Genetic variability in the ACE gene region surrounding the Alu I/D polymorphism is maintained by balancing selection in human populations.
OBJECTIVE
Angiotensin-converting enzyme plays a critical role in the maintenance of cardiovascular homeostasis. Extensive research has aimed at identifying ACE genetic variants responsible for variation in enzyme plasma concentrations and associated with human diseases. These efforts have been hampered by the extensive linkage disequilibrium across the gene and the identity or location of the functional polymorphism(s) is at presently unknown. The aim of our study was to verify whether the Alu insertion/deletion (Alu I/D) polymorphism or any linked variant has been maintained by natural selection in human populations.


METHODS
We resequenced a gene region surrounding the Alu I/D polymorphism in four human populations; we applied population neutrality tests and performed haplotype analysis for this region.


RESULTS
We observed high levels of nucleotide diversity, an excess of intermediate frequency alleles and, at least in African populations, a higher level of within-species diversity compared with interspecific divergence. Analysis of haplotype genealogy indicated the presence of two major clades separated by deep branches with a coalescence time older than 1.5 million years. All these features strongly suggest the action of balancing selection and we verified that the selection signature is restricted to the gene region surrounding the Alu I/D.


CONCLUSIONS
Our data imply the presence of a functional polymorphism in the Alu I/D region and illustrate the contribution of evolutionary models to classic single nucleotide polymorphism-phenotype association approaches by providing information about the localization of candidate functional variants.
Cagliani
Rachele
R
Scientific Institute IRCCS E. Medea, Bioinformatic Laboratory, Bosisio Parini (LC), Italy.
Fumagalli
Matteo
M
Riva
Stefania
S
Pozzoli
Uberto
U
Comi
Giacomo P
GP
Bresolin
Nereo
N
Sironi
Manuela
M
D020087:Alu Elements / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013997:Time Factors
D007703:Peptidyl-Dipeptidase A