Variation of the 3'RR1 HS1.2 Enhancer and Its Genomic Context

Area of Science:

• Immunogenetics
• Human genomics
• Population genetics

Background:

• The HS1.2 enhancer in the Ig heavy-chain locus exhibits length polymorphism.
• This variation is linked to population structure, autoimmune diseases, and Ig expression changes.
• HS1.2 diversity may influence individual differences in humoral immune response.

Purpose of the Study:

• To experimentally determine HS1.2 length genotypes in a human population.
• To analyze HS1.2 allele variation and its association with genetic markers.
• To computationally assess the functional impact of HS1.2 allelic variation on transcription factor binding.

Main Methods:

• Genotyping HS1.2 length polymorphism in 72 CEU cell lines from the 1000 Genomes Project.
• Sequencing of the variable HS1.2 region and flanking DNA in 34 alleles.
• Computational analysis of transcription factor binding site potential across different HS1.2 alleles.

Main Results:

• HS1.2 alleles were assigned to haplotypes defined by 18 SNPs.
• A wealth of modular variation was observed within HS1.2, with five SNPs contributing to diversity.
• Non-random associations between HS1.2 and Gm allotypes were identified in Europeans.
• Allelic length and SNP variation influence transcription factor binding site availability.

Conclusions:

• HS1.2 diversity is highly organized, influenced by both modular composition and SNP variation.
• Selective forces likely shaped the observed patterns of HS1.2 diversity.
• This genomic region's variation is relevant to human population divergence and disease associations.