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Make a Life to Save a Life

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Presentation on theme: "Make a Life to Save a Life"— Presentation transcript:

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

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…

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

4 Learning Objectives Recognize how the number and type of chromosomes differ in a gamete compared to a somatic (body) cell. Describe how chromosomes are separated in meiosis and how this differs from mitosis. 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.

5 Matches for Organ Donation
HLA proteins encoded by several genes on chromosome 6. Many variants of gene = mutations that create differences (alleles) HLA Class I Gene A B C E F G Alleles 697 1,109 381 9 21 36 HLA Class II 1,012 6

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

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

8 Review: Mitosis Asexual reproduction. Occurs in somatic (body cells)
Sister chromatids A1 A2 B35 B44 Review: Mitosis S phase Sister chromatids 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. A1 A1 B35 B35 A2 A2 B44 B44 mitosis A1 A2 A1 A2 B35 B44 B35 B44

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. 2n (46) 2n (46) + A1 A2 A3 A26 B35 B44 B41 B35 4n = 92 too many

10 Sexual Reproduction Meiosis = specialized cell division so you have only one of each chromosome, called Gametes: (n) made only in gonad (testis, ovary) A2 n (23) n (23) + A26 B35 B44 A2 A26 2n = 46 B44 B35

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

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

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

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

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

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.

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

18 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? 100% B5-A26 50% B35-A3 & 50% B41-A26 50% B35-B41 & 50% A3-A26 100% B44-A2 B35-A26 50% B35-A26, & 50% B41-A3 A3 A26 B41 B35 Mr. Nash’s chromosome 6s

19 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? B35, B35, A1, A2 B35, B44, A2, A3 B44, B35, A2, A26 B41, B44, A26, A2 B35 A1 B44 A2 A3 A26 B41 B35 Mrs. Nash Mr. Nash

20 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? B35 A1 B44 A2 Yes No A3 A26 B41 B35 Mrs. Nash Mr. Nash

21 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? No chance 25% 50% 75% 100% Chromosome 6s for Molly Nash A2 A26 B44 B35

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?

23 Fanconi Anemia: Chromosome 9
Normal FANCC Mother Normal FANCC Father meiosis Normal FANCC Molly FANCC

24 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)? 0% 25% 50% 75% 100%

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

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.

27 Pre-Implantation Genetic Screening
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?

28 Select a Baby: HLA Match, Normal
FANCC B35 B44 A1 A2 Normal FANCC B41 A3 B35 A26 Mother Father A2 A26 B44 B35 FANCC Molly

29 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? Normal FANCC B35 B44 A1 A2 No chance 25% 50% 75% 100%

30 Alignment at Metaphase I Random:
Normal FANCC B35 B44 A1 A2 Normal FANCC B35 B44 A1 A2 Meiosis I Meiosis II Meiosis I Meiosis II B35 A1 B44 A2 A1 B35 A2 B44

31 CQ#8: If the same percentage of Mr
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? 1/2 1/4 3/16 1/8 1/16 Normal FANCC B35 B44 A1 A2 Normal FANCC B41 A3 B35 A26 Father

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

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 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: Clearance: ©czardases, licensed royalty free. Slide 2 Description: Cluttering of red blood cells. Author: Bram Janssens Source: Dreamstime, ID: 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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