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.
Resistant Genotype
Sensitive
Genotype
Background Risk Level (low)
Environmental ‘insult’ e.g., increased calories in diet
Resistant Genotype Sensitive Genotype
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
Types of Mutations
Silent mutation Missense mutation
Non-sense mutation
Frameshift mutation
Chromosomal mutations
• Deletion
• Duplication • Inversion
• Translocation
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.
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.
• Genetic variability--Differences in genetic makeup of individuals due to mutations and polymorphisms.
• Variability ensures some members survive in different environmental conditions.
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.
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).
– 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.
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.
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 nucleotisulting 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.
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 cells, 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