Common SNPs are unlikely to explain all of the genetic risk for common disorders. An evolutionary model of complex diseases (24) predicts roles for common SNPs and for multiple rare variants (such as SNPs) in some genes (MRV hypothesis ). A rare variant is usually defined by a frequency below 1%, although many are so rare that they are found in only one individual in a sample).(25) Most variants carried by any one person are common SNPs, but if one sequences a chromosomal region in many people, one finds more and more rare SNP sites. The most deleterious variants die out or remain rare due to natural selection, i.e., they reduce survival. They are found in functional regions, i.e., among the SNPs in exons (protein coding regions) that alter amino acid sequence (non-synonymous or nsSNPs), or in promoters (sequences that regulate gene expression). (26, 27) But there are other, poorly-understood functional regions. Many non-coding regions are highly conserved across species, suggesting that they have a function. Gene expression can be altered by common, synonymous exonic SNPs (no coding change), and
