Fundamentals of Bioinformatics - Ogurtsov, A.N. 2013

Information Principles in Biotechnology
Genome Analysis
Single Nucleotide Polymorphisms

A single nucleotide polymorphism (SNP, usually pronounced "snip") is a variation in a DNA sequence occupying a position of a single nucleotide. The conditions for The Emergence of SNPs are restricted to a single initial base pair where a substitution, insertion, or deletion may occur.

Sickle Cell anemia (hemoglobinopathy) is an example of a disorder caused by a specific SNP: an A→T substitution in the sixth codon of the gag ß-globin Gene results in a Glu→Val replacement. This mutation is designated as E6V, meaning that As a result of the mutation, valine (V) appears in the sixth position of the protein chain instead of glutamic acid (E). Such a substitution alters the overall charge state of Hemoglobin, making its surface prone to "sticking". Consequently, hemoglobin molecules clump together into large particles and precipitate, which dramatically reduces the elasticity of red Blood Cells. They lose The ability to pass through the capillaries of the Circulatory system and clog them, manifesting as chronic Hypoxia (oxygen deficiency) in the corresponding organ or tissue, potentially leading to organ damage (such as renal or pulmonary failure, blindness, severe infection, recurrent bone crises, etc.).

SNPs dispersed throughout The Genome occur on average once every 500 NUCLEOTIDES. Despite being caused by Mutations, many positions containing SNPs exhibit low mutation rates and can be employed as stable markers for gene mapping. A consortium of four academic genome research centers and 11 private companies is creating a high-density, high-quality, publicly accessible human SNP map: The SNP Consortium - http://snp.cshl.org/.

On the International HapMap Project website, SNP data are presented in the form of human haplotype maps (HapMap) - http://hapmap.ncbi.nlm.nih.gov/.

Not all SNPs are associated with diseases. Many of them occur within non-functional regions, although, as a rule, SNP density is higher than average within gene-containing regions. However, this is largely because gene-containing regions have been studied in greater detail and thus more SNPs have been discovered there, whereas extensive intergenic regions are less studied and therefore fewer SNPs have been found in them—which by no means implies that there are actually fewer of them there. This serves as a good example of how data banks often fail to provide a representative sample, and unfortunately, it is far from always possible to draw correct statistical Conclusions based on massive Data analysis.

Some SNPs occurring within exons result in a synonymous codon substitution or a change that has a negligible effect on protein functionality. Other types of SNPs can cause more severe alterations in the protein than local ones:

1) the replacement of a sense codon with a stop codon, leading to the premature termination of Protein Synthesis;

2) a deletion or insertion that causes a reading frame shift.

For instance, the A, B, and O alleles that determine Blood Groups are caused by SNP substitutions. They encode related Proteins that attach different saccharide residues to the antigen On the surface of red blood cells.

In the A allele, the sequence ...gctggtgacccctt... leads to the attachment of N-acetylgalactosamine to the antigen. In the B allele, the sequence ...gctcgtcaccgcta... leads to the attachment of galactose to the antigen. The O allele has undergone a mutation that caused a reading frame shift ...cgtggt-acccctt... and does not produce an active enzyme.

Type O red blood cells contain neither A nor B Antigens. Therefore, individuals with blood group O are universal Donors for blood transfusions. The loss of protein activity apparently entails no adverse consequences. Indeed, people with blood group O exhibit increased resistance to smallpox.

A strong correlation between a disease and specific SNPs can be utilized in clinical practice, as these are relatively easy to detect in patients. However, if a disease stems from the dysfunction of a specific protein, there may be multiple mutation sites capable of causing this inactivation. A particular site may predominate if:

1) all carriers of the gene are descendants of a single individual in whom the mutation occurred;

2) the disease arises from a gain of function rather than a loss of a specific feature, such as the ability of sickle cell hemoglobin to polymerize;

3) the mutation rate at a given site is unusually high. For example, the Glu380→Arg mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which causes Achondroplasia (chondrodystrophia fetalis) — a hereditary human disorder manifested by impaired enchondral ossification amidst normal periosteal and endosteal ossification, leading to dwarfism due to the underdevelopment of long bones.

On the other hand, an increased predisposition to the early onset of breast and Ovarian Cancer correlates with multiple independent mutations in the BRCA1 and BRCA2 genes, whereas the normal gene product acts as a tumor suppressor. Mutants resulting from insertions or deletions that cause a reading frame shift typically either fail to produce a protein or produce an inactive one. However, this rule cannot be applied a priori regardless of whether a substitution in the BRCA1 or BRCA2 genes will affect the risk of developing cancer.

When treating diseases caused by defective proteins or a complete lack of a protein, the following approaches are employed.

1. Supplying the Organism with a normal protein, such as Insulin for diabetes and factor VIII for hemophilia. Another example is the administration of human Growth Hormone to patients suffering from its total or partial deficiency. The Use of recombinant proteins reduces the risk of transmitting AIDS via blood transfusions or developing Creutzfeldt-Jakob disease, which occurs when Prions appear in the Brain, deposit on The Cell surface, interact with normal proteins, and alter their Structure into a pathological one (pathological proteins accumulating on the cell surface block membrane-bound processes and trigger apoptosis).

2. Modifying lifestyle to make the affected pathway non-essential. Phenylketonuria (PKU) is a genetic disorder caused by a deficiency of phenylalanine hydroxylase, the enzyme that catalyzes The conversion of phenylalanine to Tyrosine. The accumulation of large amounts of phenylalanine causes developmental issues, including mental retardation. These symptoms can be avoided through a low-phenylalanine diet. In the USA and many other countries, newborn screening for blood phenylalanine levels is legally mandated.

3. Gene Therapy to replace a missing protein is currently an active area of research and development.

Other medical Applications of SNPs reflect The Link Between genotype and therapeutic response (pharmacogenomics). For instance, an SNP in the N-acetyltransferase gene NAT-2 is associated with peripheral neuropathy—weakness, numbness, and pain in the hands, arms, and feet as a side effect of isoniazid Treatment for tuberculosis. Patients carrying this SNP are prescribed alternative treatments.

SNP data have major applications in evolutionary biology, offering key insights into historical population size fluctuations as well as migration patterns.

The degree of genetic diversity is expressed in terms of population size. The founder population refers to the initial set of individuals from which an entire population descends. These may be either original colonists, such as the Polynesians who first settled in New Zealand, or merely surviving individuals in a population that faced the brink of extinction.

For example, cheetahs currently represent a population that is estimated to have bottlenecked on the brink of extinction 10,000 years ago amid severe resource scarcity. All living cheetahs are as closely related genetically as siblings.

Extrapolating Mitochondrial DNA from various individuals of the same age and its observed Variability suggests the existence of a common maternal ancestor who lived 140,000 to 200,000 years ago. Calling her Eve implies she was the first woman. However, fossil evidence proves that humans existed much earlier. Mitochondrial Eve was simply the founding mother of the surviving Lineage of a population that had been on the verge of extinction.

Population-specific SNP data provide valuable insights into migration patterns. Mitochondrial sequences reveal maternal ancestry, while Y-chromosome sequences trace paternal lineage.

For instance, the results of such analyses indicate that the population of Iceland, first settled over 1,100 years ago, descends from Scandinavian men and women originating from both Scandinavia and the British Isles. Medieval Icelandic chronicles also document hostile raids on settlements located in the British Isles.

Anthropological studies of DNA sequences have revealed clear correlations between human DNA profiles and their language families. These investigations have proven useful, for example, in establishing connections among Native American languages. Similarly, it has been demonstrated that the Basques, renowned as a linguistically isolated population, were genetically isolated as well.

In The Study of isolated populations, anthropological genetics has yielded invaluable medical data, as mapping disease-causing genes is significantly facilitated when Background genomic variation is minimal. In Europe, genetically isolated populations include not only the Basques, but also the Finns, Icelanders, Welsh, and Sami (a Finno-Ugric people inhabiting northern Russia (Murmansk Oblast), Norway, Sweden, and Finland). Iceland boasts exceptional genealogical and medical records. In 1998, the Icelandic government passed legislation authorizing the creation of a database containing the medical records, family histories, and genetic sequences of the country's 275,000 residents. The Icelandic company Decode Genetics (http://www.decode.com/) plans to collaborate with pharmaceutical companies worldwide by utilizing these data.