1Sex 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…

2What Morgan saw

Reciprocal cross produced a different result:

Inheritance of eye color depended on sex of the fly.

3Morgan 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.

4significance

• 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.

5Crisscross inheritance

http://www.udl.es/usuaris/e4650869/docencia/segoncicle/genclin98/temes_teoria/imatges_temes_teoria/image3.gif

Carrier mother passes allele to son who expresses it, passes allele to daughter who carries it, etc.

Hemophilia & color blindness: examples in humans.

6Sex 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

7More on sex determination

• Temperature affects sex determination in many reptile species– Females result from low, high, or extremes of

temperature.– Hypothesis:

8History

• 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

9Abnormalities in chromosome number result from non-disjunction

Homologues fail to separate during Meiosis I.

10Abnormalities in chromosome number result from non-disjunction-2

Sister chromatids fail to separate during Meiosis II.

11Evidence for XX/XY

• 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

12Other 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.

13About 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.

14Male specific region Y

• X-transposed 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.

15Evidence 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

16Gene 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?

17Dosage 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

18Lyon 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

20Formation of Barr bodies-2

http://www.petstreetmall.com/merchant/Embroidery/Cat/CalicoCatBody.gif.jpe

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.

21Molecular 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.

22Active and inactive regions

Red: active genes.

Black: inactive

23Human sexuality

• http://info.med.yale.edu/therarad/summers/wgss255a%20lecture%2013.ppt#1

• Interesting powerpoints with more questions than answers– Caution: graphic images