SNP array
Encyclopedia
In molecular biology
and bioinformatics
, a SNP array is a type of DNA microarray
which is used to detect polymorphisms
within a population. A single nucleotide polymorphism
(SNP), a variation at a single site in DNA
, is the most frequent type of variation in the genome. For example, there are around 10 million SNPs that have been identified in the human genome
. As SNPs are highly conserved throughout evolution
and within a population
, the map of SNPs serves as an excellent genotypic marker for research.
, and solid surface DNA capture. The three mandatory components of the SNP arrays are:
To achieve relative concentration independence and minimal cross-hybridization, raw sequences and SNPs of multiple databases are scanned to design the probes. Each SNP on the array is interrogated with different probes. Depending on the purpose of experiments, the amount of SNPs present on an array is considered.
. The most important application of SNP array is in determining disease susceptibility and consequently, in pharmacogenomics by measuring the efficacy of drug therapies specifically for the individual. As each individual has many single nucleotide polymorphisms that together create a unique DNA sequence, SNP-based genetic linkage
analysis could be performed to map disease loci, and hence determine disease susceptibility genes for an individual. The combination of SNP maps and high density SNP array allows the use of SNPs as the markers for Mendelian diseases with complex traits efficiently. For example, whole-genome genetic linkage analysis shows significant linkage for many diseases such as rheumatoid arthritis
, prostate cancer
, and neonatal diabetes. As a result, drug
s can be personally designed to efficiently act on a group of individuals who share a common allele
- or even a single individual. A SNP array can also be used to generate a virtual karyotype
using software to determine the copy number of each SNP on the array and then align the SNPs in chromosomal order.
In addition, SNP array can be used for studying the loss of heterozygosity
(LOH). LOH is a form of allelic imbalance that can result from the complete loss of an allele or from an increase in copy number
of one allele relative to the other. While other chip-based methods (e.g. comparative genomic hybridization
) can detect only genomic gains or deletions, SNP array has the additional advantage of detecting copy number neutral LOH due to uniparental disomy
(UPD). In UPD, one allele or whole chromosome from one parent are missing leading to reduplication of the other parental allele (uni-parental = from one parent, disomy = duplicated). In a disease setting this occurrence may be pathological when the wildtype allelle (e.g. from the mother) is missing and instead two copies of the mutant allelle (e.g. from the father) are present.
Using high density SNP array to detect LOH allows identification of pattern of allelic imbalance with potential prognostic and diagnostic utilities. This usage of SNP array has a huge potential in cancer diagnostics as LOH is a prominent characteristic of most human cancers. Recent studies based on the SNP array technology have shown that not only solid tumor
s (gastric cancer, liver cancer
etc.) but also hematologic malignancies
(ALL, MDS
, CML etc.) have a high rate of LOH due to genomic deletions or UPD and genomic gains. The results of these studies may help to gain insights into mechanisms of these diseases and to create targeted drugs.
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
and bioinformatics
Bioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
, a SNP array is a type of DNA microarray
DNA microarray
A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome...
which is used to detect polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
within a population. A single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
(SNP), a variation at a single site in DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, is the most frequent type of variation in the genome. For example, there are around 10 million SNPs that have been identified in the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
. As SNPs are highly conserved throughout evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
and within a population
Population
A population is all the organisms that both belong to the same group or species and live in the same geographical area. The area that is used to define a sexual population is such that inter-breeding is possible between any pair within the area and more probable than cross-breeding with individuals...
, the map of SNPs serves as an excellent genotypic marker for research.
Principles
The basic principles of SNP array are the same as the DNA microarray. These are the convergence of DNA hybridization, fluorescence microscopyFluorescence microscope
A fluorescence microscope is an optical microscope used to study properties of organic or inorganic substances using the phenomena of fluorescence and phosphorescence instead of, or in addition to, reflection and absorption...
, and solid surface DNA capture. The three mandatory components of the SNP arrays are:
- The array that contains immobilized nucleic acidNucleic acidNucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
sequences or target; - One or more labeled allele-specific oligonucleotide (ASO) probes;
- A detection system that records and interprets the hybridization signal.
To achieve relative concentration independence and minimal cross-hybridization, raw sequences and SNPs of multiple databases are scanned to design the probes. Each SNP on the array is interrogated with different probes. Depending on the purpose of experiments, the amount of SNPs present on an array is considered.
Applications
A SNP array is a useful tool to study the whole genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. The most important application of SNP array is in determining disease susceptibility and consequently, in pharmacogenomics by measuring the efficacy of drug therapies specifically for the individual. As each individual has many single nucleotide polymorphisms that together create a unique DNA sequence, SNP-based genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
analysis could be performed to map disease loci, and hence determine disease susceptibility genes for an individual. The combination of SNP maps and high density SNP array allows the use of SNPs as the markers for Mendelian diseases with complex traits efficiently. For example, whole-genome genetic linkage analysis shows significant linkage for many diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, and neonatal diabetes. As a result, drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s can be personally designed to efficiently act on a group of individuals who share a common allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
- or even a single individual. A SNP array can also be used to generate a virtual karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
using software to determine the copy number of each SNP on the array and then align the SNPs in chromosomal order.
In addition, SNP array can be used for studying the loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
(LOH). LOH is a form of allelic imbalance that can result from the complete loss of an allele or from an increase in copy number
Gene copy number
Copy-number variations —a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted or duplicated on certain...
of one allele relative to the other. While other chip-based methods (e.g. comparative genomic hybridization
Comparative genomic hybridization
Comparative genomic hybridization or Chromosomal Microarray Analysis is a molecular-cytogenetic method for the analysis of copy number changes in the DNA content of a given subject's DNA and often in tumor cells....
) can detect only genomic gains or deletions, SNP array has the additional advantage of detecting copy number neutral LOH due to uniparental disomy
Uniparental disomy
Uniparental disomy occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.. UPD could involve isodisomy or heterodisomy ....
(UPD). In UPD, one allele or whole chromosome from one parent are missing leading to reduplication of the other parental allele (uni-parental = from one parent, disomy = duplicated). In a disease setting this occurrence may be pathological when the wildtype allelle (e.g. from the mother) is missing and instead two copies of the mutant allelle (e.g. from the father) are present.
Using high density SNP array to detect LOH allows identification of pattern of allelic imbalance with potential prognostic and diagnostic utilities. This usage of SNP array has a huge potential in cancer diagnostics as LOH is a prominent characteristic of most human cancers. Recent studies based on the SNP array technology have shown that not only solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s (gastric cancer, liver cancer
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
etc.) but also hematologic malignancies
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
(ALL, MDS
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
, CML etc.) have a high rate of LOH due to genomic deletions or UPD and genomic gains. The results of these studies may help to gain insights into mechanisms of these diseases and to create targeted drugs.
Further reading
- Barnes, M.R. (2003) Chapter 3: Human Genetic Variation: Databases and Concepts, Bioinformatics for geneticists, edited by Barnes, M.R. and Gray, I.C., John Wiley and Sons, Ltd.
- Hehir-Kwa, J., Egmont-Petersen, M., Janssen,I., Smeets, D., Geurts van Kessel, A., Veltman, J. (2007) "Genome-wide copy number profiling on high-density BAC, SNP and oligonucleotide microarrays: a platform comparison based on statistical power analysis" DNA Research. 14:1-11. Link: http://dnaresearch.oxfordjournals.org/cgi/content/full/14/1/1
- John, S., Shephard, N., Liu, G., Zeggini, E., Cao, M., Chen, W., Vasavda, N., Mills, T., Barton, A., Hinks, A., Eyre, S., Johes, K.W., Ollier, W., Silman, A., Gibson, N., Worthington, J., and Kennedy, G.C. (2004) "Whole-Genome scan, in a complex disease, using 11,245 single-nucleotide polymorphism: comparison with microsatellites." American Journal of Human Genetics. 75(1):54-64. PMID 15154113
- Mei, R., Galipeau, P.C., Prass, C., Berno, A., Ghandour, G., Patil, N., Wolff, R.K., Chee, M.S., Reid, B.J., and Lockhart, D.J. (2000) "Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays." Genome Research. 10:1126-1137. PMID 10958631
- Schaid, D.J., Guenther, J.C., Christensen, G.B., Hebbring, S., Rosenow, C., Hilker, C.A., McDonnell, S.K., Cunningham, J.M., Slager, S.L., Blute, M.L., and Thibodeau, S.N. (2004) "Comparison of Microsatellites Versus Single Nucleotide Polymorphisms by a Genome Linkage Screen for Prostate Cancer Susceptibility Loci", American Journal of Human Genetics. 75 (6): 948-65. PMID 15514889
- Sellick GS, Longman C, Tolmie J, Newbury-Ecob R, Geenhalgh L, Hughes S, Whiteford M, Garrett C, Houlston RS., "Genome-wide linkage searches for Mendelian disease loci can be efficiently conducted using high-density SNP genotyping arrays." Nucleic Acids Research. 32(20):e164. PMID 15561999
- Sheils, O., Finn, S. and O'Leary J. (2003) "Nucleic acid microarray: an overview." Current Diagnostic Pathology. 9:155-158.