1 Fall 2006 7 03 Looking back 7 03 Lecture 10 Chromosomal Abnormalities Deletions Recently we have been talking about homologous recombination and how it creates new phenotypic classes of offspring that differ from their parents Recombination can also create large chromosomal abnormalities that can affect phenotype drastically Duplications Inversions Translocations A review of chromosome structure a chromosome from mom the homologous chromosome from dad a A b B c C d D The centromere dictates chromosome segregation during mitosis and meiosis Non coding DNA is incredibly common in genomes Less than 5 of the DNA in the human genome codes for proteins This non coding DNA often consists of small repeated sequences For instance 5 of the human genome is a repeat of 280 bp the Alu repeat and there are 750 000 copies of it in the human genome many copies on each chromosome a gene encodes RNA and or protein non coding DNA does NOT encode RNAs or protein 1 2 Fall 2006 7 03 Recombination between repeated DNA regions is rare but it can generate deletions duplications inversions and translocations Deletions Duplications Inversions Translocations A Deletion is loss of a segment of DNA Deletions are complete loss of function a repeat such as Alu a A b B c C d D Deletions most often cause recessive phenotypes Recombination between these two repeats creates A NO GENE B The exception to this rule are genes for which 1 2 the RNA or protein is NOT SUFFICIENT to perform the gene s function this is called HAPLOINSUFFICIENCY C D 2 3 Fall 2006 7 03 An example of a human disease caused by a deletion Cri du Chat Syndrome Caused by a heterozygous deletion of part of chromosome 5 Deletions Duplications Symptoms mental retardation small head facial abnormalities infant s cry sounds like the meowing of a cat Inversions Translocations A Duplication is when a segment of DNA chromosome is repeated twice a repeat such as Alu a b c Duplications can have a phenotype a A B C Recombination between these two repeats creates b A B If a duplication causes a phenotype then it is because too much of a specific gene product is detrimental to the organism Thus the phenotype will be dominant and will be visible in a heterozygote c C d D d D 3 4 Fall 2006 7 03 An example of a human disease caused by a duplication Charcot Marie Tooth syndrome Often caused by the heterozygous duplication of a gene on chrom 17 This duplication increases the amount of the PMP22 myelin protein which coats nerve cells Symptoms Muscle degeneration problems with walking and grasping tingling sensations sensory loss loss of reflexes Deletions Duplications Inversions Translocations Incidence 1 2 500 1 10 000 Is the most common form of neuropathy An Inversion Reverses the Order of Genes Heterozygotes inverted chromosome normal have genetic consequences they suppress recombination b B c C d D A Recombination between these two repeats creates B A C a they produce inviable gametes An inversion produces 1 2 inviable gametes if the inversion does not include the centromere An inversion produces gametes with deletions or duplications if the inversion includes centromere D 4 5 Fall 2006 7 03 Chromosome Pairing in an Inversion heterozygote during meiosis I c b 50 of the time is caused by an inversion on the X chromosome This inversion destroys the function of a gene encoding the blood protein Factor VIII D d A a a d c C b B B C An example of a human disease caused by an inversion Severe Hemophilia A Symptoms Bleeding and bruising D A The same inversion accounts for 50 of all cases of severe hemophilia A which affects a total of 1 10 000 males A Translocation is a segment of one chromosome exchanging places with a segment from a nonhomologous chromosome Deletions Duplications Inversions Translocations e a A b B c C d D e E f F g G Recombination between these two repeats creates A B f C g D 5 6 Fall 2006 7 03 A picture of a translocation heterozygote s chromosomes pairing during meiosis I If chromosomes segregate like this inviable gametes will be produced A A a If chromosomes segregate like this viable progeny will be produced g G f F B b a C c D d B b A a C c D d f F e E g G e E A a If chromosomes segregate like this inviable gametes will be produced g G f F B b C c D d B b C c D d f F e E g G e E 6 7 Fall 2006 7 03 Translocations have genetic consequences In a heterozygote a translocation will Lead to some abnormal zygotes that are inviable In a heterozygote the translocation could cause the formation of deleterious fusion genes OR cause the disruption of a gene because of where the breakpoints that caused the translocation were located An example of a human disease caused by a translocation Chronic Myelogenous Leukemia CML CML is a type of cancer that has been in the news a lot in the last five years because it is treatable by a new drug called Gleevec Caused by a heterozygous translocation between chrom 9 and 22 called the Philadelphia chromosome This translocation causes the fusion of two genes Bcr and Abl Incidence is 1 50 000 1 100 000 Accounts for 7 20 of all leukemias We will talk a lot more about the kinds of mutations that lead to cancer at the end of the semester Looking ahead Chromosome abnormalities can also be caused by non homologous recombination Non homologous recombination is when pieces of broken DNA join with each other even though their ends are not homologous Non homologous recombination can be induced by agents that break DNA such as X rays and chemicals 7
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