Single nucleotide polymorphisms or SNPs are the most common genetic variations among individuals. With the advancement of next-generation sequencing technologies, SNP genotyping has become a powerful tool for studying human genetics and discovering disease-associated variants.
Introduction to SNP Genotyping
A SNP occurs when a single nucleotide differs between members of the same species or between paired chromosomes in an individual. SNPs make up over 90% of all human genetic variation. By comparing SNPs in DNA samples from many individuals, researchers can map genetic variations associated with traits and disease susceptibilities. There are several high-throughput methods available today for identifying SNPs across the human genome at an unprecedented scale and resolution.
Microarray-based Genotyping
One of the earliest and most widely used SNP genotyping platforms is microarray-based hybridization assays. In this approach, DNA samples are amplified and fluorescently labeled before being hybridized onto microarrays with hundreds of thousands of locus-specific oligonucleotide probes. Depending on the sequence at the SNP site, varying fluorescent signals allow genotyping of the locus. Some popular microarray platforms include Affymetrix GeneChip and Illumina Infinium arrays, capable of genotyping over a million SNPs simultaneously in a single experiment.
Sequencing-based Genotyping
With the advent of next-generation sequencing technologies like Illumina sequencing and Ion Torrent semiconductor sequencing, direct SNP Genotyping and Analysis detection from sequencing reads has become feasible. Whole genome or targeted sequencing followed by alignment to the reference genome and variant calling can identify millions of SNPs across samples in a single run. This avoids probe-specific biases of microarrays and allows discovery of new genetic variants as well. However, sequencing-based methods currently have higher per sample costs compared to microarrays.
Data Analysis and Quality Control
Regardless of the genotyping platform, extensive bioinformatics analysis and quality control are required to derive reliable genotypes from raw intensity data. Pre-processing involves operations like normalization, assignment of confidence scores and allele calls. Various quality control metrics examine call rates, heterogeneity between replicates, departure from Hardy-Weinberg equilibrium and population stratification to filter out low quality SNPs and samples from analysis. Genotype imputation is also commonly done to statistically infer missing genotypes. Properly analyzed high quality genotypes form the foundation for downstream analyses.
SNPs Associated with Complex Diseases
With genetic data from hundreds of thousands of individuals, genome-wide association studies have successfully mapped thousands of loci associated with complex traits and diseases. For example, over 180 genetic risk variants have been identified for coronary artery disease alone. Many loci have small effects but cumulatively explain a significant portion of genetic risk. Identified regions provide biological insights and potential drug targets. Companies like 23andMe now offer direct-to-consumer genetic health risk testing by genotyping variants associated with common diseases. With much larger cohorts and whole genome sequencing on the horizon, our knowledge of disease genetics is rapidly advancing.
Personalized Medicine Applications
As we gain a better understanding of how genetic variations contribute to disease susceptibility and drug response, there is increasing focus on actualizing personalized medicine approaches. Pharmacogenomics studies the influence of genetic variations, including SNPs, on drug metabolism and efficacy. Genotyping patients enables predicting drug response, avoiding adverse reactions and selection of optimal therapies. SNPs are also investigated for stratifying cancer patients to personalized therapy regimens. Direct-to-consumer testing provides a means for informed disease screening and lifestyle choices based on one's genomic profile. Overall, SNP genotyping is playing a key role in transitioning medicine towards a more individualized, preventive and precise model of healthcare delivery.
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