BIL 104 - Sex and the Single Chromosome

SEX CHROMOSOMES

Most species have a defined number of HOMOMORPHIC (same shape) autosomes. In some species, these may influence gender morphology & development.

Usually, however, sex is determined by one (or more) pair(s) of HETEROMORPHIC sex chromosomes. In humans and other mammals, these are the sex chromosomes, X and Y (which some people have mapped a little bit differently.

The human Y chromosome has relatively few gene loci compared to the X chromosome.

The X and Y have homologous regions (i.e., with matching gene loci) which pair up during meiosis (synapsis) and undergo limited crossing over. These regions of homology are called PSEUDOAUTOSOMAL regions.

Most of the X and Y are not homologous, however, and undergo NO CROSSING OVER. Traits coded on this DIFFERENTIAL regions of the X and Y exhibit inheritance patterns that are quite different from those shown by autosomal genes, and may be

X-linked (located on the differential region of the X c'some)

Y-linked (located on the differential region of the Y c'some).

Y-linked traits, which exist only in males, are known as HOLANDRIC traits. Under normal circumstances, females never express them.

Recall that when an individual has the normal number of chromosomes (two per homologous pair), then each trait on a given chromosome is either

HOMOZYGOUS or
HETEROZYGOUS

Because males have only one allele for (almost all) genes located on the X chromosome, they are said to be HEMIZYGOUS for those X-linked traits. They have only ONE copy instead of two. This can spell trouble!

The X chromosome has a large number of functional genes, whereas the Y is believed to have relatively few. A human can survive with a sex chromosome genotype of Xo, but not with Yo, since many vital genes are located on the X.

Sex Chromosomes and their Special Inheritance Consider an important implication of the XX and XY genotypes. Does this mean that females get twice the "dose" of the products on the X that males get?

NO.

This is prevented by the Amazing Phenomenon of DOSAGE COMPENSATION.

At a critical point in development, ONE X CHROMOSOME IN EACH CELL OF A FEMALE'S BODY is randomly inactivated (it curls up into a little loop and is never "used")
In humans, this occurs 12 days after fertilization (fusion of egg and sperm nuclei).
Mary Barr and Ewart Bertram (1949) first reported finding a dark-staining spot in the nucleus of female cat cells. Males lacked this stained area.
Mary Lyon (1960) proposed that this was an inactivated X c'some, and named it the BARR BODY.
The Lyon Hypothesis: An inactivated X chromosome supercoils and becomes inactive. It is visible with the stains used by Barr and Bertram.
The genes on the inactivated X chromosome are not transcribed or translated.

Evidence supporting the Lyon Hypothesis: Humans with abnormal numbers of X chromosomes have one fewer Barr body than # of X chromosomes:

XXX - 2 Barr Bodies
XXXX - 3 Barr Bodies, etc...

Cytological analysis has revealed that the Barr Body is, indeed a little ring of supercoiled heterochromatin, mostly non-transcribable. The process of Barr Body formation is now called LYONIZATION.

In effect, each individual cell in a female's body is HEMIZYGOUS for traits on the X chromosome, as are males. However, because the random inactivation means that at least SOME of each of the two alleles are active, she won't express harmful X-linked conditions such as

red-green color blindness
hemophilia
Androgen Insensitivity Syndrome (more on this later!)

There are exceptions, however: the 18 genes on the PSEUDOAUTOSOMAL REGION of the X chromosomes are not inactivated. As in males, both copies (on both X chromosomes) are actively transcribed and translated.

How do these 18 genes avoid being inactivated? We don't yet know!

However, the RANDOM inactivation still prevents full expression of deleterious recessives on the differential region, since normal X product will always be produced by at least some active X chromosomes.

A classic example: calico & tortoiseshell cats: One gene coding for fur color in cats is located on the X chromosome.

dominant = yellow fur (B)
recessive - black fur

Let's do a Punnett Square.

The expression of genes on either one or the other X chromosomes throughout the body of a female mammal is known as MOSAIC EXPRESSION.
(You all know what a mosaic is, right?)

Mosaic expression is not always as visible as the color of cat fur.
Most X-linked products are not obvious to the naked eye, and may be as subtle as two forms of an enzyme produced by in certain tissues of the body.

Remember that X-LINKED traits should not be confused with SEX INFLUENCED TRAITS, which are autosomal, but expressed differently depending on the sex of the individual. Examples:

Male pattern baldness
- dominant in males
- recessive in females)
Finger length ratios in humans
- ring finger length > index finger length - dominant in males, recessive in females
- index finger length > ring finger length - recessive in males, dominant in females
These traits are influenced sometime during development (including adult development) by the presence of male androgens (e.g. testosterone and/or DHT)

More about SEX The ratio of males to females in a population is known as the SEX RATIO.

The PRIMARY SEX RATIO is the ratio of males : females CONCEIVED.
The SECONDARY SEX RATIO is the ratio of males : females BORN

All things being equal, what would you predict the ratio of males to females conceived would be?

All things being equal, what would you predict the ratio of males to females born would be? In reality, more males are conceived than females.

Examples of PRIMARY SEX RATIOS (derived from huge numbers of abortions and miscarriages analyzed):

U.S. - white - 1.08
U.S. - black - 1.02
Korea - 1.6

Why do you suppose this might be?

But wait! There's more! The SECONDARY SEX RATIOS of the above are:

U.S. - white - 1.06
U.S. - black - 1.03
Korea - 1.15

There is a decrease between PRIMARY and SECONDARY sex ratios! More males are conceived than females, but this number is higher than the number of males born compared to females.

WHY?

(Only if you came to class did you get these explanations!)

Some interesting X-linked traits:

hemophilia ("Bleeding disease") - traced back to Queen Victoria (recessive)

Androgen Insensitivity Syndrome (once called Testicular Feminization Syndrome) (recessive) - let's take a closer look.

(Note: a hermaphrodite is an organism with both male and female reproductive systems; a pseudohermaphrodite is an organism with characteristics of both sexes, but the reproductive tract of only one sex.)

Before we can fully understand this, we must take a short foray into the Wonderful World of How Babies Become Boys or Girls.
A model for sex initiation was first proposed by Eva Eicher and Linda Washburn (Jackson Lab) in 1986. Simplified, it goes like this...

Here's a very simple diagram of the pelvic region of a very early (i.e., prior to 8 weeks) human embryo.

In humans, at the eighth week of development, if the SRY gene is present, it turns on and the generalized gonads begins their transformation into testes. Once this is complete, the new testes begin to secrete male hormones called ANDROGENS (testosterone and dihydrotestosterone (DHT) ).
The androgens trigger a cascade of developmental genetic events that culminate in the embryo becoming MALE.
Part of this cacade involves suppression of the expression of the Od ("ovary determining") gene present in everyone, male or female.
In the presence of androgens, the Od gene is switched "off", and the Mullerian ducts atrophy
The Wolffian ducts develop into the internal male genital tract.
In the absence of androgens, the Od gene turns on at about week 13, starting a cacade of developmental events that culminate in the embryo's becoming female. In this case, the Wolffian ducts atrophy and the Mullerian ducts develop into the internal female tract.
Yes, this means that in mammals--including humans--the female sex is the "default" pathway. We all start out as females, and only if a genetic "switch" is flipped do we become male.
The genetic "switches" are complex, but they involve the presence of very specific proteins on the plasma membrane of the cells, which act as portals for hormones (such as testosterone and DHT) to enter the cell and trigger the genetic events that cause an embryo to develop into a male.

"Androgen Insensitivity Syndrome" (rare; X-linked) is a mutation which inactivates one such protein portal which serves as an androgen receptor in the plasma membrane found in normal males.

A person with AIS has:

XY sex chromosomes
Female body shape
Enlarged breast with juvenile nipples
Absent or scanty axillary or pubic hair
Female external genitalia with small labia
Blind-ending vagina
Absent or rudimentary internal genitalia
Cryptorchid (undescended testicles) gonads
Normal male blood levels of testosterone
Testes produce androgens and estrogen
Elevated production of gonadotrophins
No male pattern baldness

WHY?

When sry turns on at 8 weeks, the generalized gonads are changed into testes. These are present in the AIS adult, either up in the groin or descended into the labia, and secrete normal amounts of testosterone.

Because the testosterone cannot enter the cells to turn the "male determining" genes on/off, the cells follow the "default" pathway, which is female.

The resulting phenotype is that of a female, though genotype is XY.

The individual is sterile: there are no internal Mullerian structures (no uterus, fallopian tubes or ovaries), and only a blind-end vagina.

Certain structural genes on the Y c'some are still operational, and are expressed normally. For example, persons with this syndrome often have...

long, well-developed legs
greater than average height for a female
flawless complexion (no hormone-driven acne at puberty)
physique often more angular and "athletic" than average female

Another form of human pseudohermaphroditism is 5-AR Deficiency

In this case, the enzyme (5-alpha reductase) responsible for converting testosterone to its other androgen derivative, dihydrotestosterone (DHT), is non-functional.
The gene responsible for normal conversion of testosterone to DHT is autosomal--not sex-linked.
Persons exhibiting this syndrome are genetically male.
All characteristics whose development is driven by testosterone are normal:
- Mullerian duct system degenerates during early development
- Wolffian duct system develops into normal, male internal sex organs
All characteristics whose development is driven by DHT are abnormal, including...
- external genitalia are "ambiguous" at birth:
- penis resembles enlarged clitoris (to which it is homologous)
- scrotum resembles labia majora (to which it is homologous)
Since masculinization at puberty is primarily driven by testosterone, at the onset of puberty, 5-AR deficient individuals undergo masculinization, including
- deepening of voice
- normal production of sperm/semen
- normal capacity to ejaculate & father children (they're not sterile)

Treatments once included surgical "repair" of external genitalia. Before this condition was fully understood, parents of 5-AR deficient individuals were often given the option of choosing a gender for the child. Unfortunately, because testosterone-driven development is that of a normal male, this adversely affected the psyche of many individuals who were "forced" to become female without their consent.

Well-informed practitioners generally do NOT recommend feminization of these male individuals as a treatment option.