基因突变、多态性及疾病基因的定位和鉴定

frame-shift mutations: a class of insertion/deletion mutations which occur within an ORF and “change the frame” of codon usage.
others: mutations in regulatory or splicing regions, chromosomal rearrangements, etc.
– One gene/protein/reaction at a time. – Test/validate isolated models at bench.
• New ‘systems biology’ approach:
– All DNA, RNA, or proteins surveyed at once. – Test/validate models experimentally and computationally. – Made possible by invention of high-throughput approaches such as the microarray technology. – Has had profound effects on biology & medicine.
异表达的基因
等位基因/ 基因座/ 基因型/ 表型
• Allele: One of the different forms of a gene pair. At each autosomal locus an individual possessed two alleles, one inherited from mum and one from dad. • Locus: Unique chromosomal location defining the
SNP distribution is not uniform
• 1/3 in coding, 2/3 in non-coding.
- Types of coding region SNPs: + Synonymous: the substitution causes no amino acid change to the protein. + Non-Synonymous: the substitution results in an alteration of the encoded protein.
position of an individual gene or DNA sequence (often used as a synonym for gene).
• Genotype: The combination of alleles that an individual possesses. • Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.
Types of Mutations
Silent mutation Missense mutation
Non-sense mutation
Frameshift mutation
Chromosomal mutations
• Deletion
• Duplication • Inversion
• Translocation
Polymorphisms
• ‘Mutations’ that are propagated and maintained in the population at relatively high frequencies are called polymorphisms. • Polymorphism is defined as the existence of two or more alleles, where the rare allele appears with a frequency greater than 1% in the population. • Most mutations are quickly lost from population due to deleterious effects (natural selection) or genetic drift (random fluctuations). • Mutations may become polymorphisms due to selective advantage (heterozygotes for hemoglobin sickle cell mutation are more resistant to malaria) or genetic drift (founder effect, small group of individuals found a new population).
Gene Mutation, Polymorphism, Gene mapping and identification
General organization of human genome
20000 25000
持家基因/ 奢侈基因
• Housekeeping gene : Genes which express proteins common to all ceFra Baidu bibliotekls, e.g. ribosomal, chromosomal and cytoskeletal proteins. (βactin)几乎在一切体细胞中均能被表达的基因 • Luxury gene: are those coding for specialized functions synthesized (usually) in large amounts in particular cell types.特
• Genetic variability--Differences in genetic makeup of individuals due to mutations and polymorphisms.
• Variability ensures some members survive in different environmental conditions.
nonsense mutations: changes in DNA which generate a termination codon and thus stop translation.
read-through mutations: changes in DNA which eliminate a ‘termination codon’ to add new sequence. insertions or deletions: changes in DNA which introduce or remove bases.
Single Nucleotide Polymorphism (SNP)
• A SNP is a source variance in a genome. A SNP is a single base mutation in DNA. • SNPs are the most simple form and most common source of genetic polymorphism in the human genome (90% of all human DNA polymorphisms). • There are two types of nucleotide base substitutions （置换） resulting in SNPs: – Transition（转换）: substitution between purines (A, G) or between pyrimidines (C, T). Constitute two thirds of all SNPs. – Transversion（颠换）: substitution between a purine and a pyrimidine.
The ‘-omics’ vocabulary
genome
genomics
transcriptome
proteome metabolome
proteomics metabolomics
physiome
physiomics
Mutations
- A mutation is a change in DNA sequence due to errors in DNA replication or repair. - Mutations may or may not result in an expressed phenotype. - Mutations that have no phenotype are called neutral mutations. - Mutations can alter RNA expression, processing and/or stability. - Mutations can also affect protein expression, processing, stability.
From Genotype to Phenotype
DNA (genes) Cells Tissues & Organs
Population
Organism
Environment and genotype affect phenotype
Phenotype
No environmental ‘insult’
Phenotypic variation is vital to species survival
• A striking feature of natural populations is a large amount of variability between individuals. This applies to all organisms including humans. • Phenotypic variability--Differences in observable characteristics (e.g., weight, height, eye color, disease state) caused by interactions of genetic and environmental factors.
Resistant Genotype
Sensitive
Genotype
Background Risk Level (low)
Environmental ‘insult’ e.g., increased calories in diet
Resistant Genotype Sensitive Genotype
2-fold risk of obesity
6-fold risk of obesity
Phenotype “begins” within a cell
Genotype
Phenotype
Genomic era in biology & medicine
• Traditional ‘reductionist’ approach:
- Mutations can be inherited not inherited
(genetic/germline mutations) (somatic mutations)
Types of Mutations
point mutations: change in one base pair of DNA. silent mutations: changes in DNA which do not affect protein expression or function. missense mutations: changes in DNA which lead to a change in an amino acid.