Lecture 8: Sex Linkage

Describe the various mechanisms in which organisms determine sex.

• In some organisms, like humans, sex is determined by the X and Y sex chromosomes

  • Females are XX

  • Males are XY

• In other organisms, like birds, butterflies, and some reptiles, sex is determined by the X and Z chromosomes

  • Females are ZW

  • Males are ZZ

• In some organisms, such as turtles and alligators, sex is determined by the temperature at which eggs are incubated

The X and Y sex chromosomes pair during meiosis and segregate, but are not homologous — most genes on the X chromosome differ from genes on the Y chromosome, and this difference in the number of sex-linked alleles produces distinct patterns of inheritance in males and females.

Thomas Hunt Morgan’s fruit fly experiments

Morgan was breeding fruit flies when he noticed an interesting phenotype: some fruit flies had white instead of red eyes

Question: What is the genetic basis of the white-eyed phenotype?

• Bred a white-eyed fly (ww) and a red-eyed (W+W+) fly

• F1 generation (W+w) all had red eyes

  • Pattern of inheritance seemed to be Mendelian

  • Morgan expected a 3:1 ratio in F2 offspring

• But instead, Morgan found that 100% of females were red-eyed, 50% of males were red-eyed, and 50% of males were white-eyed
  

Conclusion: The white-eyed phenotype in fruit flies was not transmitted through Mendelian patterns of inheritance.

Fruit fly eye color is sex-linked, with red eyes being dominant and white eyes being recessive. If a heterozygous red-eyed female is crossed with a red-eyed male, what are the expected phenotypic ratios in the offspring?

Red-eyed female: XW+ Xw

Red-eyed male: XW+ Y

Punnett square ratios:

• XW+ XW+ (red-eyed female)

• XW+ Xw (red-eyed heterozygous female)

• XW+ Y (red-eyed male)

• Xw Y (white-eyed male)

Expected results: 100% red-eyed females, 50% red-eyed males, 50% white-eyed males

Describe the significance of Morgan’s experiments.

• Morgan’s work showed that the gene for eye color in fruit flies was located on the X chromosome only, and that no homologous allele is present on the Y chromosome → proved that genes are inherited on chromosomes, supporting the chromosome theory of inheritance
  

• Female organisms have cells with two X chromosomes (XX) — females can be homozygous or heterozygous for the eye-color allele

• Male organisms have cells with one X and one Y chromosome (XY) — males cannot be homozygous or heterozygous because they only have 1 copy of the X chromosome

  • Males are hemizygous (only having one copy of a gene or  chromosome) for X-linked loci

X chromosome

Contains genetic information essential for both males and females — at least one copy of this chromosome is required for proper cell functioning

Sex-determining region Y (SRY)

Also known as the male-determining gene; located on the Y chromosome

• A single Y, even in the presence of several Xs, still produces a biological male phenotype

• The absence of Y results in a biological female phenotype

XX with an insertion of the SRY gene on an X chromosome will result in…

A biological male phenotype

XO with an insertion of the SRY gene on an autosomal chromosome will result in…

A biological male phenotype

Karyotyping

A technique to visualize chromosomes — actively dividing cells are halted in metaphase by treatment with a mitotic spindle inhibitor, and chromosomes are arranged according to size

Turner syndrome

XO → biological female phenotype

Memorization trick: turner = “turn her" (biological female sex, two syllables)

Klinefelter syndrome

XXY, XXXY, XXXXY, XXYY → biological male phenotype

Memorization trick: Kline “felt her” (many Xs but biological male sex)

Poly-X females

XXX, XXXX, or more → biological female phenotype

Pseudoautosomal regions

• The only regions where the X and Y chromosomes are homologous

• Located at both tips of the X and Y chromosomes

• Essential for X-Y chromosome pairing in meiosis in males

Define aneuploidy and explain how aneuploidy can occur because of errors in meiosis I, meiosis II, and mitosis.

A change in the number of individual chromosomes

Polyploidy

An increase in the number of sets of chromosome

Describe the types of aneuploidy.

Nullisomy: loss of both members of a homologous chromosome pair (2n-2)
Tetrasomy: gain of a homologous chromosome pair (2n+2)

Monosomy: loss of a single chromosome (2n-1)
Trisomy: gain of a single chromosome (2n+1)

Explain the problem of XX-XY gene dosage.

In females, there are two copies of the X chromosome and two copies of each autosome, so the genes on the X chromosome and autosomes are in balance

In males, there is only one copy of the X chromosome and two copies of every autosome, so males are likely to produce lower amounts of proteins encoded by X-linked genes than of proteins encoded by autosomal gene

• Some organisms have evolved mechanisms to overcome this problem and equalize the amounts of protein produced by the single X chromosome and two autosomes

Dosage compensation

Mechanisms to equalize the different amounts of protein produced by the single X chromosome and two autosomes in males

X-inactivation in females

An important mechanism to normalize X gene dosage between females (XX) and males (XY)

• Within each female cell, one of the two X chromosomes is randomly inactivated

• The inactivated X chromosome condenses into a Barr body

Because of X-inactivation, females are hemizygous at the cellular level for X-linked genes

• In females that are heterozygous at an X-linked locus, 50% of the cells express one allele and 50% express the other allele — proteins encoded by both alleles are produced, but not within the same cell

• The cells in an individual female are not identical with respect to expression of the genes on the X chromosome

• Females are mosaics for the expression of X-linked genes!

Random X-inactivation

• Occurs early in development

• After an X chromosome has become inactivated in a cell, it remains inactive in that cell and in all somatic cells that descend from that cell

• Neighboring cells tend to have the same X chromosome inactivated, producing a patchy mosaic pattern in heterozygous females (ex. calico cats)

Describe the three reasons for non-random X-inactivation.

1. Random chance
   

2. Genetic bias — found in females heterozygous for a disease

• Example: Buildup of uric acid in Lesch-Nyhan syndrome due to mutations in the X-linked HPRT1 gene

  • Females heterozygous for this disease experience less severe effects due to cell sharing of the HPRT1 enzyme across gap junctions 

  • Wild-type cells that express the HPRT1 enzyme are able to share the enzyme with mutant cells lacking it

  • This is an example of non-random X-inactivation due to genetic bias, where cells are more likely to inactivate the mutated X chromosome to facilitate sharing of the enzyme

3. Cellular selection — due to a growth advantage or disadvantage

• Example 1: Loss-of-function mutation in TORC1

  • TORC1 is a protein complex that is part of the G1 cell cycle checkpoint, responsible for sensing nutrient availability

  • If nutrients are limited, TORC1 will arrest the cell cycle in G1

  • If there is a mutation in TORC1 so that TORC1 is unable to sense nutrient availability, cells with the mutation will divide without adequate nutrients and die

  • If the mutated TORC1 is on the Xm chromosome, those cells will have a higher chance of dying, so there will be non-random X-inactivation where cells that inactivate the mutated Xm chromosome have a survival advantage over cells that inactivate the normal Xp chromosome

• Example 2: Gain-of-function mutation in TORC1

  • A gain-of-function mutation in TORC1 will stimulate the cell cycle and result in increased rates of cell division for cells containing the mutated Xm chromosome — therefore, there will be non-random X-inactivation because cells containing the mutated Xm chromosome will outcompete cells containing the normal Xp chromosome

Explain the significance of biological females being genetic mosaics.

• Females almost always have less severe manifestations of X-linked diseases, because heterozygous females are not homozygous for the pathogenic variant and contain both affected and unaffected cells

  • Variant cells expressing the deleterious allele receive sufficient levels of protein from cells expressing the normal allele to carry out essential metabolic functions → a way for females to ameliorate the effects of pathogenic variants