[PDF] Lecture 4: Mutant Characterization I Mutation types (and

Dominant-negative DISC1 transgenic mice display schizophrenia

Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans Takatoshi Hikida*, Hanna Jaaro-Peled*, Saurav Seshadri*, Kenichi Oishi†, Caroline Hookway*, Stephanie Kong*,

Current Perspective on Dominant Negative Mutations: Trends

dominant alleles will be discussed considering the hypothetical dap-1 gene 2 Dominant-negative alleles An allele can show dominant, semi-dominant, or recessive function depending on the accomplice allele and phenotype considered For clarification, consider alleles C and D, with genotypes CC, CD, and DD

IKK-β Recombinant Adenovirus (Dominant Negative)

dominant negative form of human IKK-β (S177A, S181A) mutant Safety Consideration Remember that you will be working with samples containing infectious virus Follow the recommended NIH guidelines for all materials containing BSL-2 organisms Always wear gloves, use filtered tips and work under a biosafety hood Methods

Lecture 4: Mutant Characterization I Mutation types (and

• Dominant-negative mutations – alleles of a gene encoding subunits of multimers that block the activity of subunits produced by normal alleles Rarely, loss-of-function mutations are dominant Fig 8 31 b

A Recessive Mutation in the APP Gene with Dominant-Negative

familial forms show an autosomal dominant pat-tern of inheritance with virtually complete pene-trance and are linked to mutations in the APP, presenilin1,andpresenilin2genes( 5) TheAPP mutations close to the sites of b-org-secretase www sciencemag SCIENCE VOL 323 13 MARCH 2009 1473 REPORTS CORRECTED 10 JULY 2009; SEE LAST PAGE

Dominant negative effect of the loss-of-function γ-secretase

whether the dominant negative effect of PS1 mutant allele is effected through the proteolytic activity of γ-secretase In this study, we provide compelling evidence to prove a dominant negative effect by the loss-of-function γ-secretase mutants on the production of Aβ42/40 by WT γ-secretase through hetero-oligomerization

Today’s lecture

“Gain-of-function” mutations are almost always dominant Hereditary pancreatitis is caused by a mutation that causes a digestive enzyme, trypsin, to become aberrantly active inside the pancreas Normally, the pancreas is protected because active trypsin will destroy itself by cutting at R117 This will split the trypsin and inactivate it

Devoir surveillé n (4 heures)

p2N dé nies par : pour tout entier naturel p, u p= Xp k=0 1 k coe cient dominant et coe cient constant de P n un entier peut être positif ou négatif

LES EVOLUTIONS TECHNOLOGIQUES EN LIEN AVEC L’IMPERATIF ECOLOGIQUE

transport en commun, ou n'auraient pas du tout été effectués Impact négatif sur l'environnement Troisième critique : à tout vouloir numériser, à générer de la donnée à tout-va, on oublie le coût environnemental du secteur informatique D’énormes quantités d’énergie sont en effet nécessaires pour

[PDF] mutation spontanée et ponctuelle

[PDF] mutation conservatrice

[PDF] transversion définition

[PDF] lancelot ou le chevalier de la charrette

[PDF] chapitre 2 les mutations des sociétés depuis 1850

[PDF] séquence 6ème récits de création

[PDF] mon amie se mutile comment l'aider

[PDF] comment aider quelqu'un qui se mutile

[PDF] comment arreter quelqu'un de se mutiler

[PDF] texte de science fiction court

[PDF] comment arreter de se mutiler

[PDF] vocabulaire science fiction cycle 3

[PDF] récit de science fiction cm1

[PDF] automutilation

[PDF] scarification chez adulte

Lecture 4: Mutant Characterization I

Mutation types (and molecular nature)

Complementation tests

Read: 285-293

Fig. 8.28, 8.29, 8.30, 8.31

Homework#1 will be posted today!

Terminologies: Minimal medium, complete medium

Auxotroph vs. prototroph

Hot spot, trinucleotide repeats

ORF

Silent, nonsense, missense, neutral mutations

null, hypomorph, hypermorph, neomorph, antimorph recessive, dominant, dominant-negative, haploid-insufficient •Mutations in a gene's coding sequence can alter the gene product. -Missense mutations replace one amino acid with another. -Nonsense mutations change an amino-acid-specifying codon to a stop codon. -Frameshift mutations result from the insertion or deletion of nucleotides within the coding sequence. -Silent mutations do not alter amino acid specified.

Fig. 8.28

•Mutations outside of the coding sequence can also alter gene expression. -Promoter sequences -Termination signals -Splice-acceptor and splice-donor sites -Ribosome binding sites

Fig. 8.28 b

Terminology about different mutations

a)Loss-of-function:

Null mutation: complete absence of activity

Hypomorph: reduced activity

b) gain-of-function

Hypermorph: increased activity

Neomorph: new function of gene

c) suppressors- compensate for other mutations d) enhancer- enhances phenotype of a mutation

Fig. 8.29

1: null mutation; 2: hypomorphic mutation

Both 1 and 2 are recessive

The underlying nature of recessive or dominant mutations

Recessive

hypomorph: reduced level or a protein with a weak function

Null: complete loss of function

Dominant

hypermorph: increased level or more effective activity neomorphic: new function dominant-negative: poisonous effect haploid-insufficient

Ectopic expression

Semi-dominant (incomplete dominant)

Fig. 8.30

r 0 : null; r 50
: hypomorph; R : wild type

Incomplete dominance

Rarely, loss-of-function mutations are dominant.

•Haploinsufficiency - one wild-type allele does not provide enough of a gene product Heterozygotes for the null mutation of the T locus in mice have short tails because the have an insufficient amount of protein to produce a wild-type tail.

Fig. 8.31 a

•Dominant-negative mutations - alleles of a gene encoding subunits of multimers that block the activity of subunits produced by normal alleles

Rarely, loss-of-function mutations are dominant.

Fig. 8.31 b

Kinky: A dominant-negative mutation in mice

causing a kink in the tail

Fig. 8.31 c

Threshold

For gain of

function

3/33/wt

3: hypermorphic mutation

3 is dominant

Gain-of-function mutations are almost always dominant. •Rare mutations that enhance a protein function or even confer a new activity on a protein Antennapedia is a neomorphic mutation causing ectopic expression of a leg-determining gene in structures that normally produce antennae.

Fig. 8.31 d

1/4 c

1 /c 1

2/4 c

1

1/4 + /+

Recessive

colorless red red dominant colorless colorless red Determine recessive or dominant nature of the mutation c 1 c 1 (Colorless mutant) X +/+ (Red: WT) c 1 (red: recessive) (colorless: dominant) X (self)

Complementation tests

"Complementation group" equals "Gene"

If two mutations failed to complement,

they are alleles of the same gene they are allelic to each other they belong to the same complementation group

If two mutations complements each other,

they are alleles of different genes they are not allelic to each other they belong to different complementation groups

Determine allelism by complementation tests

male c 1 c 1 c 2 c 2 c 3 c 3 c 4 c 4 c 5 c 5 c 6 c 6 female c 1 c 1 c 2 c 2 c 3 c 3 c 4 c 4 c 5 c 5 c 6 c 6 Colorless red red colorless red red colorless colorless red red red colorless red red red colorless red red colorless colorless colorless

Maize kernel mutants:

c 1 -c 6 : colorless, recessive wt:red

Three complementation groups:

1. c 1 , c 4 2. c 2 , c 3 3. c 5 , c 6 Pairwise crosses between homozygotes and examine F1 for phenotype only applicable for recessive mutationsquotesdbs_dbs8.pdfusesText_14