SNP-PHAGE: High-Throughput SNP Discovery Pipeline

Abstract

High-throughput genotyping technologies have become popular in studies that aim to reveal the genetics behind polygenic traits such as complex disease and the diverse response to some drug treatments. These technologies utilize bioinformatics tools to define strategies, analyze data, and estimate the final associations between certain genetic markers and traits. The strategy followed for an association study depends on its efficiency and cost. The efficiency is based on the assumed characteristics of the polymorphisms’ allele frequencies and linkage disequilibrium for putative casual alleles. Statistically significant markers (single mutations or haplotypes) that cause a human disorder should be validated and their biological function elucidated. The aim of this chapter is to present a subset of bioinformatics tools for haplotype inference, tag SNP selection, and genome-wide association studies using a high-throughput generated SNP data set.

Glossary

Allele

– One of the variant forms of a gene or a genetic locus.

Causative SNPs

– Changes in a single nucleotide that cause a disease or trait.

Coding SNPs (cSNPs)

– SNPs that occur in regions of a gene that are transcribed into RNA (i.e., an exon) and eventually translated into protein. cSNPs include synonymous SNPs (i.e., confer identical amino acid) and nonsynonymous SNPs (i.e., confer different amino acid).

Genetic map

– Also known as a linkage map. A genetic map shows the position of genes and/or markers on chromosomes relative to each other, based on genetic distance (rather than physical distance). The distance between any two markers is represented as a function of recombination.

Genetic marker

– A DNA sequence whose presence or absence can be reliably measured. Because DNA segments that are in close proximity tend to be inherited together, markers can be used to indirectly track the inheritance pattern of a gene or region known to be nearby.

Genotype

– The combination of alleles carried by an individual at a particular genetic locus.

Haplotype

– Haplotypes are an ordered set of alleles located on one chromosome. They reveal whether a chromosomal segment was maternally or paternally inherited and can be used to delineate the boundary of a possible disease-linked locus.

Haplotype tagging SNPs (htSNPs)

– Those SNPs that represent the variation in each block based on the linkage disequilibrium among the markers considered within a block.

Hardy–Weinberg equilibrium (HWE)

– The equilibrium between the frequencies of alleles and the genotype of a population. The occurrence of a genotype stays constant unless mating is nonrandom or inappropriate, or mutations accumulate. Therefore, the frequency of genotypes and the frequency of alleles are said to be at “genetic equilibrium.” Genetic equilibrium is a basic principle of population genetics.

Intronic SNPs–

Single-nucleotide polymorphisms that occur in noncoding regions of a gene that separate the exons (i.e., introns).

Linkage disequilibrium (LD)

– Phenomenon by which the alleles that are close together in the genome tend to be inherited together (haplotype).

Linkage map

Mendelian pattern of inheritance

– Refers to the predictable way in which single genes or traits can be passed from parents to children, such as in autosomal dominant, autosomal recessive, or sex-linked patterns.

Minor allele frequency (MAF)

– Given an SNP, its minor allele frequency is the frequency of the SNP’s less frequent allele in a given population.

Mutation

– A change in the DNA sequence. A mutation can be a change from one base to another, a deletion of bases, or an addition of bases. Typically, the term “mutation” is used to refer to a disease-causing change, but technically any change, whether or not it causes a different phenotype, is a mutation.

Penetrance

– Penetrance describes the likelihood that a mutation will cause a phenotype. Some mutations have a high penetrance, almost always causing a phenotype, whereas others have a low penetrance, perhaps only causing a phenotype when other genetic or environmental conditions are present. The best way to measure penetrance is phenotypic concordance in monozygotic twins.

Phenotype

– Visible or detectable traits caused by underlying genetic or environmental factors. Examples include height, weight, blood pressure, and the presence or absence of disease.

Polygenic disorders

– Disorders that are caused by the combined effect of multiple genes, rather than by just one single gene. Most common disorders are polygenic. Because the genes involved are often not located near each other, their inheritance does not usually follow Mendelian patterns in families.

Surrogate SNPs

– Single-nucleotide polymorphisms that do not cause a phenotype but can be used to track one because of their strong physical association (linkage) to an SNP that does cause a phenotype.

Susceptibility

– The likelihood of developing a disease or condition.