Thành viên:Naazulene/Đa hình gene

Đối với other concepts, xem Polymorphism.

Genes which control hair colour are polymorphic.

Gen đa hình là gen có nhiều alen có tần số >1%. Nói cách khác, tính đa hình của gene là trạng thái ở cùng một locus xuất hiện nhiều hơn một alen có tần số > 1%.

Đa hình gene:

• có thể xuất hiện ở bất cứ đâu trong hệ gene.
• đa phần là "câm", tức chúng không làm thay đổi biểu hiện của gene. Một số đa hình không câm. Ví dụ, ở chó, locus E có thể có 1 hoặc 2 trong 5 alen E, E^m, E^g, E^h, e qui định những màu lông khác nhau ở chó.

Một biến dị đa hình có thể dẫn đến biểu hiện dị thường của gen; sự dị thường này có thể gây bệnh hay liên quan đến bệnh. Ví dụ, một biến dị đa hình của gen mã hóa enzyme CYP4A11 trong đó thymidine thay thế cytosine ở nucleotide số 8590, khiến phenylalanine bị thay thành serien ở amino acid số 434. Protein biến dị này có hoạt tính xúc tác thấp hơn đối với acid arachidonic. Những người mang alen này (đồng hợp hay dị hợp) có nguy cơ mắc cao hơn với các bệnh: tăng huyết áp, đột quỵ thoáng qua và bệnh động mạch vành.

Đáng chú ý, gene mã hóa phức hệ tương thích histo chính (MHC) là gene đa hình nhất, sản phẩm của gen là phân tử MHC tham gia vào hệ miễn dịch và tương tác với tế bào T. Gen này có hơn 32000 allele khác nhau, và khoảng 200 biến dị chỉ trong loci HLA-B HLA-DRB1.

Một số đa hình được ổn định bởi chọn lọc cân bằng.

Khác biệt giữa đa hình và đột biến

Quy tác chung là lấy mốc ở 1%, nếu tần số alen thấp hơn 1% thì là đột biến, cao hơn thì là đa hình. Tuy nhiên, một số đa hình có thể diễn ra ở tần số alen thấp, quy tắc này không phải luôn đúng (ví dụ như trong trường hợp có quá nhiều alen đa hình, trong đó tất cả alen đều không đạt 1%). Các alen đột biến nên được hiểu là sai khác, dị thường; còn các alen đa hình là tất yếu.

- Ở sinh vật đơn bào, không có sự khác biệt

- Ở những sinh vật đa bào sinh sản hữu tính, gần như tất cả đột biết không được truyền đạt lại cho những thế hệ kế cận. Nếu đột biến diễn ra ở tế bào sinh dưỡng (ví dụ như tế bào da dưới tác dụng của tia UV) thì alen đột biến đó không được truyền lại cho đời sau). Nếu đột biến diễn ra ở tế bào sinh sản (ví dụ như đột biến giảm phân) thì đột biến có khả năng được truyền lại cho đời sau, nếu giao tử chứa alen đột biến tham gia dung hợp.

A rule of thumb that is sometimes used is to classify genetic variants that occur below 1% allele frequency as mutations rather than polymorphisms. However, since polymorphisms may occur at low allele frequency, this is not a reliable way to tell new mutations from polymorphisms. A mutation is a change to an inherited genetic sequence.

• In unicellular organisms, there isn't a distinction.
• In multi-cellular organisms which replicate via sexual reproduction nearly all mutations are not passed on to subsequent generations. A mutation may, or may not, be passed on to off-spring (e.g. if is a mutation that happens in some replicating cells that are not part of the germline, none of the off-spring will bear the mutation.
  • For example, a mutation may occur in a skin cell as a result of ultraviolet light resulting in a thiamine dimer which is not properly repaired before the skin cell undergoes mitosis and divides.
  • This is quite distinct from a mutation which occurs during meiosis, which can be subsequently passed on to future generations, and it is very helpful to be clear when discussing mutations whether it is a somatic mutation or gemline mutation.

In the case of silent mutations there isn't a change in fitness, and the pressures responsible for Hardy-Weinberg equilibrium have no impact on the accumulation of silent polymorphisms over time. Most often, a polymorphism is variation in a single nucleotide (SNP), but also can be insertion or deletion of one or more nucleotides, changes in the number of times a short or longer sequence is repeated (both of these are common in parts of DNA that don't directly code for a protein, as are SNPs, but can have major effects on gene expression). Polymorphisms which result in a change in fitness are the grist for the mill of evolution by natural selection. All genetic polymorphisms start out as a mutation, but only if they are germline and are not lethal can they spread into a population. Polymorphisms are classified based on what happens at the level of the individual mutation in the DNA sequence (or RNA sequence in the case of RNA viruses), and what effect the mutation has on the phenotype (i.e. silent or resulting in some change in function or change in fitness). Polymorphisms are also classified based on whether the change is in the sequence of the resulting protein or in the regulation of the expression of the gene, which can occur at sites that are typically upstream and adjacent to the gene, but not always.

Identification

Polymorphisms can be identified in the laboratory using a variety of methods. Many methods employ PCR to amplify the sequence of a gene. Once amplified, polymorphisms and mutations in the sequence can be detected by DNA sequencing, either directly or after screening for variation with a method such as single strand conformation polymorphism analysis.

Phân loại

Một đa hình có thể là bất cứ đoạn nucleic acid sai khác nào, bao gồm các loại:

A polymorphism can be any sequence difference. Examples include:

• Single nucleotide polymorphisms (SNPs) are a single nucleotide changes that happen in the genome in a particular location. The single nucleotide polymorphism is the most common form of genetic variation.
• Small-scale insertions/deletions (Indels) consist of insertions or deletions of bases in DNA.
• Polymorphic repetitive elements. Active transposable elements can also cause polymorphism by inserting themselves in new locations. For example, repetitive elements of the Alu and LINE1 families cause polymorphisms in human genome.
• Microsatellites are repeats of 1-6 base pairs of DNA sequence. Microsatellites are commonly used as a molecular markers especially for identifying the relationship between alleles

Clinical significance

Many different human disease result from polymorphisms. Polymorphisms also play significant role as risk factors for development of disease. Finally, polymorphisms in drug metabolism, esp. cytochrome p450 isoenzymes, proteins involved in drug transport (whether into the body, into protected areas of the body like the brain, or secreted out) as well as in specific cell surface receptor proteins alter the effect of various drugs. This is a rapidly evolving area of drug safety research. Resources such as HapMap, DbSNP,Ensembl, DNA Data Bank of Japan, DrugBank, Kyoto Encyclopedia of Genes and Genomes (KEGG), GenBank, and other parts of the International Nucleotide Sequence Database Collaboration have become crucial in Personalized medicine,bioinformatics, and pharmacogenomics.

Lung cancer

Polymorphisms have been discovered in multiple XPD exons. XPD refers to "xeroderma pigmentosum group D" and is involved in a DNA repair mechanism used during DNA replication. XPD works by cutting and removing segments of DNA that have been damaged due to things such as cigarette smoking and inhalation of other environmental carcinogens. Asp312Asn and Lys751Gln are the two common polymorphisms of XPD that result in a change in a single amino acid. This variation in Asn and Gln alleles has been related to individuals having a reduced DNA repair efficiency. Several studies have been conducted to see if this diminished capacity to repair DNA is related to an increased risk of lung cancer. These studies examined the XPD gene in lung cancer patients of varying age, gender, race, and pack-years. The studies provided mixed results, from concluding individuals who are homozygous for the Asn allele or homozygous for the Gln allele had an increased risk of developing lung cancer, to finding no statistical significance between smokers who have either allele polymorphism and their susceptibility to lung cancer. Research continues to be conducted to determine the relationship between XPD polymorphisms and lung cancer risk.

As a cornerstone of Peronalized medicine cancers, Sequence analysis is becoming increasingly important to understand the specific mutations involved in the individual's cancer, such as needed to select specific molecular targets such as mutations in various receptors, but also understanding the polymorphisms they inherited which play important roles in diagnosis, prognosis, and treatment, such as treatment of leukemia with 6-mercaptopurine where toxicity largely depends on polymorphisms in multiple different genes involved in its metabolism.

Asthma

Asthma is an inflammatory disease of the lungs and more than 100 loci have been identified as contributing to the development and severity of the condition. By using the traditional linkage analysis, these asthma correlated genes were able to be identified in small quantities using genome-wide association studies (GWAS). There have been a number of studies looking into various polymorphisms of asthma-associated genes and how those polymorphisms interact with the carrier's environment. One example is the gene CD14, which is known to have a polymorphism that is associated with increased amounts of CD14 protein as well as reduced levels of IgE serum. A study was conducted on 624 children looking at their IgE serum levels as it related to the polymorphism in CD14. The study found that IgE serum levels differed in children with the C allele in the CD14/-260 gene based on the type of allergens they regularly exposed to. Children who were in regular contact with house pets showed higher serum levels of IgE while children who were regularly exposed to stable animals showed lower serum levels of IgE. Continued research into gene-environment interactions may lead to more specialized treatment plans based on an individual's surroundings.