1. Chapter 15: Chromosomal Basis of Inheritance

2. Sex linked traits 1910 | 1933 Genes are on sex chromosomes
as opposed to autosomal chromosomes
first discovered by T.H. Morgan at Columbia U.
Drosophila breeding
good genetic subject
prolific
2 week generations
4 pairs of chromosomes
XX=female, XY=male

3. Classes of chromosomes
autosomal chromosomes
sex chromosomes

4. Discovery of sex linkage
true-breeding
red-eye female
true-breeding
white-eye male X P
100%
red eye offspring F1
generation
(hybrids)
100%
red-eye female
50% red-eye male
50% white eye male F2
generation

5. What’s up with Morgan’s flies?x x RR rr Rr Rr  r r R r R Rr Rr R RR Rr R Rr Rr r Rr rr
100% red eyes
3 red : 1 white

6. 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

7. Let’s reconsider Morgan’s flies…x x
XRXR
XrY
XRXr
XRY Xr Y XR Y  XR XR
XRXr
XRY
XRXR
XRY XR Xr
XRXr
XRY
XRXr
XrY
100% red females
50% red males; 50% white males
100% red eyes

8. 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.

9. 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
Human X chromosome
Sex-linked
usually means “X-linked”
more than 60 diseases traced to genes on X chromosome

10. Map of Human Y chromosome?
< 30 genes on Y chromosome
Sex-determining Region Y (SRY)
linked
Channel Flipping (FLP)
Catching & Throwing (BLZ-1)
Self confidence (BLZ-2) note: not linked to ability gene
Devotion to sports (BUD-E)
Addiction to death & destruction movies (SAW-2)
Scratching (ITCH-E)
Spitting (P2E)
Inability to express affection over phone (ME-2)
Selective hearing loss (HUH)
Total lack of recall for dates (OOPS)
Air guitar (RIF)

11. 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.

12. Hemophilia XHXh XHY Hh x HH XH XHXh XH Y Xh XHXH XHXH XHY XHY XH Xh XH
sex-linked recessive
Hemophilia
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

13. X-inactivation Female mammals inherit 2 X chromosomes XH XHXh Xh
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

14. Male pattern baldness Sex influenced trait
autosomal trait influenced by sex hormones
age effect as well = onset after 30 years old
dominant in males & recessive in females
B_ = bald in males; bb = bald in females

15. Environmental effects
Phenotype is controlled by both environment & genes
Human skin color is influenced by both genetics & environmental conditions
Coat color in arctic fox influenced by heat sensitive alleles
The relative importance of genes & the environment in influencing human characteristics is a very old & hotly contested debate
a single tree has leaves that vary in size, shape & color, depending on exposure to wind & sun
for humans, nutrition influences height, exercise alters build, sun-tanning darkens the skin, and experience improves performance on intelligence tests
even identical twins — genetic equals — accumulate phenotypic differences as a result of their unique experiences
Color of Hydrangea flowers is influenced by soil pH

16. 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

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

18. 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

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

20. Nondisjunction Baby has wrong chromosome number trisomy monosomy
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

21. Human chromosome disorders
High frequency in humans
most embryos are spontaneously aborted
alterations are too disastrous
developmental problems result from biochemical imbalance
imbalance in regulatory molecules?
hormones?
transcription factors?
Certain conditions are tolerated
upset the balance less = survivable
but characteristic set of symptoms = syndrome

22. 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.

23. Down syndrome & age of mother
Mother’s age
Incidence of Down Syndrome
Under 30
<1 in 1000 30
1 in 900 35
1 in 400 36
1 in 300 37
1 in 230 38
1 in 180 39
1 in 135 40
1 in 105 42
1 in 60 44
1 in 35 46
1 in 20 48
1 in 16 49
1 in 12
Rate of miscarriage due to amniocentesis:
1970s data 0.5%, or 1 in 200 pregnancies
2006 data <0.1%, or 1 in 1600 pregnancies

24. Genetic testing Amniocentesis in 2nd trimester Analysis of karyotype
sample of embryo cells
stain & photograph chromosomes
Analysis of karyotype

25. 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

26. 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

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

28. 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

29. 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?

30. 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?