1. Genetic Disorders & Sex Linked Traits
Biology

2. Genetics of Sex X Y X XX XY X XX XY
In humans & other mammals, there are 2 sex chromosomes: X & Y
2 X chromosomes
develop as a female: XX
an X & Y chromosome
develop as a male: XY X Y X XX XY X XX XY
50% female : 50% male

3. Genes on sex chromosomes
Y chromosome
few genes other than SRY
sex-determining region
master regulator for maleness
turns on genes for production of male hormones
many effects = pleiotropy!
X chromosome
other genes/traits beyond sex determination
mutations:
hemophilia
Duchenne muscular dystrophy
color-blindness
Duchenne muscular dystrophy affects one in 3,500 males born in the United States.
Affected individuals rarely live past their early 20s.
This disorder is due to the absence of an X-linked gene for a key muscle protein, called dystrophin.
The disease is characterized by a progressive weakening of the muscles and loss of coordination.

4. Human X chromosome Sex-linked usually means “X-linked”
Duchenne muscular dystrophy
Becker muscular dystrophy
Ichthyosis, X-linked
Placental steroid sulfatase deficiency
Kallmann syndrome
Chondrodysplasia punctata,
X-linked recessive
Hypophosphatemia
Aicardi syndrome
Hypomagnesemia, X-linked
Ocular albinism
Retinoschisis
Adrenal hypoplasia
Glycerol kinase deficiency
Incontinentia pigmenti
Wiskott-Aldrich syndrome
Menkes syndrome
Charcot-Marie-Tooth neuropathy
Choroideremia
Cleft palate, X-linked
Spastic paraplegia, X-linked,
uncomplicated
Deafness with stapes fixation
PRPS-related gout
Lowe syndrome
Lesch-Nyhan syndrome
HPRT-related gout
Hunter syndrome
Hemophilia B
Hemophilia A
G6PD deficiency: favism
Drug-sensitive anemia
Chronic hemolytic anemia
Manic-depressive illness, X-linked
Colorblindness, (several forms)
Dyskeratosis congenita
TKCR syndrome
Adrenoleukodystrophy
Adrenomyeloneuropathy
Emery-Dreifuss muscular dystrophy
Diabetes insipidus, renal
Myotubular myopathy, X-linked
Androgen insensitivity
Chronic granulomatous disease
Retinitis pigmentosa-3
Norrie disease
Retinitis pigmentosa-2
Sideroblastic anemia
Aarskog-Scott syndrome
PGK deficiency hemolytic anemia
Anhidrotic ectodermal dysplasia
Agammaglobulinemia
Kennedy disease
Pelizaeus-Merzbacher disease
Alport syndrome
Fabry disease
Albinism-deafness syndrome
Fragile-X syndrome
Immunodeficiency, X-linked,
with hyper IgM
Lymphoproliferative syndrome
Ornithine transcarbamylase
deficiency
Sex-linked
usually means “X-linked”
more than 60 diseases traced to genes on X chromosome

5. Sex-linked Genes
Genes on the X chromosome are called “sex- linked”, because they expressed more often in males than in females
There are very few genes on the Y chromosome.
Since males only have one X chromosome, all genes on it, whether dominant or recessive, are expressed. . So, most people with sex- linked genetic conditions are male.

6. Why can females have 2 copies of the X chromosome, when males only have 1?
Answer:
In each cell one of the X chromosomes ‘turns off’.
This turned off chromosome is known as a Barr body.
The effect of Barr bodies can be seen in Calico colored cats.

7. Female mammals inherit 2 X chromosomes
X-inactivation
Female mammals inherit 2 X chromosomes
one X becomes inactivated during embryonic development
condenses into compact object = Barr body
which X becomes Barr body is random
patchwork trait = “mosaic”
patches of black
XH
XHXh
Xh
tricolor cats can only be female
patches of orange

8. Colorblindness
We have 3 color receptors in the retinas of our eyes. They respond best to red, green, and blue light.
Each receptor is made by a gene. The blue receptor is on an autosome, while the red and green receptors are on the X chromosome (sex-linked).

9. Colorblindness
Most colorblind people are males, who have mutated, inactive versions of either the red or the green (sometimes both) color receptors. Most females with a mutant receptor gene are heterozygous: the normal version of the receptor genes gives them normal color vision.

10. Colorblind Test! You will see circles with many colors of dots
The dot pattern makes up a number
What number do you see?

11. With Color Vision:

12. This one you can even see in black and white

13. Color Blind Test
What number do you see?

14. Color Blind Test
What number do you see?

15. This what you would see if you were color blind
What number do you see?

16. Color Blind Test
What number do you see?

17. Color Blind Test
What number do you see?

18. Color Blind Test
What number do you see?

19. Color Blind Test
What number do you see?

20. 5 With color vision you see this:
But if you were red-green colorblind….
You would see the #: 5

21. What do the colorblind see?
Types of Colorblindness
NORMAL
PROTAN:
Red Blind
DEUTERAN:
Green Blind
TRITAN:
Blue Blind
RED
YELLOW
GREEN
CYAN
BLUE
MAGENTA

24. Types of Colorblindness –
Normal
No color vision
Protanopia: no red
Deuteranopia: no green
Tritanopia: no blue

25. How to write Alleles for X-Linked Traits
Women:
Normal: XBXB
Carrier: XBXb
Colorblind: XbXb
Men:
Normal: XBY
Colorblind: XbY

26. Hemophilia
Hemophilia is a disease in which the blood does not clot when exposed to air. People with hemophilia can easily bleed to death from very minor wounds. Hemophilia is another sex-linked trait.
Hemophilia is treated by injecting the proper clotting proteins, isolated from the blood of normal people. In the early 1980’s, the blood supply was contaminated by HIV, the AIDS virus, and many hemophiliacs contracted AIDS at that time.
Small cuts, scrapes and bruises can be life threatening
1 in 10, 000 males
1 in 100,000,000 females

27. Hemophilia XHXh XHY Hh x HH XH XHXh XH Y Xh XHXH XHXH XHY XHY XH Xh XH
sex-linked recessive
XHXh
XHY
Hh x HH XH
XHXh XH Y
male / sperm Xh
XHXH
XHXH
XHY
XHY XH Xh
female / eggs XH
XHY
XHXh
XHXh
XhY
XhY Y
carrier
disease

29. Common amongst royalty in Europe
Queen Victoria = Carrier

30. Hemophilia is a sex-linked recessive trait defined by the absence of one or more clotting factors.
These proteins normally slow and then stop bleeding.
Individuals with hemophilia have prolonged bleeding because a firm clot forms slowly.
Bleeding in muscles and joints can be painful and lead to serious damage.
Individuals can be treated with intravenous injections of the missing protein.

31. Following Traits in Families
Pedigrees
Following Traits in Families

32. Pedigree: A diagram that follows the traits through a family
Circles and Squares represent people
Shaded circles/squares represent people that have the trait “being followed”
A half-shaded symbol represents a ‘carrier’

33. Pedigree analysis
Pedigree analysis reveals Mendelian patterns in human inheritance
data mapped on a family tree
= male
= female
= male w/ trait
= female w/ trait

34. Simple pedigree analysis
What’s the likely inheritance pattern? 1 2 3 4 5 6 1 2 3 4 5 6

35. Genetic counseling
Pedigree can help us understand the past & predict the future
Thousands of genetic disorders are inherited as simple recessive traits
from benign conditions to deadly diseases
albinism
cystic fibrosis
Tay sachs
sickle cell anemia
PKU

36. Douglas and Lauren have three children, two girls and a boy.
This line indicates a family
Douglas Lauren
Children are left to right, oldest to youngest

37. Douglas has brown hair. We will ‘follow’ this trait
Douglas has brown hair. We will ‘follow’ this trait. Show the brown hair trait by shading in the circle
Douglas Lauren

38. Lauren has blonde hair so we do not shade her in.
Douglas Lauren

39. Their oldest daughter and youngest son have brown hair also.
Douglas Lauren

40. Shade them in as well.
Douglas Lauren

41. Sex-Influenced Traits
Some traits appear to be specific to one sex, but are not sex-linked: their genes are not on the X chromosome. It is sex-influenced.
Baldness is dominant in males: heterozygotes and homozygotes both become bald. In females, baldness is recessive: only homozygotes (which are relatively rare) become bald. Also, females tend to lose hair more evenly than men, giving a sparse hair pattern rather than completely baldness.

42. Errors of Meiosis
Chromosomal Abnormalities

43. Chromosome Structure Variations
Chromosomes can be broken by X-rays and by certain chemicals. The broken ends spontaneously rejoin, but if there are multiple breaks, the ends join at random. This leads to alterations in chromosome structure.
Breaking the chromosome often means breaking a gene. Since most genes are necessary for life, many chromosome breaks are lethal or cause serious defects.
Also, chromosomes with structural variations often have trouble going through meiosis, giving embryos with missing or extra-large regions of the chromosomes.

44. Chromosome Variations
Aneuploidy: having an extra or missing chromosome–fairly common in sperm and eggs. Errors in meiosis causes chromosomes to not separate equally into the gametes.
rate of aneuploidy in males is constant: 1-2% of sperm have an extra or missing chromosome.

45. Chromosome Variations
In females, the rate increases with age.
This is illustrated by the frequency of Down syndrome births at different ages of mother.
Down syndrome is the most frequent result of aneuploidy.

46. Chromosomes Karyotype: ordered display of an individual’s chromosomes.
Collection of chromosomes from mitotic cells.
Staining can reveal visible band patterns, gross anomalies.

47. Karyotypes arrange chromosomes in order by size: Largest to smallest

48. Chromosomes
Some large like #1
Some small like #22

49. Homologous pairs Same Length Centromere in same location
Same bands (genes)

50. Centromere Position
The centromere is not exactly in the center of the chromosome
“p” arm: (p=petite) the shorter arm of the chromosome
“q” arm: the longer arm of the chromosome

51. Locus (plural=loci)
The position that a given gene occupies on a chromosome. (Its like an address for your genes)
Written like this: 15p23

52. Example: 15p23=Chrom 15 small arm, 23rd band from the centromere

53. Trisomy:
*Having 3 chromosomes of each kind instead of 2 *Normally trisomy results in death.
1 Example

54. Down Syndrome:
a genetic condition in which the individual has 3 copies of the 21st chromosome.
Genotype: 3 copies of 21st chromosome

55. Down Syndrome:
Phenotype: Skin folds above the eye, some cardiac deformities, some levels of mental disability, large tongue.
Occurs about 1 in 1000 births.

57. Sex chromosomes abnormalities
Human development more tolerant of wrong numbers in sex chromosome
But produces a variety of distinct syndromes in humans
XXY = Klinefelter’s syndrome male
XXX = Trisomy X female
XYY = Jacob’s syndrome male
XO = Turner syndrome female

58. Klinefelter’s syndrome
XXY male
one in every 2000 live births
have male sex organs, but are sterile
feminine characteristics
some breast development
lack of facial hair
tall
normal intelligence

59. Klinefelter’s syndrome
How many Barr bodies would you expect?

60. Jacob’s syndrome male XYY Males 1 in 1000 live male births
extra Y chromosome
slightly taller than average
more active
normal intelligence, slight learning disabilities
delayed emotional maturity
normal sexual development

61. Trisomy X XXX 1 in every 2000 live births produces healthy females
Why?
Barr bodies
all but one X chromosome is inactivated
How many Barr bodies would you expect?

62. Turner syndrome Monosomy X or X0 1 in every 5000 births
varied degree of effects
webbed neck
short stature
sterile
How many Barr bodies would you expect?

63. A few oddities
It is possible to be XY and female. Two ways this can happen:
1. the SRY gene can be inactivated by a mutation. If SRY doesn’t work, testes don’t develop and the embryo develops as a normal female.
2. In a condition called “androgen insensitivity”, the person is XY with a functional SRY gene, but her cells lack the testosterone receptor protein, so the cells don’t ever get the message that the testosterone is sending. Testes develop in the abdominal cavity, and no ovaries, fallopian tubes, or uterus develop. At puberty, the internal testes secrete testosterone, which gets converted into estrogen and the body develops as a normal (but sterile) adult female.

64. Hermaphrodites ?!?
Hermaphrodite: An individual that has all female reproductive parts, and all male reproductive parts
No such thing in Humans

65. Hermaphrodites
In some cases, the cells respond a little bit to testosterone produced by the testes. The embryo develops with ambiguous genitalia, neither completely male not completely female.
Another condition, congenital adrenal dysplasia, causes the adrenal glands to produce an abnormally large amount of testosterone in a female embryo, This can also cause development of ambiguous genitalia.
Another rare condition: a chimera occurs when two separate embryos fuse together. This can result in a person with some XX cells and some XY cells. This condition is extremely rare: more people say they have it than actually do.

66. Twins 2% of births Monozygotic (Identical) 30% of twins
A single zygote splits into two. This happens between 1 to 9 days after the zygote forms.
The twins share the same genome

67. Twins Dizygotic (Fraternal) 70% of twins
Two separate eggs are fertilized with two separate sperm. Two totally independent zygotes are created.
The twins have different genomes

68. Twins Conjoined twins – very rare (1 in 200,000)
Identical twins who fail to completely separate after the 13th day after fertilization
This may be due to the fusion, or incomplete separation of zygotes
May be two fully formed individuals connected at various locations, or rarely, parasitic twins, where one is much smaller and less formed, or even completely contained.

69. Genetic Disorders
Biology
Unit 6
Velekei

70. Recessive Disorders
Disorders that are only expressed in the phenotype when 2 recessive alleles are present.
DD = Normal
Dd = Carrier
dd = Affected by disorder

71. 2 Examples of Recessive Disorders

72. Tay-Sachs Disease
Cause: gene to make the enzyme Hex-A is not working. Hex-A is an enzyme that breaks down lipids in the brain.
Result: Without this enzyme the lipid accumulates on nerve cells, specifically in the brain causing severe brain damage. Victims of this disease to not live past age 5

73. Tay-Sachs Brain

74. Common in Eastern European Ashkenazi Jews
This is a group of people descendent of medieval Jews from the Rhineland area. (Rhineland: near the river Rhine in Germany)
Common in this population (1 in 30)

75. How is Tay-Sachs disease passed? Each parent must be a Carrier
Offspring:
25% Normal
50% Carriers
25% Tay-Sachs

76. Cause of Cystic Fibrosis
A defect in the CFTR gene
The CFTR gene makes a protein that controls the movement of salt and water in and out of your body's cells.
In people who have CF, the gene makes a protein that doesn't work well.

77. Results of Cystic Fibrosis
Thick mucus is produced by the body
Mucus fills lungs causing lung infections
Mucus blocks pancreas which causes digestive problems
Mucus can block bile ducts in liver causing liver failure.

78. Cystic Fibrosis

79. Cystic Fibrosis Most common in Caucasian (white) populations
(1 in 2500 to 3500)
1 in 17,000 African Americans
1 in 31,000 Asian Americans

80. Carriers of Cystic Fibrosis
Offspring:
25% Normal
50% Carriers
25% Cystic Fibrosis

81. Dominant Disorders
Disorders expressed in heterozygous and homozygous dominant individuals
DD = Affected
Dd = Affected
dd = Normal

82. 2 Examples

83. 1) Huntington’s Disease
Cause:
Brain cells degenerate over time
Results:
Mood swings, loss of muscle control,
loss of memory and inability to learn, death
Usually adult-onset, appears around ages 40-50
Outlook is years of survivability
hh = Normal
HH or Hh = will get and die of this disease

84. Huntington’s is most common in certain parts of Venezuela (700 in 100,000) Generally affect 3-7 in 100,000 of European ancestry Less common in African-American & Asian American

85. Person with Huntington’s (heterozygous) and a person without Huntington’s
Hh x hh
Offspring:
50% Huntington’s
50% Normal

86. 2) Marfan’s Syndrome
Cause: Defective gene for fibrillin-1 that results in abnormal connective tissue
Results: Aorta may stretch or become weak, causing aortic rupture, the leading cause of death
Eye/lens problems
Excessive long bone growth (long arms & fingers)
Hypermobile joints (too flexible)

88. Sickle Cell: Autosomal Co-Dominant Disorder
Mutation in the hemoglobin gene affecting the shape of red blood cells
1/3 of people in Sub-Saharan Africa have this gene

89. Sickle Cell: Cross two heterozygous individuals
25%
Normal Hemoglobin: _____
Sickle Cell Trait: _____
Sickle Cell Anemia: _____
50% H S
25% H HH HS HS SS S

90. Sickle Cell: Autosomal Co-Dominant Disorder
Sickle shaped cells are resistant to Malaria