1 Mutation and polymorphism mutation change in the nucleotide sequence or arrangement in DNA genomic mutation change in chromosome number chromosome mutations change in chromosome structure gene mutations change in an individual gene 2 Mutation and polymorphism mutation change in the nucleotide sequence or arrangement in DNA genomic mutation change in chromosome number chromosome mutations change in chromosome structure gene mutations change in an individual gene mutation may occur in a somatic cell or in a germ cell germ cells give rise to egg and sperm 3 genomic mutation change in chromosome number error in separation in mitosis or meiosis non-disjunction results in aneuploidy occurs in 1 in 25-50 meiotic cell divisions a change in chromosome number may have serious consequences spontaneous abortions in many (most) cases monosomy and trisomy Turners syndrome - 45 X Kleinfelters syndrome 47 XXY 4 chromosome mutation change in chromosome structure part of chromosome is duplicated deleted inverted translocated (moved to another spot on the same chromosome or another chromosome) occurs in 1 in 1700 cell divisions rarely transmitted to the next generation may cause transformation of cell to a cancer cell 5 gene mutation change in nucleotide sequence in a gene may involve a single base pair to thousands of base pairs due to an error in replication or failure of repair mechanism (most often replication errors failure of proof-reading) occurs in 1 in 10 million base pairs during replication often invisible may be spontaneous or may be induced spontaneous are generally replication errors induced are due to exposure to mutagen
6 gene mutation change in nucleotide sequence in a gene DNA change loss of a base or change in base structure may be spontaneous may be caused by mutagens x-rays gamma rays or UV irradiation causes loss of a base or changes base structure these changes are not as readily repaired as replication errors 7 molecular basis of mutation point mutations involve one to a few base pairs point mutations generate alleles different expressions of a single gene 2 alleles at a given locus polymorphism locus is polymorphic e.g. ABO blood groups individual with two identical alleles homozygous individual with two different alleles heterozygous alleles present constitute the genetic makeup of individual genotype genetic composition at a locus phenotype appearance of the individual genotype not always evident from phenotype 8 molecular basis of mutation point mutations involve one to a few base pairs base pair substitutions (nucleotide substitutions) transiti ons purine replaces purine A-T G-C transversions purine replaces pyrimidine A-T C-G or T-A 9 molecular basis of mutation transitions more frequent hot-spots in DNA cytosine is methylated esp. at C on 5 side of a G 5----CG-----3 deamination of methylated cytosine occurs C converted to T 5---CG---3 5---TG---3 3---GC---5 3---GC---5 DNA replication or repair 5---CG---3 5---TG---3 3---GC---5 3---AC---5 10 effect of base pair substitutions (nucleotide substitutions) missense mutations change the codon different amino acid inserted generate an incorrect stop codon affect transcription reduce amount of mRNA (alter RNA polymerase binding site) affect mRNA processing abolish splicing site provide alternate splicing site 11 insertions and deletions may involve a small to a large portion of a gene or entire gene often detectable with molecular techniques Southern blot or PCR 12 Southern blot DNA cut with restriction enzymes bacterial enzymes which cut DNA at specific sequences sequences usually 6 base pairs long palindromes 13 Southern blot 14 Southern blot ASO allele-specific oligonucleotide 15 PCR polymerase chain reaction generate large amounts of DNA of interest test with allele-specific probes 16 insertions and deletions may involve a small to a large portion of a gene or entire gene small deletions or insertions affect only a small number of base pairs frameshift mutations one to two base pairs changes the codons from the mutation point onward ----ACG GCAUUUCGCACG--- ----ACGGCAUUUCCGCACG--- ----ACGC AUUUCGCACG----- 17 insertions and deletions large deletions more common than insertions insertions may be due to L1 family of repetitive DNA L1 copied into RNA RNA copied into free DNA free DNA inserts anywhere in genome some cases of hemophilia A have an L1 region inserted inactivating the gene 18 insertions and deletions large deletions caused by recombination errors errors in crossing over in meiosis I chromosomes pair very tight pairing brings homologous regions together breakage and exchange may occur between homologs crossing over 19 insertions and deletions repeated sequences may align followed by crossing over inversion 20 crossing over breakage exchange generally reciprocal 21 crossing over breakage exchange unequal crossing over leads to deletion on one chromosome leads to duplication on the other 22 duplications newly discovered mutations Huntington disease fragile X syndrome trinucleotide repeat in the coding region of a gene or in a transcribed but not translated region trinucleotide expands and interferes with gene expression - generates an abnormal protein - alters mRNA transcription or processing ---ABCABCABCDEFGHIJ--- (3 ABC) ---ABCABCABCABCABCDEFGHIJ--- (5ABC) 23 Genetic diversity many changes dont affect gene function - dont alter protein structure or activity - are in non-coding regions of the genome result is genetic diversity generates genetic polymorphism 24 Genetic polymorphism within every 1000 base pairs there is about 1 difference between any 2 individuals alleles different version of a DNA sequence in a gene locus when alleles are common (more than 1 of the chromosomes in the population) the alleles constitute a genetic polymorphism (if less than 1 - rare variants) 25 Genetic polymorphism ABO blood typing system and Rh factor RBC have a surface antigen with two variants A B phenotypes O A B AB gene on chromosome 9 3 alleles A B O A B are codominant O is recessive product of A adds N-acetylgalactosamine to H protein product of B adds galactose to H protein no product from O no modification of H protein genes A B 4 base pair difference amino acid differences change enzyme gene O 1 base pair difference a deletion frameshift mutation 26 Genetic polymorphism Rh factor - plays a role in hemolytic disease in neonates and transfusions phenotypes Rh and Rh- gene on chromosome 1 Rh have polypeptide on RBC Rh- dont have the polypeptide hemolytic disease in neonates Rh- mother forms antibodies to Rh factor during pregnancy 27 Genetic polymorphism serum protein polymorphism a1-antitrypsin enzyme elastase from leukocytes breaks down elastin a1-antitrypsin blocks elastase activity deficiency early onset emphysema gene for a1-antitrypsin on chromosome 14 several rare alleles each a different version of the protein Z allele medically significant several common alleles M1 M2 and M3 28 genetic diversity changes in nucleotide sequence in non-coding areas are not visible in protein changes in nucleotide sequence may alter cleavage sites of restriction enzymes changes sizes of DNA fragments everyone has different distribution of cleavage sites for restriction enzymes gives variation in Southern blots 29 Restriction Fragment Length Polymorphism RFLP 30 Restriction Fragment Length Polymorphism RFLP 31 RFLP based on change in restriction cleavage site based on insertion/deletion between cleavage sites variable amount of DNA one class due to insertion of tandem repeat of a 10-100 bp sequence minisatellite class known as Variable Nucleotide Tandem Repeat VNTR 32 VNTRVariable Nucleotide Tandem Repeat DNA fingerprinting three sets of twins two identical one fraternal 33 microsatellite markers
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