1. Sex Linkage and Determination
In humans, fruit flies, XX = female; XY = male.
Because there are genes on sex chromosomes, inheritance of certain traits can be sex-linked.
Early 1900s, Thomas Hunt Morgan was doing classical genetics on fruit flies, looking for mutants and checking out the patterns of inheritance.
He studied the white eye phenotype and discovered something odd…

2. What Morgan saw Reciprocal cross produced a different result:
Inheritance of eye color depended on sex of the fly.

3. Morgan and the F2 generation
When the all red eyed F1 heterozygotes were crossed, a 3:1 ratio was observed, but not evenly divided between the sexes.

4. significance
With regard to X linked traits, males have only one allele, not two. They are said to be hemizygous.
Morgan’s work led to the understanding that genes are located on chromosome’s because inheritance of certain traits corresponded to inheritance of a visibly different chromosome.
Inheritance of X-linked traits results in typical crisscross inheritance: mother to son.

5. Crisscross inheritance
Carrier mother passes allele to son who expresses it, passes allele to daughter who carries it, etc.
Hemophilia & color blindness: examples in humans.

6. Sex determination
Different organisms have different chromosomal mechanisms for determining sex.
XX/XO: typically, the male has one copy.
Nematodes, e.g. C. elegans
XX/XY: as in humans, fruit flies, XX = female; XY = male.
Heterogametic sex is the one that produces a mixture of gametes. Usually the male but:
Female can be heterogametic in some species
Designation is ZZ/ZW where female is ZW

7. More on sex determination
Temperature affects sex determination in many reptile species
Females result from low, high, or extremes of temperature.
Hypothesis:

8. History Sex determination studies began in late 1800’s
Work in humans started around 1912, but didn’t get it right until 1956.
Keys to understanding sex determination in humans:
Improved karyotype methods
Study of aneuploidy of sex chromosomes
Aneuploidy is the wrong number of a particular chromosome.
Aneuploidy results from non-disjunction

9. Abnormalities in chromosome number result from non-disjunction
Homologues fail to separate during Meiosis I.

10. Abnormalities in chromosome number result from non-disjunction-2
Sister chromatids fail to separate during Meiosis II.

11. Evidence for XX/XY If XXY is still male and XO is female
47, XXY Klinefelter syndrome
male in appearance, but some feminization; sterile.
slow to learn, but not retarded.
XXXY etc. similar, but more severe symptoms
45, XO Turner syndrome
Monosomy, the only one occurring in humans
female, sterile, short webbed neck, broad chest, short.
majority aren’t born
If XXY is still male and XO is female
Y must be determinant of maleness

12. Other sex chromosome aneuploidies
47, XXX
Some phenotypically normal
Others, sterility, mental retardation
47, XYY
1965 study: higher number of inmates with XYY
revisited: no real correlation with criminal behavior
Controversial research, no clear answer.
taller than average, slightly lower IQ on average.

13. About the Y Y chromosome has been shrinking.
Now missing many of genes that X has.
Two regions: PAR and MSY
PAR= pseudoautosomal region
Regions near p telomere and q telomere are homologous to X chromosome. Crossing over can occur there during meiosis. Because of this, genes in this location do not behave as sex-linked traits, thus said to be pseudoautosomal because they behave like genes on autosomes rather than sex chromosomes.

14. Male specific region Y X-transposed region X-degenerative region
99% identical to X chromosome region, but only 2 genes; the rest are not expressed.
X-degenerative region
Contains DNA related to X chromosome regions
Several functional genes
Contains SRY that codes for testis-determining factor, necessary for maleness during development.
Ampliconic region
Highly similar genes related to male development and fertility.

15. Evidence for SRY SRY contains gene for testis determining factor
Crossing over in meiosis
Males with two X chromosomes; SRY found on one
Females with X and Y; SRY is missing from Y
Transgenic mice
Remove SRY from Y chromosome
Mice are XY but are female
Reciprocal experiment also done

16. Gene dosage It matters how many copies of genes there are.
Snapdragons: heterozygous flowers are pink.
Multiple histone genes.
Too many of some genes is deleterious.
3 copies of chromosome 21 = Down Syndrome
What about sex chromosomes? XX vs. XY
Y chromosomes are missing most of genes X has.
So, if 1 set of genes on the X is good for males, is two sets (2 X chromosomes) bad for females?

17. Dosage compensation: Barr, Ohno, and Lyon
Barr noticed that in the nucleus of females, but not males, a darkly staining body is visible.
Ohno hypothesized that this was an inactivated X chromosome in females so that there would only be 1 functional copy of genes, as in males.
Inactivated X is called a Barr body.
Individuals with incorrect numbers of sex chromosomes have appropriate number of Barr bodies.
E.g. XXX females have 2 Barr bodies

18. Lyon Hypothesis
X chromosome inactivation takes place early in development.
In placental mammals, it can be either X chromosome.
All the descendents of that cell have the same X chromosome inactivated.
Results in a mosaic, patches of tissue with different lineages.
Human females: anhidrotic epidermal dysplasia, no sweat glands; X linked gene, female has patches of skin w/o sweat glands, cells descended from a cell in which the X chromosome with the normal gene was inactivated.
G6PD alleles; Patches of color blindness

19. Descent of cells:
How mosaics are made.
Two homologous chromosomes, blue & red.
Black indicates inactivation = Barr body

20. Formation of Barr bodies-2
Classic example: the calico cat.
One X chromosome codes for orange fur, the other for black. Cat shows characteristic mosaic patterns caused by one or the other X chromosome being inactivated.
White fur results from the effect of another gene.

21. Molecular basis of Barr body formation
Xic is a region on the X near the centromere.
Xic region includes a region called Xist (X inactivation specific transcript)
This area is transcribed, but RNA isn’t used to make a protein; it binds to the DNA of the rest of the X chromosome.
This promotes molecular changes that inactivate the chromosome including extensive methylation (except for XIC) and condensation of DNA (into smaller space).
In the OTHER X chromosome, Xic region is methylated so it will NOT be active.

22. Active and inactive regions
Red: active genes.
Black: inactive

23. Human sexuality
Interesting powerpoints with more questions than answers
Caution: graphic images