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Make a Life to Save a Life. by Peggy Brickman University of Georgia. 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…. The Case. Matching Organs: HLA.

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make a life to save a life

Make a Life to Save a Life

by

Peggy Brickman

University of Georgia

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…The Case
matching organs hla
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

matches for organ donation
Matches for Organ Donation
  • HLA proteins encoded by several genes on chromosome 6.
          • Many variants of gene = mutations that create differences (alleles)

6

hla proteins present foreign antigens
foreign cell

Macrophage

Lysosome digests proteins

HLA Proteins Present Foreign Antigens

Peptides displayed by HLA proteins

slide6
HLA: Inherited from Parents

Mrs. Nash is

diploid = two

homologues

of chromosome 6

HLA-A1

HLA-A2

HLA-B35

HLA-B44

why do diploid organisms need to have specialized sex cells
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

sexual reproduction
A2Sexual Reproduction
  • Meiosis = specialized cell division so you have only one of each chromosome, called
  • Gametes: (n) made only in gonad (testis, ovary)

n (23)

n (23)

+

A26

B35

B44

A2

A26

2n = 46

B44

B35

slide9
A1

A2

B35

B44

Question 1:

When Mrs. Nash produces eggs, they would have which combinations of the HLA-A and HLA-B genes and in what proportions? Explain your answer.

100% B35-A1

50% B35-B44 & 50% A1-A2

50% B35-A1 & 50% B44-A2

100% B44-A2

50% B35-A2, & 50% B44-A1

Mrs. Nash’s chromosome 6s

chromosome pairing synapsis
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

slide11
Sister chromatids

Sister chromatids

A1

A2

B35

B44

meiosis I

mitosis

A1

A2

A1

A2

B35

B44

B35

B44

Mitosis

Meiosis I

A1

A1

B35

B35

Homologues Pair

A2

A2

B44

B44

A1

A2

A2

A1

A1

A2

A1

A2

B44

B44

B35

B44

B35

B44

B35

B35

update meiosis i completed
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.
meiosis ii sister chromatids separate
meiosis II

meiosis II

Meiosis II: Sister chromatids separate

End result: Four haploid cells total

A1

A2

A2

A1

B44

B44

B35

B35

A1

A1

A2

A2

B35

B35

B44

B44

slide14
Question 2:

When Mr. Nash produces sperm, the sperm would have which combinations of the HLA-A and HLA-B genes and in what proportions? Explain your answer.

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

slide15
A1

A2

B35

B44

Question 3:

Which of the following shows one combination of HLA-A and HLA-B genes expected in an offspring of Lisa and Jack Nash? Explain your answer.

B35, B35, A1, A2

B35, B44, A2, A3

B44, B35, A2, A26

B41, B44, A26, A2

A3

A26

B41

B35

Mrs. Nash

Mr. Nash

slide16
A1

A2

B35

B44

Questions 4:

Is it possible for any child born to this couple to be identical in both HLA-A and HLA-B with either parent?

  • Yes
  • No

A3

A26

B41

B35

Mrs. Nash

Mr. Nash

slide17
Question 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? Explain using a Punnett square.

No chance

25%

50%

75%

100%

Chromosome 6s for Molly Nash

A2

A26

B44

B35

slide18
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.
slide19
Question 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)? Use a Punnett Square to explain your answer.

0%

25%

50%

75%

100%

pre implantation genetic screening
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.
slide21
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.

Question 7:

Describe/Explain two ethical objections someone might have to allowing the Nashes to use this technique.

Question 8:

Describe/Explain two reasons why you think the Nashes should be allowed to use this technique.

Question 9:

What kind of regulations if any should be used for parents hiring doctors to do this procedure? When do YOU think it is OK to carry out this procedure?

Pre-Implantation Genetic Screening

select a baby hla match normal
A3

A26

B41

B35

FANCC

Normal

A1

A2

B35

B44

FANCC

Normal

FANCC

FANCC

Select a Baby: HLA Match, Normal

Mother

Father

A2

A26

B44

B35

Molly

slide23
A1

A2

B35

B44

FANCC

Normal

Question 10:

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?

No chance

25%

50%

75%

100%

slide24
A3

A26

B41

B35

FANCC

Normal

A1

A2

B35

B44

FANCC

Normal

Question 9:

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? Explain your answer.

1/2

1/4

1/8

1/16

1/32

Father

slide25
A2

A2

A2

A2

A2

A2

A2

A2

A1

A1

A1

A1

A1

A1

A1

A1

A3

A3

A3

A3

A3

A3

A3

A3

A26

A26

A26

A26

A26

A26

A26

A26

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

B41

B41

B41

B41

B41

B41

B41

B41

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B35

B44

B44

B44

B44

B44

B44

B44

B44

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

A26

A26

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

FANCC

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

B35

B35

A3

A3

B41

B41

A2

A1

A2

A1

B44

B35

B44

B35

update on the nashes
Update on the Nashes

After four in vitro fertilization attempts, Lisa Nash gave birth to a baby boy, Adam, on August 29, 2000. 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 visitsthe doctors 35-40times a year to screen for solid-tumor cancers. A common cold could have dire consequences for her, but her bone marrow is functioning normally.

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