1. X-Linked Traits
Biology
Unit 6
Velekei

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
gene redundancy, like autosomal chromosomes
an X & Y chromosome
develop as a male: XY
no redundancy 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.

6. Sex-linked Genes
In contrast, a mutant gene on an X chromosome in a female is usually covered up by the normal allele on the other X. Most mutations are recessive. So, most people with sex-linked genetic conditions are male.
Another fact about sex-linked genes. Males produce ½ their sperm with their X chromosome, and half with their Y chromosome. The X-bearing sperm lead to daughters and the Y-bearing sperm lead to sons. So, sons get their only X from their mothers, and the father’s X goes only to daughters.
The Y chromosome is passed from father to son.

7. 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.

8. 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

9. 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).

10. 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.

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

12. With Color Vision:

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

14. Color Blind Test
What number do you see?

15. Color Blind Test
What number do you see?

16. This what you would see if you were color blind
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. Color Blind Test
What number do you see?

21. 5 With color vision you see this:
But if you were red-green colorblind….
You would see the #: 5

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

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

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

27. 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

28. 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

30. Common amongst royalty in Europe
Queen Victoria = Carrier

31. 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.

32. 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.
The best human example is male pattern baldness.
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.

33. Errors of Meiosis
Chromosomal Abnormalities

34. Chromosomal abnormalities
Incorrect number of chromosomes
nondisjunction
chromosomes don’t separate properly during meiosis
breakage of chromosomes
deletion
duplication
inversion
translocation

35. Nondisjunction
Problems with meiotic spindle cause errors in daughter cells
homologous chromosomes do not separate properly during Meiosis 1
sister chromatids fail to separate during Meiosis 2
too many or too few chromosomes 2n
n-1 n
n+1

36. Alteration of chromosome number
error in Meiosis 1
error in Meiosis 2
all with incorrect number
1/2 with incorrect number

37. Nondisjunction trisomy monosomy cells have 3 copies of a chromosome
Baby has wrong chromosome number
trisomy
cells have 3 copies of a chromosome
monosomy
cells have only 1 copy of a chromosome
n+1 n
n-1 n
trisomy
2n+1
monosomy
2n-1

38. Down syndrome
Trisomy 21
3 copies of chromosome 21
1 in 700 children born in U.S.
Chromosome 21 is the smallest human chromosome
but still severe effects
Frequency of Down syndrome correlates with the age of the mother
Trisomy 13 occurs in about 1 out of every 5,000 live births. It is a syndrome with multiple abnormalities, many of which are not compatible with life. More than 80% of children with trisomy 13 die in the first month. Trisomy 13 is associated with multiple abnormalities, including defects of the brain that lead to seizures, apnea, deafness, and eye abnormalities. The eyes are small with defects in the iris (coloboma ). Most infants have a cleft lip and cleft palate, and low-set ears. Congenital heart disease is present in approximately 80% of affected infants. Hernias and genital abnormalities are common.
Trisomy 18 is a relatively common syndrome affecting approximately 1 out of 3,000 live births, and affecting girls more than three times as often as boys. The presence of an extra number 18 chromosome leads to multiple abnormalities. Many of these abnormalities make it hard for infants to live longer than a few months.
The cri du chat syndrome is caused by the deletion of information on chromosome 5. It is likely that multiple genes on chromosome 5 are deleted. One deleted gene, called TERT (telomerase reverse transcriptase) is involved in control of cell growth, and may play a role in how some of the features of cri cu chat develop. The cause of this rare chromosomal deletion is not known, but it is expected that the majority of cases are due to spontaneous loss of a piece of chromosome 5 during development of an egg or sperm. A minority of cases result from one parent carrying a rearrangement of chromosome 5 called a translocation. Between 1 in 20,000 and 1 in 50,000 babies are affected. This disease may account for up to 1% of individuals with severe mental retardation. Infants with cri du chat syndrome commonly have a distinctive cat-like cry. They also have an extensive grouping of abnormalities, with severe mental retardation being the most important.

39. 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

40. 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

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

42. 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

43. 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?

44. 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?

45. Changes in chromosome structure
deletion
loss of a chromosomal segment
duplication
repeat a segment
inversion
reverses a segment
translocation
move segment from one chromosome to another
error of replication
error of crossing over

46. 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.

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

48. 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.

49. 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
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
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.