Research Article: Understanding Human Variation in Infectious Disease Susceptibility through Clinical and Cellular GWAS

Date Published: August 1, 2013

Publisher: Public Library of Science

Author(s): Dennis C. Ko, Thomas J. Urban, Joseph Heitman.


Partial Text

Over the last ten years, advances in genotyping and high-throughput sequencing technologies have resulted in an explosion of genetic information. Whereas prior attempts at discovering human genetic differences affecting susceptibility to disease relied on genotyping one or a handful of candidate genetic variants, genome-wide association studies (GWAS) have now become a common means of searching for susceptibility genes in an unbiased way. These studies have highlighted the relevance of particular pathways in pathogenesis of infectious and autoimmune disease. Thus, GWAS of clinical phenotypes can alert host-pathogen researchers to unexpected links between their pathway of study and human disease. Complementary to this, cellular GWAS using pathogens as probes can reveal how genetic variation affects cellular processes important for disease pathogenesis.

In GWAS, controls and cases with a disease are genotyped at hundreds of thousands to millions of loci and the genotype frequencies are compared to identify alleles that may be protective or result in increased susceptibility [1]. Prior to the advent of GWAS, a handful of examples demonstrated that common genetic variation could have profound effects on infectious disease susceptibility. The sickle cell allele of hemoglobin protecting against malaria [2] and the CCR5 deletion allele protecting against HIV infection [3] are textbook examples. GWAS provide a way to systematically search for such genetic differences.

While clinical GWAS have been successful at highlighting important pathways in disease pathogenesis, there is clearly a need for additional approaches directed at understanding how specific genetic variants affect disease. How can we more effectively move from lists of SNPs to greater biological insight? One approach is to complement the GWAS of organismal/clinical traits with GWAS of different phenotypic scales (Figure 1). For several years, molecular GWAS of gene expression have identified genes whose level of transcription is associated with nearby genetic variation (cis-eQTLs; expression quantitative trait loci [23], [24]). These resources are useful for GWAS researchers in trying to narrow down what genes are affected by functional genetic variants within a genomic region. Researchers can take advantage of online tools such as the eQTL Browser [25] to determine if there is human genetic variation near their gene of interest that may regulate levels of expression. The availability of cell lines with alternative alleles, as well as genome engineering approaches to introduce genetic differences into isogenic backgrounds [26], makes this an exercise that can lead to hypothesis-driven experiments to understand how human variants alter cell biology.

For the last twenty years, cellular microbiology has provided amazing insights into the physiology of cells [27]. Cellular microbiology is now well poised to contribute to the field of human genetics. Pathogens have clearly been a driving force, and perhaps have even been the main selective pressure, during human evolution [35]. What better way to study functional consequences of common genetic variants that have undergone natural selection than with the agents that have driven that change? Discoveries await both cellular microbiologists and human geneticists, and the results should benefit our understanding of basic biology and susceptibility to disease.




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