Genetic variation and human disease

Single base mutation which substitutes one nucleotide for another Single Nucleotide Polymorphisms (SNPs) SNPs are the most common form of polymorphism Example: a single SNP from T to A on the hemoglobin beta locus of chromosome 11 causes a missense coding event changing glutamine to valine, leading to the sickle cell anemia phenotype. Insertion or deletion of one or more nucleotide(s) Tandem Repeat Polymorphisms Tandem repeats or variable number of tandem repeats (VNTR) are a very common class of polymorphism, consisting of variable length of sequence motifs that are repeated in tandem in a variable copy number VNTRs are subdivided into two subgroups based on the size of the tandem repeat units. Microsatellites or Short Tandem Repeat (STR) repeat unit: 1-6 (dinucleotide repeat: CACACACACACA) Minisatellites repeat unit: 14-100 Example: Spinocerebellar ataxia Type10 (SCA10) is caused by the largest tandem repeat seen in the human genome. Normal population has 10-22 mer pentanucleotide ATTCT repeat in intron 9 of SCA10 gene; where as SCA10 patients have 800-4500 repeat units, which causes the disease allele to be up to 22.5 kb larger than the normal one. Insertion/Deletion Polymorphisms (indels) Common and widely distributed in the human population Association between coronary heart disease and a 287 bp indel polymorphism located in intron 16 of the angiotensin converting enzyme (ACE) have been reported. This indel, known as ACE/ID is responsible for 50% of the inter-individual variability of plasma ACE concentration.