chapter outline chapter
8
主讲教师：王亚梅
? 8.1 The genetic code ? 8.2 Transcription: From DNA to RNA ? 8.3 Translation: From mRNA to Protein ? 8.4 Differences in gene expression between prokaryotes and eukaryotes
? 8.5 The effects of mutations on gene expression and function
同义突变错义突变
无义突变
移码突变
Mutations in the coding sequence of a gene can alter the gene product n Conservative – similar to the original amino acid
e.g. aspartic acid [(-)charged] → glutamic acid [(-)charged]
n Nonconservative – different
e.g. aspartic acid [(-)charged] → alanine (uncharged)
Missense mutations
8.5 The effects of mutations on gene expression and function
8.5.1 Mutations outside the coding sequence can disrupt gene expression
n
Promoter sequences n
Termination signals n
Splice-acceptor and splice-donor sites n Ribosome binding sites 基因转录RNA 稳定性内含子剪接翻译起始
8.5.2 Loss-of-function and gain-of-function mutations
n Loss-of-function mutations 功能缺失突变
n Null (a morphic) mutations 无效突变
n Hypo morphic mutations低效突变
n Gain-of-function mutations 功能增强突变
n Hyper morphic mutations增效突变
n Neo morphic mutations 新效突变
n Dominant-negative mutations显性负效突变
anti morphic
“Morphs” by Hermann Muller, to classify mutations:
a morph, hypo morph, hyper morph, anti morph and neo morph
8.5.2 Loss-of-function mutations result in reduced or abolished
protein activity
n Loss-of-function 功能缺失 mutations are usually recessive n Null (amorphic) mutations – completely block function of a gene
product (e.g. deletion of an entire gene)
n Hypomorphic mutations– gene product has weak, but detectable,
activity
黄嘌呤脱氢酶
10% Null Hypomorphic
Threshold
for wild-type
eye color
Fig. 8.28100%
50%55%
5%
0%
Some loss-of-function mutations can be dominant Incomplete dominance – phenotype varies with the amount of functional gene product (Fig 8.30)
Fig. 8.308.5.2 Incomplete dominance arises when phenotype varies with the amount of functional protein
R +r 50r 0100%酶活性
50%酶活性无酶活性
受单一色素生成基因控制
8.5.3 Rarely, loss-of-function mutations are dominant Haploinsufficiency (单倍剂量不
足)– phenotype is sensitive to gene
dosage (i.e. 50% of gene product)
8.5.4 Gain-of-function mutations enhance a function
n Gain-of-function mutations are usually dominant
n Hypermorphic mutations – generate more gene product or the same amount of a more efficient gene product
Normal FGFR Hypermorphic FGFR G480R Array持续
激活
Achondroplasia, a form of dwarfism, is caused by a dominant
hypermorphic mutant allele of the FGFR3 gene, FGFR3G480R
8.5.5 Gain-of-function mutations confer a new activity
n Neomorphic mutations – generate gene product with new function or that is expressed at inappropriate time or place (ectopic expression)
ectopic expression of a leg-determining gene in structures that normally produce antennae
Antp Ns antenna-to-leg transformation
Mutation within the transcriptional
control region of the gene
8.5.6 Some gain-of-function mutations can be dominant-negative normal protein in complex
mutant protein complex complex of mutant protein and normal protein Active Inactive Inactive
n
Usually occurs in genes that encode multimeric proteins
n Dominant-negative mutations (显性负效突变)anti morphic : Alleles that block the activity of wild-type alleles of the same gene, causing a loss of function even in heterozygotes.
Loss-of-Function
Mutation Type A morphic (null)Hypo morphic (leaky) Occurrence Common Common
Possible Dominance Relations Usually recessive
Can be incompletely dominant if phenotype varies continuously with gene product
Can be dominant in cases of haploinsufficiency
8.5.7 Summary on mutations classified by their effects on
protein function
Gain-of-Function
Mutation Type Hyper morphic Neo morphic Anti morphic
(dominant negative) Occurrence Rare Rare Rare
Possible Dominance Relations Usually dominant
or incompletely
dominant
Usually
dominant
Usually dominant
or incompletely
dominant
n Mutations in genes encoding gene products for transcription, RNA processing, translation, and protein processing are usually lethal , i.e. ribosomal proteins.
n Such mutations affect the synthesis of all proteins in a cell n Mutations in tRNA genes can suppress mutations in protein-coding genes.
n Nonsense suppressor tRNAs
8.5.8 Mutations in genes encoding the molecules that implement gene expression may have global effects
8.5.8.1 A nonsense mutation in a protein-coding gene creates
a truncated, nonfunctional protein
生成截短、
无功能蛋白
8.5.8.2 Mutations in tRNA genes can suppress mutations in protein-coding genes
Nonsense suppressor 无义抑制因子tRNAs : A second, nonsense suppressing mutation in the anticodon of a tRNA gene allows production of a full-length polypeptide.in-frame UAG nonsense mutation 生成完整、
有功能蛋白
n The suppressing tRNA must have only a weak affinity for the stop codons normally found at the ends of mRNA coding regions.
n
The cell must have other tRNAs that recognize the same codon as the suppressing tRNA recognized before mutation altered its anticodon.
主讲教师：王亚梅