Polymorphism and single nucleotide polymorphisms (SNPs)



genome-wide association studies


restriction fragment length polymorphism


single nucleotide polymorphism

Genetic Polymorphism – Single Nucleotide Polymorphisms (SNPs) and Restriction Fragment Length Polymorphism (RFLPs)

Genetic diversity arises due to mutation and is important to the adaptability and survival of the species. Any two unrelated humans share 99.5% of their DNA sequence. Variation in the remainder of the sequence that is stable and present in >1% population is called ‘polymorphism’. When the sequence differs by a single nucleotide this is known as a SNP (pronounced ‘snip’), e.g., someone may have an ‘A’ nucleotide at a particular locus, while another has a ‘G’ nucleotide. SNPs are the most common type of genetic variation in humans and occur on average about once in every 300 base pairs.

This variability is shown by DNA fingerprinting. Restriction enzymes cleave DNA at specific DNA sequences (restriction sites). Polymorphism at restriction sites (RFLP) can inactivate cleavage sites, meaning that cleavage of a DNA sample by a restriction enzyme produces a unique pattern, the DNA fingerprint, when the fragments are separated by electrophoresis (Fig. 1) [1]. SNPs in close proximity on the chromosome are correlated because the chance of separation by recombination that takes place once per generation during fertilisation is small. Thus, patterns of SNPs are informative regarding genealogy and parentage.

Figure 1.

(a) Action of restriction enzymes exemplified by BamH1, a restriction enzyme that cleaves DNA at specific DNA sequence (GGATCC). (b) After cleavage by the restriction enzyme, fragments are separated by electrophoresis to produce a ‘DNA fingerprint’. Polymorphism in restriction sites means that fragments of different sizes are produced from DNA rendering this fingerprint identifiable to an individual. This is useful in forensic science. SNPs in restriction sites are inherited from parents and this is of use in evaluating parentage. Identical twins B and C are the offspring off mother A. The paternal DNA is D, rather than E or F who are unrelated males. Adapted from the original description of this technique by Jeffreys et al. [1] in 1985. Nowadays, SNPs are detected by techniques incorporating sequencing, SNP microarrays and PCR.

SNPS and Disease

These genetic variations underlie differences in our susceptibility to disease. The severity of illness and the way our body responds to treatments. Over a hundred million known SNPs have been identified and catalogued. Most of these SNPs lie within sequences of DNA that do not code for amino acids directly (introns and intergenic regions). These SNPs affect gene splicing, transcription factor binding, messenger RNA degradation and other factors influencing gene transcription and translation of mRNA into protein.

Heritability of Prostate Cancer

Striking differences in incidence of prostate cancer have been observed for different ethnic groups. Incidence is high in the Afro-Caribbean population and first-degree relatives of men with prostate cancer. Consequently, the estimated heritability is high. Some degree of heritability is due to inheritance of single susceptibility genes, e.g. BRCA1 or BRCA2, but this is estimated to account for only 15% of cases [2]. Most of the heritability is attributed to interaction of multiple low penetrance susceptibility genes and shared environmental factors within these families.

Studying SNPs in Prostate Cancer

SNPs have typically been used for cancer-association studies in different ways: One is by genome-wide association studies (GWAS) to examine cancer association of large numbers of SNPs within a large population. To date GWAS have identified replicated associations between prostate cancer and almost 70 specific SNPs. The penetrance of these associations is low, meaning that a single SNP confers a small increase in prostate cancer risk (odds ratio 1.1–2.1). Considered altogether, these explain ≈30% of the heritability [3].

Clinical Importance of SNPs

Unselected PSA screening has not been shown to be cost effective. Screening of those at higher risk of prostate cancer is a rational strategy to improve effectiveness. Genotyping many low penetrance SNPs may be one way to identify susceptible patients and may, in time, be useful in this respect and in predicting disease behaviour. A recent assessment of prostate cancer susceptibility genes identified by GWAS studies in predicting outcome with active surveillance suggests that we are still some way off this goal [4].Variation in serum PSA levels has been associated with SNPs in the PSA gene and a personalised PSA threshold for prostate biopsy, based on genetic profile has been proposed [5].

The paper by Tefik et al. [6] shows an association between polymorphisms in enzymes involved with free radical production and clearance during inflammation. SNPs in catalase (T allele at C-262T confers increased risk) and myeloperoxidase (G allele at G-463A confers increased risk) are associated with prostate cancer risk. Catalase (T allele at C-262T) polymorphism also predicts increased local invasion of prostate cancer. This association supports the hypothesis that inflammation and free radicals play a role in the aetiology of prostate cancer [7].

Conflict of Interest

None declared.