Mendelian inheritance

Mendelian inheritance (or Mendelian genetics or Mendelism) is a set of primary tenets relating to the transmission of hereditary characteristics from parent organisms to their offspring; it underlies much of genetics. They were initially derived from the work of Gregor Johann Mendel published in 1865 and 1866 which was "re-discovered" in 1900, and were initially very controversial. When they were integrated with the chromosome theory of inheritance by Thomas Hunt Morgan in 1915, they became the core of classical genetics.

History

Main article: History of genetics

The laws of inheritance were derived by Gregor Mendel,a 19th century Austrian Priest/monk conducting hybridization experiments in garden peas (Pisum sativum).[1] Between 1856 and 1863, he cultivated and tested some 29,000 pea plants. From these experiments he deduced two generalizations which later became known as Mendel's Principles of Heredity or Mendelian inheritance. He described these principles in a two part paper, Experiments on Plant Hybridization that he read to the Natural History Society of Brno on February 8 and March 8, 1865, and which was published in 1866.[2]

Mendel's conclusions were largely ignored. Although they were not completely unknown to biologists of the time, they were not seen as generally applicable, even by Mendel himself, who thought they only applied to certain categories of species or traits. A major block to understanding their significance was the importance attached by 19th century biologists to the apparent blending of inherited traits in the overall appearance of the progeny, now known to be due to multigene interactions, in contrast to the organ-specific binary characters studied by Mendel.[1] In 1900, however, his work was "re-discovered" by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak. The exact nature of the "re-discovery" has been somewhat debated: De Vries published first on the subject, mentioning Mendel in a footnote, while Correns pointed out Mendel's priority after having read De Vries's paper and realizing that he himself did not have priority. De Vries may not have acknowledged truthfully how much of his knowledge of the laws came from his own work, or came only after reading Mendel's paper. Later scholars have accused Von Tschermak of not truly understanding the results at all.[1]

Regardless, the "re-discovery" made Mendelism an important but controversial theory. Its most vigorous promoter in Europe was William Bateson, who coined the term "genetics", "gene", and "allele" to describe many of its tenets. The model of heredity was highly contested by other biologists because it implied that heredity was discontinuous, in opposition to the apparently continuous variation observable for many traits. Many biologists also dismissed the theory because they were not sure it would apply to all species, and there seemed to be very few true Mendelian characters in nature. However later work by biologists and statisticians such as R.A. Fisher showed that if multiple Mendelian factors were involved in the expression of an individual trait, they could

produce the diverse results observed. Thomas Hunt Morgan and his assistants later integrated the theoretical model of Mendel with the chromosome theory of inheritance, in which the chromosomes of cells were thought to hold the actual hereditary material, and create what is now known as classical genetics, which was extremely successful and cemented Mendel's place in history.

Mendel's findings allowed other scientists to predict the expression of traits on the basis of mathematical probabilities. A large contribution to Mendel's success can be traced to his decision to start his crosses only with plants he demonstrated were true-breeding. He also only measured absolute (binary) characteristics, such as color, shape, and position of the offspring, rather than quantitative characteristics. He expressed his results numerically and subjected them to statistical analysis. His method of data analysis and his large sample size gave credibility to his data. He also had the foresight to follow several successive generations (f2, f3) of his pea plants and record their variations. Finally, he performed "test crosses" (back-crossing descendants of the initial hybridization to the initial true-breeding lines) to reveal the presence and proportion of recessive characters. Without his hard work and careful attention to procedure and detail, Mendel's work could not have had the impact it made on the world of genetics.

[edit] Mendel's Laws

Mendel discovered that when crossing white flower and purple flower plants, the result is not a blend. Rather than being a mix of the two, the offspring was purple flowered. He then conceived the idea of heredity units, which he called "factors", one of which is a recessive characteristic and the other dominant. Mendel said that factors, later called genes, normally occur in pairs in ordinary body cells, yet segregate during the formation of sex cells. Each member of the pair becomes part of the separate sex cell. The dominant gene, such as the purple flower in Mendel's plants, will hide the recessive gene, the white flower. After Mendel self-fertilized the F1 generation and obtained the 3:1 ratio, he correctly theorized that genes can be paired in three different ways for each trait: AA, aa, and Aa. The capital "A" represents the dominant factor and lowercase "a" represents the recessive. (The last combination listed above, Aa, will occur roughly twice as often as each of the other two, as it can be made in two different ways, Aa or aA.)

Mendel stated that each individual has two factors for each trait, one from each parent. The two factors may or may not contain the same information. If the two factors are identical, the individual is called homozygous for the trait. If the two factors have different information, the individual is called heterozygous. The alternative forms of a factor are called alleles. The genotype of an individual is made up of the many alleles it possesses. An individual's physical appearance, or phenotype, is determined by its alleles as well as by its environment. An individual possesses two alleles for each trait; one allele is given by the female parent and the other by the male parent. They are passed on when an individual matures and produces gametes: egg and sperm. When gametes form, the paired alleles separate randomly so that each gamete receives a copy of one of the two alleles. The presence of an allele doesn't promise that the trait will be expressed in the

individual that possesses it. In heterozygous individuals the only allele that is expressed is the dominant. The recessive allele is present but its expression is hidden.

Mendel summarized his findings in two laws; the Law of Segregation and the Law of Independent Assortment.

[edit] Law of Segregation (The "First Law")

The Law of Segregation states that when any individual produces gametes, the copies of a gene separate so that each gamete receives only one copy. A gamete will receive one allele or the other. The direct proof of this was later found following the observation of meiosis by two independent scientists, the German botanist, Oscar Hertwig in 1876, and the Belgian zoologist, Edouard Van Beneden in 1883. In meiosis, the paternal and maternal chromosomes get separated and the alleles with the traits of a character are segregated into two different gametes.

OR

The two coexisting alleles of an individual for each trait segregate (separate) during gamete formation so that each gamete gets only one of the two alleles. Alleles again unite at random fertilization of gametes.

[edit] Law of Independent Assortment (The "Second Law")

The Law of Independent Assortment, also known as "Inheritance Law" states that alleles of different genes assort independently of one another during gamete formation. While Mendel's experiments with mixing one trait always resulted in a 3:1 ratio (Fig. 1) between dominant and recessive phenotypes, his experiments with mixing two traits (dihybrid cross) showed 9:3:3:1 ratios (Fig. 2). But the 9:3:3:1 table shows that each of the two genes are independently inherited with a 3:1 phenotypic ratio. Mendel concluded that different traits are inherited independently of each other, so that there is no relation, for example, between a cat's color and tail length. This is actually only true for genes that are not linked to each other.

Independent assortment occurs during meiosis I in eukaryotic organisms, specifically metaphase I of meiosis, to produce a gamete with a mixture of the organism's maternal and paternal chromosomes. Along with chromosomal crossover, this process aids in increasing genetic diversity by producing novel genetic combinations.

Of the 46 chromosomes in a normal diploid human cell, half are maternally-derived (from the mother's egg) and half are paternally-derived (from the father's sperm). This occurs as sexual reproduction involves the fusion of two haploid gametes (the egg and sperm) to produce a new organism having the full complement of chromosomes. During gametogenesis—the production of new gametes by an adult—the normal complement of 46 chromosomes needs to be halved to 23 to ensure that the resulting haploid gamete can join with another gamete to produce a diploid organism. An error in the number of

chromosomes, such as those caused by a diploid gamete joining with a haploid gamete, is termed aneuploidy.

In independent assortment the chromosomes that end up in a newly-formed gamete are randomly sorted from all possible combinations of maternal and paternal chromosomes. Because gametes end up with a random mix instead of a pre-defined "set" from either parent, gametes are therefore considered assorted independently. As such, the gamete can end up with any combination of paternal or maternal chromosomes. Any of the possible combinations of gametes formed from maternal and paternal chromosomes will occur with equal frequency. For human gametes, with 23 pairs of chromosomes, the number of possibilities is 223 or 8,388,608 possible combinations.[3] The gametes will normally end up with 23 chromosomes, but the origin of any particular one will be randomly selected from paternal or maternal chromosomes. This contributes to the genetic variability of progeny.

Figure 1: Dominant and recessive phenotypes.

(1) Parental generation. (2) F1 generation. (3) F2

generation. Dominant (red) and recessive

(white) phenotype look alike in the F1 (first)

generation and show a 3:1 ratio in the F2

(second) generation

Figure 2: The phenotypes of two independent traits show a 9:3:3:1 ratio in the F2 generation. In this

example, coat color is indicated by B (brown, dominant) or b (white) while tail length is indicated by S

(short, dominant) or s (long). When parents are homozygous for each

trait ('SSbb and ssBB), their children in the F1 generation are

heterozygous at both loci and only show the dominant phenotypes. If the children mate with each other,

in the F2 generation all combination of coat color and tail length occur: 9 are brown/short (purple boxes), 3 are white/short (pink boxes), 3 are brown/long (blue boxes) and 1 is

white/long (green box).

Figure 3: The color alleles of Mirabilis jalapa are not

dominant or recessive.(1) Parental generation. (2)

F1 generation. (3) F2

generation. The "red" and "white" allele together

make a "pink" phenotype, resulting in a 1:2:1 ratio of

red:pink:white in the F2

generation.

[edit] Background

Table showing how the genes exchange according to segregation or independent assortment during meiosis and how this translates into Mendel's laws

Mendel's law: Forget-me-not

The reason for these laws is found in the nature of the cell nucleus. It is made up of several chromosomes carrying the genetic traits. In a normal cell, each of these chromosomes has two parts, the chromatids. A reproductive cell, which is created in a process called meiosis, usually contains only one of those chromatids of each chromosome. By merging two of these cells (usually one male and one female), the full set is restored and the genes are mixed. The resulting cell becomes a new embryo. The fact that this new life has half the genes of each parent (23 from mother, 23 from father for total of 46 in the case of humans) is one reason for the Mendelian laws. The second most important reason is the varying dominance of different genes, causing some traits to appear unevenly instead of averaging out (whereby dominant doesn't mean more likely to reproduce—recessive genes can become the most common, too).

There are several advantages of this method (sexual reproduction) over reproduction without genetic exchange:

1. Instead of nearly identical copies of an organism, a broad range of offspring develops, allowing more different abilities and evolutionary strategies.

2. There are usually some errors in every cell nucleus. Copying the genes usually adds more of them. By distributing them randomly over different chromosomes and mixing the genes, such errors will be distributed unevenly over the different children. Some of them will therefore have only very few such problems. This helps reduce problems with copying errors somewhat.

3. Genes can spread faster from one part of a population to another. This is for instance useful if there's a temporary isolation of two groups. New genes developing in each of the populations don't get reduced to half when one side replaces the other, they mix and form a population with the advantages of both sides.

4. Sometimes, a mutation can have positive side effects. For example, sickle cell anemia is a mutation that can causethe benefit of malaria resistance. The mechanism behind the Mendelian laws can make it possible for some offspring to carry the advantages without the disadvantages until further mutations solve the problems.

[edit] Mendelian trait

A Mendelian trait is one that is controlled by a single locus and shows a simple Mendelian inheritance pattern. In such cases, a mutation in a single gene can cause a disease that is inherited according to Mendel's laws. Examples include sickle-cell anemia, Tay-Sachs disease, cystic fibrosis and xeroderma pigmentosa. A disease controlled by a single gene contrasts with a multi-factorial disease, like arthritis, which is affected by several loci (and the environment) as well as those diseases inherited in a non-Mendelian fashion. The Mendelian Inheritance in Man database is a catalog of, among other things, genes in which Mendelian traits cause disease.

Mendelian Genetics

Overview

This module presents the basic principles of inheritance, as first outlined by Gregor Mendel. Mendel's four postulates will be presented, and will be used to demonstrate how the genetic make-up of parents can be used to predict the characteristics of their offspring. Examples of crosses will be presented involving one, two, and three separate genes.

Objectives

1. Learn the relationship between dominant and recessive alleles. 2. Learn Mendel's four postulates, and understand how the postulates apply to the

behavior of genes and chromosomes. 3. Learn how to determine the phenotypes of offspring of monohybrid, dihybrid, and

trihybrid crosses. 4. Learn how to use testcrosses to determine the genotypes of specific offspring

from the above crosses. 5. Learn to use the product law to determine the probabilities of combinations of

characteristics occurring together.

Gregor Mendel

Humans tried for more than 2000 years to understand the principles of heredity, so that domesticated animals and plants could be bred more efficiently to exhibit certain characteristics. The efforts to understand failed, but in spite of this, people learned to breed animals and plants empirically, with some success.

Finally, in 1856, Gregor Mendel, a monk and teacher of natural sciences, performed a successful study of inheritance in the pea plants that he tended in his garden. How did Mendel succeed where so many others had failed?

First, he made a lucky choice of an organism to study. Pea plants are easy to grow and interbreed, they grow to maturity in one year, and they can reproduce by either self-fertilization or by crossing between plants.

Second, as a monk (with lots of time on his hands?), Mendel was a meticulous record keeper. He was able to analyze large amounts of carefully recorded data.

Mendel published the results of his studies, but they were ignored for nearly 50 years. Finally, Mendel's work was discovered in the early 20th century, which led to the start of modern genetics.

So what exactly did Mendel do?

He picked seven pairs of traits of pea plants, such as tall vs. dwarf plants, yellow vs. green seeds, round vs. wrinkled seeds. He had strains of pea plants that 'bred true' for these characteristics, meaning that (for example) if a tall plant was bred with a tall plant, all of the offspring would be tall. Using these true breeding stocks, Mendel looked at each pair of traits separately.

The Monohybrid Cross

In studying each pair of traits, Mendel mated two true-breeding individuals (the parental or P1 generation), each exhibiting one of the two contrasting forms of the characteristic. For example, if the characteristic was plant height, a dwarf plant was mated with a tall plant. The offspring of such a cross are known as the first filial or F1 generation. When F1's are allowed to self-fertilize (sometimes referred to as "self"ing), they produce an F2 generation.

Here's an example of what Mendel observed:

Tall X Dwarf

F1 generation: all plants were tall

F1 self-fertilization: 3/4 of F2's were tall, 1/4 were dwarf

Mendel got the same result, regardless of which parent (tall or dwarf) provided the pollen, and which parent provided the ovum. (Therefore the characteristic was independent of sex.)

Mendel also observed the same result with the other characteristics:

E.g. P1: round x wrinkled - 3/4 of the F2's were round, 1/4 wrinkled

P1: yellow x green - 3/4 of the F2's were yellow, 1/4 were green

In each case that he studied, Mendel found a 3:1 ratio in the F2 generation.

Mendel's Postulates

To explain his results, Mendel formulated three postulates:

1. Genetic factors exist in pairs in individual organisms. In the above example, there would be three possible pairwise combinations of the two factors.

2. When two unlike factors for a single characteristic are present, one factor is dominant to the other. (The other factor is considered recessive.) In the above example, the factor for tall is dominant to the factor for dwarf.

3. During gamete formation, factors segregate randomly so that each gamete receives one or the other with equal likelihood. The offspring of an individual with one of each type of factor has an equal chance of inheriting either factor.

Mendel didn't know the identity of his factors, because at that time cells were poorly understood. As we will see, Mendel's 'factors' are in fact genes.

Applying Mendel's postulates to the tall/dwarf example above, Mendel reasoned that the tall and dwarf parental plants contained identical pairs of factors, because the plants bred true. (We'll designate 'd' as the dwarf factor and 'D'as the tall factor.) So the tall plant was DD and the dwarf plant was dd. Therefore, the F1 plants received one tall factor and one dwarf factor, making them all Dd. These plants, heterozygous for the one characteristic being considered, are monohybrids. Tall is dominant to dwarf in this case, so all of the F1's were tall. F1 gametes would receive one factor or the other with equal probability, so self fertilization would produce four possible combinations of factors in the F2:

DD, Dd, dD, dd

All would appear with equal frequency. Any of the plants with a D factor would be tall; only the dd would be dwarf. Therefore, 3/4 would be tall, and 1/4 dwarf.

Terminology

To better discuss genetic principles, we need to introduce some new terms. Look up each of the following terms in the glossary:

Phenotype Genotype Gene Allele Wild Type Homozygote Heterozygote Product Law

Another thing to know is the Punnett square. This tool is used to predict the probability of genotypes and phenotypes occurring in the offspring of a particular mating or cross. To use a Punnett square, Take the parental genotypes, and determine all of the possible combinations of alleles that could occur in gametes. List one parent's gametes across the top of the square, and the other parent's gametes down the side of the square. Then, within the square, combine all of the possible gametes from each parent to produce all of

the possible combinations of alleles in the offspring. I'll illustrate this by showing a Punnett square of the tall/dwarf example we considered:

Cross: Dd X Dd (F1)

In this case, only one characteristic (plant height) is being considered. Both parents are heterozygous, and each gamete will receive one allele from the parent, D or d. This is true of both parents in this case. When gametes are combined to form new individuals (in the square), we see that 1/4 of the offspring should be DD, 2/4 (or 1/2) should be Dd, and 1/4 should be dd. These are the possible genotypes of the next generation, and the probabilities of each occurring. This illustrates the genotypic ratio of the monohybrid cross - 1 homozygous dominant : 2 heterozygous : 1 homozygous recessive. Because tall (D) is dominant to dwarf (d), 3/4 of the offspring should be tall , and 1/4 should be dwarf. This illustrates the phenotypic ratio of the monohybrid cross - 3 dominant : 1 recessive.

The Test Cross

One last tool to consider: If you perform the above monohybrid cross, and get the expected 3/4 tall plants and 1/4 dwarf plants, how can you tell which of the tall plants are homozygous and which are heterozygous? There's no way to tell just by looking at the plants. To tell for sure, Mendel devised a test cross. To do a test cross, you take the individual in question, and cross it to a homozygous recessive individual (test crosses are always done using homozygous recessives). To see how this works, lets consider our example again. Look at the possible results of testcrosses involving a homozygous dominant, and involving a heterozygote:

DD Dd

So if you take a tall plant, and cross it with a homozygous recessive, and all of the offspring are tall plants, then you know that the tall plant in question is homozygous. If, on the other hand half of the offspring are tall and half are dwarf (a 1 : 1 ratio), then the tall plant being tested is heterozygous.

The Dihybrid Cross

After examining each characteristic individually, Mendel also studied them in pairs. For example, he looked at seed shape (round vs. wrinkled) and seed color (yellow vs. green). Each of these characteristics studied individually had shown the typical 3:1 phenotypic ratio. When Mendel crossed true-breeding plants that produced yellow, round seeds with true breeding plants that produced green, wrinkled seeds, he observed the following results:

P1: yellow, round X green, wrinkled

F1: all yellow, round

F2: 9/16 yellow, round ; 3/16 yellow, wrinkled ; 3/16 green, round ; 1/16

green, wrinkled

The F1 and F2 generations were identical to those shown above even if the parents were yellow, wrinkled and green, round.

How can we explain the phenotypic ratio in this case? Well, it's fairly straightforward if we consider it as two monohybrid crosses done separately:

Yellow (G) is dominant to green (g), therefore the F1's are all yellow, and the F2's are 3/4 yellow, 1/4 green

Round (W) is dominant to wrinkled (w), therefore the F1's are all round, and the F2's are 3/4 round, 1/4 wrinkled

According to the Product Law, the probability of getting a yellow round plant is equal to the product of the probability of getting a yellow-seeded plant (3/4) and the probability of getting a round-seeded plant (3/4).

prob. (yellow, round) = 3/4 X 3/4 = 9/16

The Product Law can be used to explain the observations for the other phenotypes as well. Take a few moments and work them out.

The fact that each trait in the dihybrid cross holds to its monohybrid probabilities strongly suggests that the two characteristics do not affect each other and are therefore independent. This led Mendel to formulate a fourth postulate.

Mendel's Fourth Postulate:

During gamete formation, segregating pairs of genetic factors assort independently of each other.

This simply means that the factors for seed color, when they segregate during gamete formation, do not affect the segregation of the factors for seed shape, and vice versa. The entire process is random.

There are two good methods for determining the theoretical outcome of any cross. One of these is the Punnett square. Let's use the Punnett square to reexamine the example of the dihybrid cross. In the dihybrid F1 plants (GgWw), the possible combinations of alleles in the gametes are GW, Gw, gW, and gw. Setting this up in the Punnet square:

It is easy to see that there are sixteen allele combinations in the Punnett square (although some are duplicates). Check each genotype, determine the phenotype, and work out the phenotypic ratio. You should find that it matches the ratio that Mendel observed, as shown above. Each of the fractions in the ratio is the probability that that phenotype will occur. For example, there is a 3/16 probability that any offspring will have green, round seeds.

The other method for determining the outcome of a cross is the forked line method. This method takes advantage of the Product Law, and exploits the fact that a cross can be broken down into a set of monohybrid crosses. The forked line method is especially useful when three or more characteristics are crossed simultaneously. For example, a trihybrid cross would require a Punnett square with 64 spaces! (If you don't believe me, try it for yourself.) This gets to be confusing, and its easier to keep things straight using the forked line method, because it deals with phenotypes rather than genotypes.

Here's how the method works (using the dihybrid cross as an example). In this case, letters will be used to designate phenotypes rather than alleles, so G means a yellow-seeded plant, g means a green-seeded plant, W means a round-seeded plant, and w means a wrinkled-seeded plant. First, we'll consider the first characteristic, seed color. In a monohybrid cross (Gg x Gg) involving seed color, the offspring have a 3/4 probability of having yellow seeds, and a 1/4 probability of having green seeds, as shown in the diagram below. Next, we'll consider seed shape. For each of the color phenotypes, there's a 3/4 probability that the seeds will be round, and a 1/4 probability that the seeds will be wrinkled. These probabilities are filled in along forked lines from the seed color probabilities. To determine the overall probability of a particular phenotype, simply multiply (i.e. use the product law) all of the probabilities along a particular line.

For more characteristics (i.e. a trihybrid cross), simply brach out from each point in the second column.

The forked line method can also be used to determine the probabilities of particular phenotypes, but this gets more complicated, because each characteristic will have three possibilities (homozygous dominant, heterozygous, homozygous recessive) instead of two (dominant trait, recessive trait).

Dihybrid Test Cross

As with the monohybrid cross, with some of the phenotypes it seems impossible to tell what the genotype is. Yellow, round-seeded plants (GGWW, GgWW, GGWw, or GgWw?); yellow, wrinkled seeded plants (GGww or Ggww?); and green, round-seeded plants (ggWw or ggWW?) are examples of such phenotypes. As with the monohybrid cross, the way to tell determine the genotype of a plant in question is to do a test cross. In this case, the plant to be tested will be crossed with a double homozygous recessive, ggww. Using a yellow, round-seeded plant as a test subject, work out all of the possible results of a test cross.

Sex Chromosomes

The nuclei of human cells contain 22 autosomes and 2 sex chromosomes. In females, the sex chromosomes are the 2 X chromosomes. Males have one X chromosome and one Y chromosome. The presence of the Y chromosome is decisive for unleashing the developmental program that leads to a baby boy.

The Y Chromosome

In making sperm by meiosis, the X and Y chromosomes must separate in anaphase just as homologous autosomes do. This occurs without a problem because, like homologous autosomes, the X and Y chromosome synapse during prophase of meiosis I. There is a small region of homology shared by the X and Y chromosome and synapsis occurs at that region.

This image, courtesy of C. Tease, shows synapsis of the X and Y chromosomes of a mouse during prophase of meiosis I. Crossing over occurs in two regions of pairing, called the pseudoautosomal regions. These are located at opposite ends of the chromosome.

The Pseudoautosomal Regions

The pseudoautosomal regions get their name because any genes located within them (so far only 9 have been found) are inherited just like any autosomal genes. Males have two copies of these genes: one in the pseudoautosomal region of their Y, the other in the corresponding portion of their X chromosome. So males can inherit an allele originally present on the X chromosome of their father and females can inherit an allele originally present on the Y chromosome of their father.

This diagram shows the structure of the human Y chromosome.

Genes outside the pseudoautosomal regions

Although 95% of the Y chromosome lies between the pseudoautosomal regions, fewer than 80 genes have been found here. Over half of this region is genetically-barren heterochromatin. Of the 80-odd genes found in the euchromatin, some encode proteins

Index to this page

The Y Chromosome o The Pseudoautosomal Regions o SRY

The X Chromosome X-Linkage X-Inactivation

o Mechanism Some genes on the X chromosome escape inactivation. X-Chromosome Abnormalities Sex Determination in Other Animals Environmental Sex Determination

Hermaphrodites

used by all cells. The others encode proteins that appear to function only in the testes. A key player in this latter group is SRY.

SRY

SRY (for sex-determining region Y) is a gene located on the short (p) arm just outside the pseudoautosomal region. It is the master switch that triggers the events that converts the embryo into a male. Without this gene, you get a female instead.

What is the evidence? 1. On very rare occasions aneuploid humans are born with such karyotypes as XXY,

XXXY, and even XXXXY. Despite their extra X chromosomes, all these cases are male.

2. This image (courtesy of Robin Lovell-Badge from Nature 351:117, 1991) shows two mice with an XX karyotype (and thus they should be female). However, as you may be able to see, they have a male phenotype. This is because they are transgenic for SRY. Fertilized XX eggs were injected with DNA carrying the SRY gene.

see Making Transgenic Animals

3. Although these mice have testes, male sex hormones, and normal mating behavior, they are sterile.

4. Another rarity: XX humans with testicular tissue because a translocation has placed the SRY gene on one of the X chromosomes

5. Still another rarity that demonstrates the case: women with an XY karyotype who, despite their Y chromosome, are female because of a destructive mutation in SRY.

(In 1996, a test based on a molecular probe for SRY was used to ensure that potential competitors for the women's Olympic events in Atlanta had no SRY gene. But because of possibilities like that in case 4, this testing is no longer used to screen female Olympic athletes.)

The X Chromosome

The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex. However, the inheritance of these genes follows special rules. These arise because:

males have only a single X chromosome almost all the genes on the X have no counterpart on the Y; thus any gene on the X, even if recessive in females, will be expressed in males.

Genes inherited in this fashion are described as sex-linked or, more precisely, X-linked.

X-Linkage: An Example

Hemophilia A is a blood clotting disorder caused by a mutant gene encoding the clotting factor VIII. This gene is located on the X chromosome (shown here in red). With only a single X chromosome, males who inherit the defective gene (always from their mother) will be unable to produce factor VIII and suffer from difficult-to-control episodes of bleeding. In heterozygous females, the unmutated copy of the gene will provide all the factor VIII they need. Heterozygous females are called "carriers" because although they show no symptoms, they pass the gene on to approximately half their sons, who develop the disease, and half their daughters, who also become carriers.

X Y

X XX XY

Xh XhX XhY

Women rarely suffer from hemophilia A because to do so they would have to inherit a defective gene from their father as well as their mother. Until recently, few hemophiliacs ever became fathers.

Click here for a discussion of red-green colorblindness; another example of X-linked inheritance.

X-Inactivation

Human females inherit two copies of every gene on the X chromosome, whereas males inherit only one (with some exceptions: the 9 pseudoautosomal genes and the small

number of "housekeeping" genes found on the Y). But for the hundreds of other genes on the X, are males at a disadvantage in the amount of gene product their cells produce? The answer is no, because females have only a single active X chromosome in each cell.

During interphase, chromosomes are too tenuous to be stained and seen by light microscopy. However, a dense, stainable structure, called a Barr body (after its discoverer) is seen in the interphase nuclei of female mammals. The Barr body is one of the X chromosomes. Its compact appearance reflects its inactivity. So, the cells of females have only one functioning copy of each X-linked gene — the same as males.

X-inactivation occurs early in embryonic development. In a given cell, which of a female's X chromosomes becomes inactivated and converted into a Barr body is a matter of chance (except in marsupials like the kangaroo, where it is always the father's X chromosome that is inactivated). After inactivation has occurred, all the descendants of that cell will have the same chromosome inactivated. Thus X-inactivation creates clones with differing effective gene content. An organism whose cells vary in effective gene content and hence in the expression of a trait, is called a genetic mosaic.

Mechanism of X-inactivation

Inactivation of an X chromosome requires a gene on that chromosome called XIST.

XIST encodes a large molecule of RNA (of a type different from those, e.g., mRNA, used in protein synthesis).

XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of the other hundreds of genes on that chromosome.

XIST RNA does not travel over to any other X chromosome in the nucleus. Barr bodies are inactive X chromosomes "painted" with XIST RNA.

The Sequence of Events

During the first cell divisions of the female mouse zygote, the XIST locus on the father's X chromosome is expressed so most of his X-linked genes are silent.

By the time the blastocyst has formed, the silencing of the paternal X chromosome still continues in the trophoblast but

in the inner cell mass (ICM) transcription of XIST ceases on the paternal X chromosome allowing its hundreds of other genes to be expressed. The shut-down of the XIST locus is done by methylating XIST regulatory sequences. So the pluripotent stem cells of the ICM express both X chromosomes.

However, as embryonic development proceeds, X-inactivation begins again. But this time it is entirely random. There is no predicting whether it will be the maternal X or the paternal X that is inactivated in a given cell.

Some genes on the X chromosome escape inactivation.

What about those 18 genes that are found on the Y as well as the X? There should be no need for females to inactivate one copy of these to keep in balance with the situation in males. And, as it turns out, these genes escape inactivation in females. Just how they manage this has yet to be discovered.

X-Chromosome Abnormalities

As we saw above, people are sometimes found with abnormal numbers of X chromosomes. Unlike most cases of aneuploidy, which are lethal, the phenotypic effects of aneuploidy of the X chromosome are usually not severe. Examples:

Females with but a single X chromosome: the most common cause of Turner's syndrome. The phenotypic effects are mild because each cell has a single functioning X chromosome like those of XX females. Number of Barr bodies = zero.

XXX, XXXX, XXXXX karyotypes: all females with mild phenotypic effects because in each cell all the extra X chromosomes are inactivated. Number of Barr bodies = number of X chromosomes minus one.

Klinefelter's syndrome: people with XXY or XXXY karyotypes are males (because of their Y chromosome). But again, the phenotypic effects of the extra X chromosomes are mild because, just as in females, the extra Xs are inactivated and converted into Barr bodies.

Sex Determination in Other Animals

Although the male fruit fly, Drosophila melanogaster, is X-Y, the Y chromosome does not dictate its maleness but rather the absence of a second X. Furthermore, instead of females shutting down one X to balance the single X of the males — as we do — male flies double the output of their single X relative to that of females.

In birds, moths, schistosomes, and some lizards, the male has two of the same chromosome (designated ZZ), whereas the female has "heterogametic" chromosomes (designated Z and W). In chickens, a single gene on the Z chromosome (designated DMRT1), when present in a double dose (ZZ), produces males while the presence of only one copy of the gene produces females (ZW).

Environmental Sex Determination

In some cold-blooded vertebrates some fishes many reptiles (e.g. certain snakes, lizards, turtles, and all crocodiles and

alligators)

as well as in some invertebrates (e.g. certain crustaceans), sex is determined after fertilization — not by sex chromosomes deposited in the egg.

The choice is usually determined by the temperature at which early embryonic development takes place.

In some cases (e.g. many turtles and lizards), a higher temperature during incubation favors the production of females.

In other cases (e.g., alligators), a higher temperature favors the production of males.

Even in cases (e.g. some lizards) where there are sex chromosomes, a high temperature can convert a genotypic male (ZZ) into a female.

Hermaphrodites

Hermaphrodites have both male and female sex organs. Many species of fish are hermaphroditic.

Some start out as one sex and then, in response to stimuli in their environment, switch to the other.

Other species have both testes and ovaries at the same time (but seldom fertilize themselves). (However, populations of C. elegans consist mostly of hermaphrodites and these only fertilize themselves — Link to a discussion.)

Hermaphroditic fishes have no sex chromosomes.

SEX DETERMINATION AND SEX CHROMOSOMES 

I.               The Chromosome Theory of Inheritance and Sex Linkage

A.       Sutton and Boveri’s chromosome theory of inheritance proposed in 1902—Genes are located on chromosomes

B.       Just previous to this (end of 19th century) biologists had discovered that half of all sperm cells carry a structure called an X body.

C.       In 1905 the X body were determined to be chromosomes—X chromosomes.

D.       Then the Y chromosome was also discovered in 1905.

E.        Together the X and Y chromosomes are known as the sex chromosomes.

F.        All other chromosomes are called autosomes.

G.       Systems of sex chromosomes

1)      XX-XO system (Protenor mode)

(a)    Female—XX

(b)    Male—X

(c)     Occurs in some insects like grasshoppers

2)      XX-XY System (Lygaeus mode)

(a)    Female—XX (homogametic sex)

(b)    Male XY (heterogametic sex)

(c)     Occurs in Drosophila, mammals and some plants

3)      ZZ-ZW System

(a)    Female—XY (heterogametic sex)

(b)    Male—XX (homogametic sex)

(c)     Occurs in birds, butterflies and some fishes

4)      X-Y-XY System

(a)    Occurs in organisms with alteration of generations (e.g., liverworts and vascular plants)

(b)    Male gametophytes—Y

(c)     Female gametophytes—X

(d)    Sporophytes—XY

H.       Morphology and pairing of X and Y

1)      Each type of sex chromosome has two regions

(a)    Pairing region

(i)        During synapsis of meiotic prophase I, the pairing regions combine

(ii)      Some genes occur in these pairing regions

(iii)    These genes exhibit X-and-Y linkage

(b)    Differential region

(i)        Differential regions do not pair during synapsis

(ii)      Differential region genes are either

1.     X-linked2.     Y-linked

(iii)        Any gene X or Y chromosome is said to be sex linked

I.         Sex determination in Drosophila

1)      Sex is determined by the ratio of the number of X chromosomes to number of autosomal sets

2)      Scheme

(a)    X/A = 1.0—female

(b)    X/A = 0.5—male

(c)     X/A > 1.0—metafemale

(d)    X/A < 0.5—metamale

J.        Sex determination in humans

1)      The presence or absence of the Y chromosome determines sex

2)      A gene on the Y chromosome called the SRY gene codes for the testis-determining factor

(a)    It controls the production of maleness

(b)    Works by inducing development of the medulla of the gonadal primordial, pairs of ridges on the embryonic kidneys

(c)     XY individuals who lack the part of the Y chromosomes with this gene are females

(d)    XX individuals who carry a tiny piece of the Y chromosome with this gene on an X chromosome are male (though sterile)

(e)    The X chromosome contains what appears to be a homologous region, though perhaps the genes there are pseudogenes

(f)     Dosage compensation in mammals, including humans

(i)   Bar bodies

1.     XYAA—0 Barr bodies

2.     XXAA—1 Barr body

3.     X0AA—0 Barr bodies

4.     XXXAA—2 Barr bodies

5.     XXYAA—1 Barr body

(ii)          Lyon hypothesis

1.     One X chromosome in each cell becomes inactivated early in development

2.     Which one is deactivated is random3.     All cells derived from cell with deactivated chromosome will

have that chromosome deactivated4.     This results in genetic mosaics

5.     Examples

a.     Calico cats

b.     Sweat gland distribution in females heterozygous for extodermal dysplasia

(g)    Anomalies

(i)   Hermaphrodites

1.     Have both ovaries and testes

2.     External genitalia are ambiguous

3.     Generally, true hermaphrodites are sterile, but not always

4.     In 1978 (at The American Society of Human Genetics meeting in Vancouver, B.C.) as case was reported in which

a.     25-year-old hermaphrodite delivered a stillborn child after 30 weeks gestation

b.     Earlier in life, this person had engaged in male sexual activity

c.     True hermaphrodites are genetic mosaics—some cells are XX, while others are XY

(ii)      Pseudohermaphrodites

1.     Pseudohermaphrodites have either testicular or ovarian tissue, but not both

2.     Generally the tissue is rudimentary

3.     External genitalia are often ambiguous

4.     Some are genetically female, but may look like males

5.     Some are genetically male, but may look like females and lead normal female sex lives

(iii)        Turner’s Syndrome in humans (45, XO)

1.     Due to nondisjunction in male or female parents to produce gametes without X chromosome

2.     Incidence: 1/5000 female births

3.     High proportion of spontaneous abortions are Turner’s and most Turner’s individuals are aborted

4.     Phenotypic features:

a.     Short stature

b.     Webbed neck—web of skin between neck and shoulders

c.     Breast development absent or nearly so

d.     Some cognitive functions affected, but intelligence often about normal

e.     Pubic and axillary hair reduced or absent

f.      Infantile genitalia

g.     Usually sterile

(iv)          Kleinfelter’s Syndrome (47, XXY)

1.     Due to nondisjunction of X chromosome in male or female parent

2.     Incidence: 1/1000 male births

3.     Tends to be maternal age effect

4.     Sometimes have more than two X chromosomes

5.     Phenotypic features

a.     Long arms

b.     Breast development

c.     Little or no sperm production

d.     Small testes

e.     Usually mentally retarded

(v)            XYY Condition

1.     Due to nondisjunction of Y chromosome in male

2.     Incidence: 1/1000 male births

3.     Phenotypic features:

a.     Above average height

b.     Fertile

c.     Sometimes (but not always) retarded

d.     May be correlation with delinquency

(vi)          Poly-X Females (XXX, XXXX, XXXXX,…)

1.     Incidence: 1/1000 female births

2.     Maternal age effect

3.     Phenotypic features:

a.     Sometimes infantile genitalia

b.     Sometimes underdeveloped breasts

c.     Fertile

d.     Sometimes mental retardation

e.     Incidence increases with increasing number of X chromosomes

(vii)        Trysomy 21 (47, XX or XY, +21)

1.     Down Syndrome

2.     Incidence: 1/700 births

3.     Mild-moderate mental retardation

4.     High risk of leukemia

5.     Phenotypic features:

a.     Short stature

b.     Brood, short skulls

c.     Flexible joints

d.     Excess skin on the back of the neck