Cellular Aging: DNA Polymorphisms

Many, if not the majority, of genetic loci in individuals in outbred, or wild, populations (including human) can have alternative versions of the gene, called alleles, that may or may not specify different genetic information. The term genetic polymorphism is used to describe a Mendelian trait that is present in at least two phenotypes (the observable physical characteristics of an organism) that are specified by different alleles and are present at a frequency of greater than 1 to 2 percent in the population. In contrast to a polymorphism, a rare genetic variant is one that is present in the population at a frequency of less than 1 percent, and most commonly at very low frequencies. Most, but not all, of the mutations that cause genetic diseases are in this category. For example, the alleles associated with Werner syndrome, a genetic disorder displaying a number of features of accelerated aging, are rare variants (see below).

The ABO blood group was the first human genetic polymorphism to be described—a discovery of immense theoretical and practical importance. Demonstrating that multiple alleles can occur at a specific genetic locus, often at comparable frequencies in the population, ultimately led to an understanding of the genetic basis of phenotypic variation in animal populations. The practical significance of this pioneering discovery is that it led to the routine use of whole-blood transfusions in the practice of medicine. Since this seminal observation, many polymorphic traits have been described and, although the precise number is not known at this time, it is now believed that the majority of the genetic loci in human genome are polymorphic. The number of alleles at any polymorphic locus is extremely variable. At some loci, such as the human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC), literally dozens of alleles have been identified. Thus, with this degree of variation throughout the human genome, it is highly likely that every individual on earth, with the exception of identical twins, possesses a unique genotype.

DNA polymorphisms are defined as any alternative DNA sequence that is present in 1 to 2 percent or more of the population. The extent of genetic variation at the DNA level greatly exceeds that which is present in gene products (i.e., proteins). DNA polymorphisms are more frequent in sequences that are not involved in the regulation or specification of gene products. This part of the genome does not seem to affect the phenotype of the organism, and, therefore, mutations in these sequences are very likely to be selectively neutral and could accumulate more rapidly than in genetically active areas.

DNA polymorphic variants can be deletions, duplications, or inversions of segments of DNA. Two types of DNA sequences that are highly polymorphic are minisatellites that are composed of tandemly repeated 10 to 60 base-pair (bp) sequences and microsatellites that are segments composed of tandem repeats of 1 to 3 bp sequences. These sequences have proven to be very useful for gene mapping because: (1) they are distributed throughout the genome; (2) they are highly polymorphic in that the number of repeats is extremely variable; and (3) individual alleles can be identified by amplification of sequences by the polymerase chain reaction (PCR) and the size difference of these sequences determined by gel electrophoresis.

The most common type of DNA polymorphism, accounting for most genetic variation among human populations, is the single nucleotide change (single nucleotide polymorphism, or SNP). Since the completion of the first drafts of the human genome sequence, the identification and location of SNPs has progressed very rapidly. A working draft of the sequence assembled by the International Human Genome Sequencing Consortium is in a public database on the World Wide Web and can be easily accessed at http://genome.ucsc.edu. As of mid-2001, 1.42 million SNPs throughout the genome had been identified, with estimates that 60,000 SNPs are within regions that are transcribed into RNA. SNPs in these sequences could cause an amino acid change in the protein product specified by the gene, which, in turn, could have biological consequences. Moreover, it is currently estimated that 85 percent of the coding regions (exons) in genes are within 5,000 bp of a SNP; thus, it is almost certain that polymorphisms air in the regulatory elements of some genes and could, therefore, have an affect on the level of activity of these loci. In addition, SNPs are of sufficient density throughout the genome to serve as markers for the identification and mapping of specific combinations of alleles (haplotypes) that are associated with specific phenotypes. To accomplish this, informative SNPs (in or near genetic loci) will have to be identified and their frequencies in various populations determined. This will require a huge number of SNPs to be identified in many thousands of individuals. This endeavor will require the development of very efficient assays to screen such large populations, and a number of laboratories are developing highly efficient screening for such studies.

A database designed to serve as a central repository for SNPs, and for short deletion and insertion polymorphisms, has been established by the National Center for Biotechnology Information (NCBI) in collaboration with the National Genome Research Institute (see its website at www.ncbi.nlm.nih.gov/SNP/index.html). This repository also contains data derived from other species, both mammalian and nonmammalian, and is linked to national databases that contain other biological information. This repository will contain a large amount of information; for example, the update of 1 July 2001 indicated that 2,985,822 SNPs had been submitted (but not all fully characterized) to this database. Other public databases of human SNPs that are accessible on the Web have been established. One is located at the University of Utah in Salt Lake City (www.genome.utah.edu/genesnps), and another has been established in Europe sponsored by a consortium of major institutions (http://hgbase.cgr.ki.se).