Abstract
The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.
Highlights
The solute carrier (SLC) gene superfamily is one of two major human gene families encoding transporters of endogenous and exogenous compounds
Across 141,456 unrelated individuals, we identified a total of 204,287 exonic single-nucleotide variants (SNVs) and indels (Fig. 1a)
We identified 3688 copy-number variations (CNVs) of SLC genes. b 99.8% of all exonic SLC variants were rare with minor allele frequencies < 1% and 57.6% were only found in a single individual. c Box and whisker plot depicting the number of variants that affect the amino acid sequence of the respective gene product
Summary
The solute carrier (SLC) gene superfamily is one of two major human gene families encoding transporters of endogenous and exogenous compounds. Human Genetics (2019) 138:1359–1377 symporters and antiporters of the SLC4 bicarbonate transporter family (Romero et al 2013) Due to their essential roles in the transport of a plethora of essential organic and inorganic substrates and the high number (> 100) of SLC transporters that have been associated with human genetic disorders, SLC transporters are being increasingly investigated as potential drug targets. One prominent example is the development of blockbuster SGLT2 (encoded by SLC5A2) inhibitors for the treatment of diabetic hyperglycaemia, which was inspired by associations between SLC5A2 mutations and familial renal glucosuria (OMIM identifier 233100). Besides their role as drug targets, SLC transporters play fundamental roles in the disposition of numerous drugs, including various chemotherapeutics, antidiabetics, and diuretics. Given the extensive genomic coverage and the critical role that SLC transporters play in mediating drug pharmacokinetics and -dynamics (PK/PD), the genetic variability of SLC genes is of considerable interest for human genetics, as well as for drug discovery and development programs
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