Worldwide genetic variation at the 3′-UTR region of the LDLR gene: Possible influence of natural selection

Nelson J.R. Fagundes, Pontificia Universidade Catolica do Rio Grande do Sul
F. M. Salzano, Universidade Federal do Rio Grande do Sul
M. A. Batzer, Louisiana State University
P. L. Deininger, Tulane University
S. L. Bonatto, Pontificia Universidade Catolica do Rio Grande do Sul


The low density lipoprotein receptor gene (LDLR) contains many Alu insertions, and is especially Alu-rich at its 3′-untranslated region (3′-UTR). Previous studies suggested that the LDLR 3′-UTR could regulate gene expression by the stabilization of its mRNA. Given the faster Alu evolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied ∼800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty-one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in one Alu insertion (Alu U), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (∼500,000 years ago). No clear geographic structure emerges from the haplotype network, the global Fst (0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide. © University College London 2005.