Ethnic divergence and linkage disequilibrium of novel SNPs in the human NLI-IF gene: Evidence of human origin and lack of association with tuberculosis susceptibility

Sequence variation in the human genome has been used as a tool in studying human diseases and the evolutionary history of man. A human inherited predisposition to tuberculosis has been suggested and studied; however, genetic mechanisms are still ambiguous. In the present study, we scanned the regulatory and coding region of Nuclear LIM Interactor-Interacting Factor gene (NLI-IF), which is physically close to the tuberculosis-associated gene NRAMP1. Thirteen biallelic single-nucleotide polymorphisms (SNPs) were identified from four ethnic populations (African-American, Caucasian, Hispanic, and Asian) with population-specific distribution of alleles. The extent of linkage disequilibrium (LD) between 402T>C, and 472-42G>A varied distinctly from complete LD in the non-African-American groups to strong but incomplete LD in African-Americans. Both SNPs were in significant LD with the polymorphism 3′ UTR in NRAMP1 among these ethnic groups (P < 0.02), except 402T>C in African-Americans. In a case-control study with a Caucasian population, three cosmopolitan SNPs (204C>A, 402T>C and 472-42G>A) in NLI-IF showed no significant association with human susceptibility to tuberculosis. Our results support the "out-of-Africa" model of human origin, and suggest the time for the common ancestor dispersing from Africa could not have been more than approximately 385,620 years ago.