BIOL10221 Molecular Biology Module 9 - Lecture 2 - Effects of Mutations II PDF

BIOL10221 Molecular Biology Module 9 - Lecture 2: Effects of mutations II Ray O’Keefe [email protected] What will we cover? Effects of mutations on organisms Genotype vs phenotype. Mutations in diploid organisms. Haploinsufficiency, large deletions, chromoso...

BIOL10221 Molecular Biology Module 9 - Lecture 2: Effects of mutations II Ray O’Keefe [email protected] What will we cover? Effects of mutations on organisms Genotype vs phenotype. Mutations in diploid organisms. Haploinsufficiency, large deletions, chromosome number defects and chromosome translocations Why is it important? Mutations are important during evolution and for diversity of organisms However, some mutations may cause disease BIOL10221 Module 9 - Lecture 2 2 Monogenic Disorders Inherited diseases caused by defects in individual genes How many known Monogenic Disorders? About 6000 known – 10,000 estimated in total One of the most common Monogenic Disorders in UK? Cystic Fibrosis BIOL10221 Module 9 - Lecture 3 2 How does a mutation affect the phenotype of an organism? phenotype = biological characteristics BIOL10221 Module 9 - Lecture 4 2 Most organisms are diploid two copies of each chromosome two copies of each gene pea chromosomes 14 chromosomes = 2 sets of seven BIOL10221 Module 9 - Lecture 5 2 Most organisms are diploid a mutation in one gene may, or may not, affect the phenotype the alternate forms of the gene are called alleles SBE1 enzyme is present No SBE1 enzyme SBE1 enzyme is present BIOL10221 Module 9 - Lecture 6 2  Humans are diploid some people carry mutant alleles that do not affect them consider the CFTR gene on human chromosome 7 Two normal CFTR genes Healthy Two mutant CFTR alleles Disease (Cystic Fibrosis) One normal CFTR allele One mutant CFTR allele Healthy heterozygote or ‘carrier’ The normal chromosome directs synthesis of enough CFTR protein for the person to remain healthy BIOL10221 Module 9 - Lecture 7 2 With some human genes, both copies must be functional a mutation in just one will cause disease this is called haploinsufficiency BIOL10221 Module 9 - Lecture 8 2 Mandibulofacial Dysostosis Guion Almeida type (MFDGA) Craniofacial disorder caused by haploinsufficiency of RNA splicing factor EFTUD2 Part of U5 snRNP – defective RNA splicing of pre-mRNAs require for development BIOL10221 Module 9 - Lecture 9 2 With some human genes, being a carrier gives a predisposition to disease retinoblastoma, cancer of the retina, is an example sporadic retinoblastoma is rare and occurs throughout the population familial retinoblastoma is more common in affected families RB is a Tumour suppressor gene BIOL10221 Module 9 - Lecture 10 3 Some diseases result from large deletion mutations example is deletion of about 500 kb from the X chromosome BIOL10221 Module 9 - Lecture 11 2 Unusual numbers of chromosomes might also lead to disease trisomy – three copies of a chromosome Down syndrome caused by three copies of chromosome 21 BIOL10221 Module 9 - Lecture 12 2 Monosomy is where one chromosome is missing monosomy 7 - one copy of chromosome 7 is missing leads to bone marrow failure, high risk of leukemia BIOL10221 Module 9 - Lecture 13 2 A chromosome translocation occurs when part of one chromosome becomes attached to another chromosome some types of translocation are relatively common an example is the exchange of segments between chromosomes 9 and 22 BCR – Breakpoint Cluster Region BIOL10221 Module 9 - Lecture 14 2 The Philadelphia chromosome is a common cause of leukemia Normal abl gene Codes for the abl protein Second messengers Stimulates cell division in controlled by the external response to signals from signals interact with this part outside the cell of the DNA They switch on the abl gene when the abl protein is needed BIOL10221 Module 9 - Lecture 15 2 The Philadelphia chromosome is a common cause of leukemia bcr-abl gene X Gene is switched on all the Control region has been lost time Second messengers have no Cell division is uncontrolled effect BIOL10221 Module 9 - Lecture 16 2  Not all human mutations are bad!! There are many interesting examples where gene mutations can be advantageous for humans BIOL10221 Module 9 - Lecture 17 2 Apolipoprotein A-I (apoAI) “Milano” variant R173C missense mutation identified in a family originating from the village of Limone sul Garda in northern Italy Low prevalence of cardiovascular disease in carriers of this mutation Infusion of apoAI-M reduces atherosclerotic lesions in animal models Clinical trials demonstrated atheroma reduction after apoAI-M given to patients with coronary disease BIOL10221 Module 9 - Lecture 18 2 LDL-Receptor–Related Protein 5 mutation G171V missense mutation in LRP5 identified in twenty members of a kindred of white ancestry from Connecticut High bone density and less broken bones in carriers of this mutation LRP5 regulates Wnt signalling which is an essential pathway for bone development BIOL10221 Module 9 - Lecture 19 2  Red hair and pain sensitivity Anecdotally individuals with red hair often required more anaesthesia than other patients, which has been confirmed for inhalational anaesthesia Loss of melanocortin 1 receptor (MC1R) function results in pigment disruption giving the red hair and fair skin phenotype Relationship between MC1R and opioid signalling that leads to increased pain sensitivity in some people with red hair BIOL10221 Module 9 - Lecture 20 2  Natural Short Sleep Human natural short sleepers are individuals with lifelong short sleep and no obvious adverse outcomes associated with the lack of sleep Missense mutation in DEC2 (DEC2-P384R) associated with Natural Short Sleep Mutant DEC2 causes increased expression of the wake-promoting peptide Orexin BIOL10221 Module 9 - Lecture 21 2 Resources Reading BROWN, Chapter 3 pages 38–39, Chapter 20 pages 413- 415, 420–422, parts of 423–429 ALBERTS (6th ed) pages 308-312 Blackboard PDF files with Objectives, Terms, Questions and Answers Further Study Module Mutations and Human Disease BIOL10221 Module 9 - Lecture 22 2  BIOL10221 Molecular Biology Module 9 - Lecture 2: Effects of mutations II Ray O’Keefe [email protected]