The variations in the DNA sequence that cause or contribute to disease are called either mutations or polymorphisms, based solely on their frequency in the population. By convention, DNA sequence variants that occur in > 1% of the population are termed polymorphisms, and those that occur in less than one percent of individuals are called mutations. Mutations are responsible for the relatively rare single-gene Mendelian disorders (Table 1
), while polymorphisms are associated with the more common complex genetic disorders (Table 2
). Mutations in DNA arise naturally or unnaturally (environmental exposure). They are not always disease causing (they are far more likely to occur in noncoding DNA than coding DNA because of the far greater number of base-pairs of noncoding DNA in the human genome). Variations in inherited DNA sequence between individuals can be due to the deletion or addition of bases, or to variable lengths of repetitive sequences within or between genes. However, the most common type of DNA sequence variants are SNPs in which a single base in the sequence is replaced by a different nucleotide. There are SNPs approximately every 200 to 300 base-pairs in the human genome. Since the genome contains approximately 3 billion base-pairs, this means that there are between 10 to 15 million sites at which > 1% of the population differ from the majority. Although this seems like a large potential for diversity, simple arithmetic shows that even the most genetically diverse people are still at least 99.9% identical. If the density of SNPs was evenly spaced over the entire genome, this would mean that there are approximately 300,000 to 600,000 SNPs within the estimated 30,000 human genes. Many of these SNPs cause functional changes by affecting transcription factor binding sites, influencing splicing or stability of messenger RNA, or altering the amino acid sequence of the protein (Fig 1
). It is this variation that, in combination with environmental factors and epigenetic modification of DNA (epigenetic changes include methylation and demethylation of regulatory sequences and/or chemical modification on the histones that influence gene expression) accounts for all of human phenotypic diversity, including disease susceptibility.