A human cell contains 23 pairs of chromosomes, structures that hold the entire genetic blueprint in the form of DNA. Chromosome 6 is a medium-sized structure spanning about 171 million base pairs and making up approximately 5.5 to 6 percent of the total DNA content. It is estimated to contain between 1,000 and 1,100 protein-coding genes. These genes are responsible for a wide variety of biological functions, from regulating metabolism and neurological development to orchestrating the body’s complex defense mechanisms. Variations or errors in its structure can have widespread effects on health and disease development.
The Major Histocompatibility Complex
The Major Histocompatibility Complex (MHC) is the most studied region on chromosome 6, located on the short arm (p-arm). In humans, this region is known as the Human Leukocyte Antigen (HLA) system, representing the most genetically diverse cluster of genes in the human genome. The HLA system’s primary function is to enable the immune system to distinguish between the body’s own cells and foreign invaders like bacteria or viruses. This is accomplished through specialized proteins that bind to small fragments of foreign material, called antigens, and display them on the cell surface for surveillance by T-cells.
The HLA genes are organized into three main functional classes, each responsible for a distinct part of the immune response. Class I genes (HLA-A, HLA-B, and HLA-C) produce proteins found on the surface of nearly all nucleated cells. These molecules present peptides derived from proteins made inside the cell, such as those from an intracellular virus, to CD8+ T-cells. If the T-cell recognizes a foreign peptide, it initiates the destruction of the infected cell.
Class II HLA genes (HLA-DR, HLA-DP, and HLA-DQ) are expressed primarily on specialized antigen-presenting cells, including dendritic cells and macrophages. Their role involves presenting peptides derived from material the cell has engulfed from outside, such as an invading bacterium. These fragments are recognized by CD4+ T-cells, which act as helper cells to coordinate a broader immune response, including stimulating antibody production.
The third group, Class III, is situated between the Class I and Class II regions. It contains genes that encode various immune-related molecules, rather than cell-surface antigen-presenting proteins. These products include components of the complement system, which helps clear pathogens and damaged cells, and molecules like tumor necrosis factor (TNF). Because these three classes are closely linked, a person inherits a complete set, or haplotype, from each parent. This co-inheritance results in a highly individualized immune identity and ensures the human population can defend against an array of pathogens.
Non-Immune Conditions Linked to Chromosome 6
While the HLA complex is the most studied region, many other genes on chromosome 6 are responsible for non-immune functions, and defects can lead to distinct health conditions. One example is hereditary hemochromatosis, a disorder caused by a mutation in the HFE gene on the short arm. This condition is characterized by the excessive absorption and storage of iron, which can damage organs like the liver, heart, and pancreas over time. Similarly, the neurological condition Spinocerebellar Ataxia Type 1 is linked to a polyglutamine expansion mutation within the ATXN1 gene, also located on chromosome 6.
Structural abnormalities in chromosome 6 can cause syndromes that affect growth and development. Deletions or duplications of large segments of the long arm (q-arm) are associated with various birth defects, intellectual disability, and delayed growth. The metabolic disorder 6q24-related transient neonatal diabetes mellitus illustrates how an error in genetic control can manifest as disease. This condition is caused by the overactivity of genes in the 6q24 region, which are normally regulated by genomic imprinting—a process that determines whether the maternal or paternal copy of a gene is active.
Other non-immune genes on chromosome 6 are involved in sensory function, such as those implicated in certain forms of autosomal nonsyndromic hearing loss. The chromosome also contains genes that play a role in the brain and nervous system, including one associated with some inherited forms of Parkinson disease. These genes influence functions ranging from iron balance and motor control to early developmental pathways.
How Chromosome 6 Influences Autoimmunity
The extreme genetic diversity of the HLA system, while beneficial for fighting infection, is the primary reason chromosome 6 is strongly linked to autoimmune diseases. Genetic variations within HLA genes can predispose an individual to self-attack, where the immune system mistakenly targets the body’s own tissues. Specific combinations of HLA alleles (haplotypes) change the shape of the peptide-binding groove on HLA proteins. These structural changes influence which self-peptides are presented to T-cells, potentially leading to the misidentification of a normal body protein as a threat.
For example, Type 1 Diabetes, where the immune system destroys insulin-producing cells, is strongly associated with the HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes. Similarly, the chronic inflammatory joint disease Rheumatoid Arthritis shows a strong association with a group of HLA-DR4 alleles, sometimes called shared epitope alleles. These specific genetic variants are thought to create a molecular environment that favors the survival and activation of T-cells reactive against the body’s own joint tissue.
The strongest known genetic link to a single disease is the association between the HLA-B27 allele and Ankylosing Spondylitis, an inflammatory disease that primarily affects the spine. A majority of individuals with this condition carry the HLA-B27 variant, though carrying the allele does not guarantee disease development, underscoring genetic susceptibility rather than direct causation. Another link exists for Celiac Disease, where individuals carrying the HLA-DQ2 or HLA-DQ8 variants are predisposed to an immune reaction to gluten. In these conditions, the specific HLA variant is thought to be less effective at regulating self-reactive T-cells, allowing them to escape into circulation and initiate an autoimmune response when triggered by environmental factors.