Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implication for pharmacogenetics and disease

Abstract

The ATP-binding cassette (ABC) transporter genes are ubiquitous in the genomes of all vertebrates. Some of these transporters play a key role in xenobiotic defense and are endowed with the capacity to efflux harmful toxic substances. A major role in the evolution of the vertebrate ABC genes is played by gene duplication. Multiple gene duplication and deletion events have been identified in ABC genes, resulting in either gene birth or gene death indicating that the process of gene evolution is still ongoing in this group of transporters. Additionally, polymorphisms in these genes are linked to variations in expression, function, drug disposition and drug response. Single nucleotide polymorphisms in the ABC genes may be considered as markers of individual risk for adverse drug reactions or susceptibility to complex diseases as they can uniquely influence the quality and quantity of gene product. As the ABC genes continue to evolve, globalization will yield additional migration and racial admixtures that will have far reaching implications for the pharmacogenetics of this unique family of transporters in the context of human health.

Figure 1. Gene duplication and fate of duplicated genes in ABC transporters.

The transporter genes ABCG2 and ABCG3 duplicated from an ancestral gene to carry out different specialized functions. ABCB1 and ABCB4 underwent duplication (both located adjacent to each other on the same chromosome) but became specialized to perform distinct functions. ABCG5 and ABCG8 duplicated from the ancestral gene and also became specialized as obligate heterodimers to perform a similar function, while the genes ABCA14-ABCA17 underwent duplication and specialization in certain mammals but were lost in primates.

Figure 2. Selected non-synonymous SNPs in ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8.

(A) The SNP A893S/T (black square) depicted in a topological diagram of ABCB1. (B) SNPs C43S (TM1), R433S and G671V (NBD1) (black squares) located in ABCC1. (C) SNP's V12M, Q141K (NBD) and D620N (extracellular loop) (black squares) in ABCG2. (D) Topological diagram of ABCG5 depicting the SNP Q604E (black square) implicated in sitosterolemia. (E) The SNPs D19H, Y54C, T400K and V632A (black squares) in a topological diagram of ABCG8.