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Make a Life to Save a Life by Peggy Brickman University of Georgia 1.

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Presentation on theme: "Make a Life to Save a Life by Peggy Brickman University of Georgia 1."— Presentation transcript:

1 Make a Life to Save a Life by Peggy Brickman University of Georgia 1

2 The Case Jack and Lisa Nash’s daughter Molly was born with a rare, incurable genetic condition called Fanconi anemia, which rendered her body unable to produce enough blood cells… 2

3 Matching Organs: HLA Finding a correct match for tissue transplantation depends on matching a specific group of proteins found on the surface of white blood cells that are used to distinguish one’s own cells from foreign cells, called HLA, for human leukocyte antigen. 3 3

4 Learning Objectives 1.Recognize how the number and type of chromosomes differ in a gamete compared to a somatic (body) cell. 2.Describe how chromosomes are separated in meiosis and how this differs from mitosis. 3.Apply the knowledge of how chromosomes separate during meiosis and the rules of probability to predict the likelihood that offspring from two parents would inherit a specific combination of chromosomes and the genes they contain. 4

5 Matches for Organ Donation HLA proteins encoded by several genes on chromosome 6. » Many variants of gene = mutations that create differences (alleles) 5 6 HLA Class I GeneABCEFG Alleles6971, HLA Class II Alleles1,012

6 HLA Proteins Present Foreign Antigens 6 foreign cell Macrophage Peptides displayed by HLA proteins Lysosome digests proteins

7 7 HLA: Inherited from Parents HLA-B35 HLA-A1 Mrs. Nash is diploid = two homologues of chromosome 6 HLA-B44 HLA-A2

8 Review: Mitosis Asexual reproduction. Occurs in somatic (body cells) for growth and division. Creates genetically identical cells. Not a way to combine traits together in reproduction. Need new method: sexual reproduction. 8 S phase mitosis B35 A1 B44 A2 Sister chromatids B35 A1 B44 A2 B35 A1 B44 A2 Sister chromatids B35 A1 B44 A2 B44 A2 B35 A1

9 Why do diploid organisms need to have specialized sex cells? Sex cells (gametes) allow traits to be combined from two organisms. Can’t just fuse any two random cells. 9 2n (46) + 4n = 92 too many B35 A1 B44 A2 B41 A3 B35 A26

10 Sexual Reproduction Meiosis = specialized cell division so you have only one of each chromosome, called Gametes: (n) made only in gonad (testis, ovary) n = 46 n (23) B44 A2 B35 A26 B35 A26 A2 B44

11 11 Mitosis versus Meiosis Meiosis has 2 divisions: Meiosis I and Meiosis II MITOSISMEIOSIS Diploid somatic cell gamete precursor duplication Diploid Haploid division

12 12 A.100% B35-A1 B.50% B35-B44 & 50% A1-A2 C.50% B35-A1 & 50% B44-A2 D.100% B44-A2 E.50% B35-A2, & 50% B44-A1 Mrs. Nash’s chromosome 6s CQ#1: When Mrs. Nash produces eggs, they would have which combinations of the HLA-A and HLA-B genes and in what proportions? B35 A1 B44 A2

13 13 Mitosis Meiosis I Homologues Pair Prophase & Metaphase Differ B35 A1 B44 A2 B35 A1 B44 A2 Sister chromatids B35 A1 B44 A2 B44 A2 B35 A1 B35 A1 B44 A2

14 Chromosome Pairing: Synapsis Close proximity favors crossing over Allows exchange of traits 14 Exchange of parts of non-sister chromatids Duplicated Maternal chromosome Duplicated Paternal chromosome sister chromatids non-sister chromatids tetrad

15 15 Mitosis Meiosis I Homologues Pair B35 A1 B44 A2 Sister chromatids B35 A1 B44 A2 Sister chromatids meiosis Imitosis B35 A1 B44 A2 B35 A1 B44 A2 B35 A1 B35 A1 B44 A2 B44 A2 B35 A1 B44 A2 B44 A2 B35 A1 B35 A1 B44 A2

16 Update: Meiosis I completed Homologous chromosomes are separated into two different cells. Each new cell has only one of each different chromosome (n, haploid). Still need to separate the sister chromatids so that the total amount of chromosomes and DNA is truly half of a normal cell. 16

17 Meiosis II: Sister chromatids separate End result: Four haploid cells total 17 meiosis II B35 A1 B44 A2 B35 A1 B44 A2 B35 A1 B35 A1 B44 A2 B44 A2

18 18 A.100% B5-A26 B.50% B35-A3 & 50% B41-A26 C.50% B35-B41 & 50% A3-A26 D.100% B44-A2 B35-A26 E.50% B35-A26, & 50% B41-A3 Mr. Nash’s chromosome 6s CQ#2: When Mr. Nash produces sperm, the sperm would have which combinations of the HLA-A and HLA-B genes and in what proportions? B41 A3 B35 A26

19 19 A.B35, B35, A1, A2 B.B35, B44, A2, A3 C.B44, B35, A2, A26 D.B41, B44, A26, A2 Mrs. NashMr. Nash CQ#3: Which of the following shows one combination of HLA-A and HLA-B genes expected in an offspring of Lisa and Jack Nash? B41 A3 B35 A26 B35 A1 B44 A2

20 20 A. Yes B. No Mrs. NashMr. Nash CQ#4: Is it possible for any child born to this couple to be identical in both HLA-A and HLA-B with either parent? B41 A3 B35 A26 B35 A1 B44 A2

21 21 A.No chance B.25% C.50% D.75% E.100% Chromosome 6s for Molly Nash CQ#5: Using the proportion of each type of sperm and egg that you calculated in questions I and II, what is the likelihood that Molly’s sibling would inherit the same combination of HLA genes and thus be a good organ donor for Molly? B35 A26 B44 A2

22 Clearly Molly’s best chance of finding a bone marrow match was with a sibling. Unfortunately, Molly was an only child. The Nashes had always wanted to have more children, but because Fanconi anemia is an inherited condition, they knew that if they had another child that child had a chance of getting the disease just as Molly had. But neither Jack nor Lisa had the disease because the mutation is recessive. In order to have Fanconi anemia like Molly, both copies of the FANCC gene would have to have this recessive mutation, and they only had one. How is that possible? 22

23 Fanconi Anemia: Chromosome 9 23 NormalFANCC Mother NormalFANCC Father meiosis NormalFANCCNormalFANCC Molly FANCC

24 24 A.0% B.25% C.50% D.75% E.100% CQ#6: Using what you know about how meiosis created eggs and sperm, what is the likelihood that Lisa and Jack Nash could conceive a sibling for Molly that would NOT have Fanconi anemia (presence of at least one normal)?

25 Punnett Squares: Show All Possible Combinations of Gametes 25 NormalFANCC Mother NormalFANCC Father NormalFANCC meiosis Normal FANCC meiosis FANCCnormal FANCC normal

26 Pre-Implantation Genetic Screening When they discovered that they could conceive a baby that was free from Fanconi Anemia, Jack and Lisa Nash underwent in-vitro fertilization followed by a procedure called pre-implantation genetic screening to choose an embryo that would have HLA proteins (B44, B35, A2, A26) that matched Molly, and to choose an embryo that would also be free of Fanconi anemia. 26

27 27 Ethics: This is the first example of the use of pre- implantation genetic screening to select for a baby solely as a treatment for its sibling. List two ethical objections someone might have to allowing the Nashes to use this technique. List two reasons why you think the Nashes should be allowed to use this technique. What kind of regulations if any should be used for parents hiring doctors to do this procedure? When is it OK, when not? Pre-Implantation Genetic Screening

28 Select a Baby: HLA Match, Normal 28 FatherMother Molly B44 A2 FANCC B35 A26 NormalFANCC B35B44 A1A2 NormalFANCC B41 A3 B35 A26

29 29 A.No chance B.25% C.50% D.75% E.100% NormalFANCC B35B44 A1A2 CQ#7: Using your knowledge of how chromosomes segregate during meiosis, what percent of Mrs. Nash’s eggs would carry a normal chromosome 9 and a chromosome 6 with the A-2, B-44 alleles?

30 Alignment at Metaphase I Random: 30 Meiosis I Meiosis II Meiosis I Meiosis II NormalFANCC B35B44 A1A2 NormalFANCC B35B44 A1A2 B35 A1 B44 A2 B44 A2 B35 A1 B35 A1 B35 A2 B44 A2 B44

31 31 A.1/2 B.1/4 C.3/16 D.1/8 E.1/16 Father NormalFANCC B41 A3 B35 A26 CQ#8: If the same percentage of Mr. Nash’s sperm carry the correct chromosome 9 (normal) and 6 (A26, B35), what is the probability that a single embryo would be a perfect HLA match for Molly and not develop Fanconi anemia? NormalFANCC B35B44 A1A2

32 32 B35 A1 B44 A2 A1 B35 A2 B44 B41 A3 B35 A26 B35 A26 B41 A3B35 A26 B41 A3 B41 A3 B41 A3 B41 A3 B41 A3 B41 A3 B41 A3 B41 A3 NormalFANCCNormalFANCCNormalFANCCNormalFANCCNormalFANCCNormalFANCCNormalFANCCNormalFANCC B35 A26 B35 A26 B35 A26 B35 A26 B35 A26 B35 A26 B35 A26 Normal FANCC Normal A2 B44 A2 B44 A2 B44 A2 B44 A2 B44 A2 B44 A2 B44 A2 B44 A1 B35 A1 B35 A1 B35 A1 B35 A1 B35 A1 B35 A1 B35 A1 B35

33 Update on the Nashes After four in vitro fertilization attempts, Lisa Nash gave birth to a baby boy, Adam, on August 29, Adam’s placenta was gathered immediately and all the cord blood saved. Molly started chemotherapy to destroy her bone marrow and received a transfusion of the cord blood cells a month later. Today Molly, Adam, and new little sister Delaine are all doing well. The transplant cured Molly’s bone marrow failure, but she still suffers from Fanconi 33 anemia and visits the doctors times a year to screen for solid- tumor cancers. A common cold could have dire consequences for her, but her bone marrow is functioning normally.

34 Slide Credits Slide 1 and Slide 33 Description: Illustration of embryo in flask. Author: czardases Source: Fotolia, ID: http://www.fotolia.com Clearance: ©czardases, licensed royalty free. Slide 2 Description: Cluttering of red blood cells. Author: Bram Janssens Source: Dreamstime, ID: http://www.dreamstime.com Clearance: ©Bram Janssens, licensed royalty free. Slide 3 Description: Illustration of MHC class I and class II. Author: David S. Goodsell and the RCSB PDB Source: Major Histocompatibility Complex, Molecule of the Month, February 2005, Clearance: Molecule of the Month illustrations are copyrighted but available for educational purposes, provided attribution is given to David S. Goodsell and the RCSB PDB.

35 Slide 5 —Bottom left Description: Drawing depicting HLA genes on chromosome 6. Author: Philip Deitiker Source: Wikimedia Commons, Clearance: Released into the public domain by the author. Slide 9 and Slide 10 Description: Figure of male and female. Author: Derived from a public domain NASA image. Source: WikiMedia, Clearance: Public domain. All remaining images appearing in this presentation were created by the author of this case study, Peggy Brickman.


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