The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

Abstract

Diversity in the antigen-binding receptors of the immune system has long been a primary interest of biologists. Recently it has been suggested that polymorphism in regulatory (noncoding) gene segments is of substantial importance as well. Here, we survey the level of variation in MHC class II gene promoters in man and mouse using extensive collections of published sequences together with unpublished sequences recently deposited by us in the EMBL gene bank using the Shannon entropy to quantify diversity. For comparison, we also apply our analysis to distantly related MHC class II promoters, as well as to class I promoters and to class II coding regions. We observe a high level of intraspecies variability, which in mouse but not in man is localized to a significant extent near the binding sites of transcription factors-sites that are conserved over longer evolutionary distances. This localization may both indicate and enhance heterozygote advantage, as the presence of two functionally different promoters would be expected to confer flexibility in the immune response.A surge of interest in the variability of regulatory, noncoding gene segments is under way. Collections have been made of promoter sequences for MHC class I and class II genes in man (Louis et al. 1993;Yao et al. 1995) and class II in mouse (Janitz et al. 1997a), which add substantially to the information previously available for promoter sequences in the hemoglobin (Weatherall 1986;Labie and Elion 1996) and glucose-6-phosphate dehydrogenase (Vulliamy et al. 1992) genes. These are all genes that encode ''extrovert'' proteins that handle diverse foreign structures such as antigens and parasites, in contrast to the ''introvert'' proteins that handle conserved structures internal to the body (Mitchison 1997); hemoglobin and glucose-6-phosphate dehydrogenase have been included in this list as extrovert proteins, as the high level of polymorphism evident in their structural genes results largely from their interaction with malaria parasites. The genes that encode extrovert proteins often vary in their coding sequences, so as to provide a range of binding sites for these foreign structures, and vary also in their noncoding regions (for reference, see Mitchison 1997). Variation in noncoding gene segments is also evident to a lesser extent among genes encoding introvert proteins, particularly among cytokines (and their receptors and natural antagonists) (Daser et al. 1996). The functional consequences of this promoter sequence variation is not generally known, but its importance in determining expression level is becoming clearer for the class II MHC genes (Louis et al. 1994;Woolfrey and Nepom 1995), the ACE I gene (Villard et al. 1996), and cytokines genes (Messer et al. 1991;Pociot et al. 1992). For these MHC genes, valuable collections have been made of very distantly related sequences (Benoist and Mathis 1990), which enable comparisons to be made with the level of intraspecific variation. Thus, the basis for systematic study of this form of variation is no...

Patterned variation in murine MHC promoters

“…H2Ea was not examined, because the laboratory strains previously analyzed showed variation only at a transcriptional enhancer located upstream of the promoter (24). As expected for this larger series, the frequency of variable sites (10%, 56͞574) is higher than that previously observed (7). Fig.…”

The evolutionary ecology of the major histocompatibility complex

“…There is a growing understanding of how gene expression can play an important role in determining phenotypic variation (Oleksiak et al, 2002;Darvasi, 2003;Abzhanov et al, 2004), and allelic variation in promoter regions controlling HLA expression (Cowell et al, 1998) implies that this may also be true for MHC. However, just as characterising MHC genes in non-model species was perceived as a potential stumbling block to the study of MHC variation in non-model species, so might the identification and analysis of MHC regulatory regions in this case.…”

Effect of Multiple Genetic Polymorphisms on Antigen Presentation and Susceptibility toMycobacterium tuberculosisInfection

“…Although polymorphisms in HLA promoters have been identified, no such polymorphism has yet been associated with susceptibility to TB (11,38). One reason for this may be the difficulty involved in measuring the total level of expression of a particular HLA class II variant both within an APC and on the APC surface simultaneously.…”

“…However, a general mechanism explaining how HLA polymorphisms affect the immune response to pathogens such as M. tuberculosis has not been established. Polymorphisms affecting HLA expression rather than the peptide-binding properties of HLA are also known, but to our knowledge, none of these polymorphisms has been tested yet for TB association (11,38). Extracellular signals in the form of cytokines, such as IFN-␥, also affect MHC expression in APCs, and polymorphisms in the IFN-␥ gene have been associated with TB.…”