offspring can significantly increase the risk of diseases:

• Ankylosing spondylitis (AS): The transmission of HLA-B27 haplotype increases the risk of offspring AS by 20-100 times. If the father carries the HLA-B27:05 haplotype and the mother is normal, the probability that the offspring will inherit the haplotype is 50%, and about 20% of them will develop into AS. It is found that the transmission of HLA-B*27 haplotype in AS patients' families follows the strict Mendelian law, regardless of gender.
• Type 1 diabetes mellitus (T1D): The transmission of HLA-DQ2/DQ8 haplotype is the main genetic risk factor for T1D. When both parents are HLA-DQ2 heterozygotes (DQA105:01/DQA101:02), the probability of offspring inheriting DQA1*05:01 homozygous is 25%, and the risk of T1D is 15 times higher than that of the general population. This risk is directly related to the co-dominant expression of HLA haplotypes.
• Rheumatoid arthritis (RA): The risk of RA can be increased by 3-5 times after the parents carrying the "Shared Epitope" haplotype (such as HLA-DRB1*04:01) are passed on to their offspring. Family studies show that the carrying rate of HLA-DRB1 shared epitope in children of RA patients is 60%, which is significantly higher than that of the general population (30%).

The familial aggregation of autoimmune diseases is also related to the linkage imbalance between HLA haplotypes and non-HLA genes. For example, the HLA-B*27 haplotype is often linked with the risk variation of the IL-23R gene, and the combined effect of them further increases the risk of AS. This synergistic effect of multiple genes makes it necessary to comprehensively consider multiple genetic factors in disease risk prediction based on HLA haplotypes.

Shared genetic background between T1D and other AIDs, stratified by HLA and non-HLA variations at a population level (Wang et al., 2025)

Special Genetic Phenomena and HLA Transmission Deviation

In the process of HLA inheritance, besides the classical Mendel law, many special genetic phenomena can lead to transmission deviation. These abnormal phenomena break the conventional transmission mode of the HLA gene, which brings challenges to paternity tests, transplant matching, and disease risk assessment, and also provides a new perspective for further understanding the genetic complexity of HLA.

Effect of Single-parent Diploid on HLA Homozygosity

Uniparental diploid (UPD) means that two homologous chromosomes of offspring are from the same parent. This abnormal transmission can increase the homozygosity of the HLA gene and break the normal Mendelian inheritance law. UPD can be divided into homodiploid and Heterodisomy. The former has two identical chromosomes, and the latter is two different chromosomes of parents.

The influence of UPD on HLA transmission is mainly manifested in the following aspects:

• Firstly, if UPD involves chromosome 6, the offspring HLA gene can be completely from the father or mother, which leads to a significant increase in HLA homozygosity. Related studies have found that the homozygous rate of HLA-A/-B/-C loci in individuals with UPD on chromosome 6 is 100%, while that in normal people is only 25%.
• Secondly, UPD may lead to the expression of recessive genetic diseases, such as HLA-related autoimmune diseases with higher risk in the homozygous state.
• Finally, UPD can interfere with the results of paternity tests, because the HLA typing of offspring may be exactly the same as that of one parent, but there is no shared alleles with the other parent, resulting in misjudgment of genetic relationship.

HLA microbeads array genotyping after mixing experiments of homozygous DNA#1 (HLA-A*01:01; B*08:01; DRB1*03:01) with decreasing amounts of heterozygous DNA#3 (HLA-A*01:01,*11:01; B*08:01,*35:01; DRB1*03:01,*11:04), with ratios of 50, 30, 20, 25 and 10% (Dubois et al., 2012)

The Transitive Law of Null Allele

Null Allele (antigen deletion allele) refers to the allele encoding nonfunctional HLA molecules, and its transmission may lead to an exception to Mendel's genetic law. The production of Null Allele mostly comes from gene deletion, frameshift mutation, or promoter defect. For example, Null Allele of HLA-A*02:01:01 may be unable to express HLA-A molecules due to exon 2 deletion.

The transmission of the Null Allele has the following characteristics: firstly, when one parent is a Null Allele heterozygote (such as HLA-A02:01/Null) and the other parent is normal, the offspring have a 50% probability of inheriting the Null Allele, which shows the lack of HLA-A antigen expression. In this case, the HLA typing of offspring may show an incomplete match with one parent, which seems to violate Mendel's law. Secondly, Null Allele homozygous individuals (Null/Null) do not express corresponding HLA molecules at all, which may lead to abnormal development of the immune system, such as T cell selection disorder; Finally, Null Allele is related to disease susceptibility. For example, HLA-B27 Null Allele does not increase the risk of ankylosing spondylitis, but it may be related to other immunodeficiency.

Conclusion

As a cross field of Mendel's genetic law and immune function regulation, the genetic transmission of HLA tissue type not only deepens the understanding of human genetic diversity but also provides key theoretical support for clinical practice. From the accurate transmission of haplotypes to the dynamic regulation of recombination events, from the probability model of transplant matching to the mechanism analysis of rare genetic phenomena, the HLA system has always demonstrated the perfect unity of genetic laws and immunological functions.

In the future, with the development of long reading and long sequencing and single-cell omics technology, HLA genetic research will move towards a new dimension of haplotype dynamic analysis and immune function prediction, which will promote the paradigm shift from gene matching to immune tolerance induction in transplantation medicine, and provide a more accurate scientific basis for cracking the family aggregation of autoimmune diseases and optimizing the selection of relatives and donors.