Human Chromosomes We have 46 chromosomes, or 23 pairs. 44 of them are called autosomes and are numbered 1 through 22. Chromosome 1 is the longest, 22 is

Human Chromosomes• We have 46 chromosomes, or 23

pairs.• 44 of them are called autosomes

and are numbered 1 through 22. Chromosome 1 is the longest, 22 is the shortest.

• The other 2 chromosomes are the sex chromosomes: the X chromosome and the Y chromosome.

• Males have and X and a Y; females have 2 X’s: XY vs. XX.

Sex Determination• The basic rule: if the Y chromosome is present, the person is male. If

absent, the person is female.

• The Y chromosome has the main sex-determining gene on it, called SRY.

• About 4 weeks after fertilization, an embryo that contains the SRY gene develops testes, the primary male sex organ. The testes secrete the hormone testosterone. Testosterone signals the other cells of the embryo to develop in the male pattern.

• If the embryo does not have the SRY gene, it develops ovaries instead, which secrete estrogen and causes development in the female pattern.

A few oddities• It is possible to be XY and female. Two ways this can happen:

• 1. the SRY gene can be inactivated by a mutation. If SRY doesn’t work, testes don’t develop and the embryo develops as a normal female.

• 2. In a condition called “androgen insensitivity”, the person is XY with a functional SRY gene, but her cells lack the testosterone receptor protein, so the cells don’t ever get the message that the testosterone is sending. Testes develop in the abdominal cavity, and no ovaries, fallopian tubes, or uterus develop. At puberty, the internal testes secrete testosterone, which gets converted into estrogen and the body develops as a normal (but sterile) adult female.

Hermaphrodites In some cases, androgen insensitivity is only partial: the cells respond a

little bit to testosterone produced by the testes. The embryo develops with ambiguous genitalia, neither completely male not completely female. Such a person is sometimes called a “hermaphrodite”.

Another condition, congenital adrenal dysplasia, causes the adrenal glands to produce an abnormally large amount of testosterone in a female embryo, This can also cause development of ambiguous genitalia, a hermaphrodite.

• Another rare condition: a chimera occurs when two separate embryos fuse together. This can result in a person with some XX cells and some XY cells. Such a person can have both testes and ovaries, a “true” hermaphrodite. This condition is extremely rare: more people say they have it than actually do.

Chromosome Variations• Changes in number and structure are

possible: first look at number variations.

• Aneuploidy: having an extra or missing chromosome– is fairly common in sperm and eggs. Non-disjunction in meiosis causes chromosomes to not separate equally into the gametes.

• The rate of non-disjunction in males is constant: 1-2% of sperm have an extra of missing chromosome. But in females, the rate increases marked with age. This is illustrated by the frequency of Down syndrome births at different ages of mother. Down syndrome is the most frequent result of non-disjunction.

Chromosome Number Variations

• Except for the X and Y, humans don’t survive with only 1 copy of any chromosome. Also, 3 copies is lethal in most cases. Aneuploidy is a major cause of spontaneous abortion in early pregnancy.

• Down Syndrome is the most common human aneuploidy. It is also called trisomy-21, meaning 3 copies of chromosome number 21.

• People with Down’s have a characteristic appearance: flattened face, turned up nose, epicanthal folds at the outer corners of the eyes. In most cases the diagnosis is made immediately at birth. Heart defects, protruding tongue, and mental retardation are also found in most people with Down’s. Occurs about 1 in 1000 births.

• There are also translocational and mosaic forms of Down syndrome.

• Translocational involves a chromosome structure change (2 chromosomes get hooked together) and is inherited. With translocational Down’s, if one child in a family has it, others are likely to also get it. Occurs in about 5% of Down’s cases.

• Mosaic Down’s means having some cells with trisomy 21 and other cells normal. The person’s physical appearance and mental condition depends on exactly which cells are which. About 3% of all Down syndrome cases.

Some Sex Chromosome Aneuploidies

• Non-disjunction can also result in a person with 2 X’s and a Y: 47,XXY. This is called Klinefelter Syndrome.

• The Y chromosome makes a person with Klinefelter’s male: possessing testes.

• Symptoms: female body hair pattern, breast development, sterile, can be some developmental delay or retardation, especially for verbal skills.

• Often not diagnosed, or diagnosed only accidentally.

• Most symptoms are helped by testosterone treatment.

Turner Syndrome• Also called XO, because people

with Turner’s have only 1 X chromosome: 45, X.

• No Y means Turner’s people are female. However, no ovaries develop, so they don’t undergo the body changes of puberty and they are sterile.

• Hormone treatment cures all but the sterility.

• Other symptoms: short stature, webbed skin and low hairline at the neck, some oddities of spatial perception. Not retarded.

Other Number Variations• Triplo-X, having 3 X chromosomes. No Y

chromosome means female. Many with this syndrome are undiagnosed because they have no symptoms. Some have slight social and developmental problems, especially language-related. Occasional fertility problems, but many have normal fertility. Not well studied.

• XYY: having 2 Y chromosomes plus an X. Male because they have a Y. Many are never diagnosed due to a lack of symptoms. Tend to be taller, more physically active, slightly retarded, prone to acne.

Chromosome Structure Variations• Chromosomes can be broken by X-rays and by

certain chemicals. The broken ends spontaneously rejoin, but if there are multiple breaks, the ends join at random. This leads to alterations in chromosome structure.

• Problems with structural changes: breaking the chromosome often means breaking a gene. Since most genes are necessary for life, many chromosome breaks are lethal or cause serious defects.

• Also, chromosomes with structural variations often have trouble going through meiosis, giving embryos with missing or extra large regions of the chromosomes. This condition is aneuploidy, just like the chromosome number variations, and it is often lethal.

• The major categories: duplication (an extra copy of a region of chromosome), deletion (missing a region of chromosome), inversion (part of the chromosome is inserted backwards, and translocation (two different chromosomes switch pieces).

Structure Variation Examples• There are lots of ways chromosomes can

change structure, so the syndromes are not as well defined as with number variations.

• Cri-du-chat syndrome comes from a deletion of one end of chromosome 5, so the person only has 1 copy of all the genes on this end of the chromosome. The name means “cat’s cry”, because their cry sounds vaguely like a cat’s meow. People with this condition are severely retarded, as well as having a variety of physical problems.

• Translocational Down syndrome is caused by most of chromosome 21 becoming joined with chromosome 14. Some children of a person with this translocation will inherit the translocation as well as 2 normal chromosome 21’s. This results in trisomy-21: having 3 copies of the chromosome, which gives Down syndrome.

Sex-linked Genes• Genes on the X chromosome are called “sex-linked”, because they

expressed more often in males than in females• There are very few genes on the Y chromosome.• Since males only have one X chromosome, all genes on it, whether

dominant or recessive, are expressed.• In contrast, a mutant gene on an X chromosome in a female is usually

covered up by the normal allele on the other X. Most mutations are recessive. So, most people with sex-linked genetic conditions are male.

• Another fact about sex-linked genes. Males produce ½ their sperm with their X chromosome, and half with their Y chromosome. The X-bearing sperm lead to daughters and the Y-bearing sperm lead to sons. So, sons get their only X from their mothers, and the father’s X goes only to daughters.

• The Y chromosome is passed from father to son.

Colorblindness• We have 3 color receptors in the

retinas of our eyes. They respond best to red, green, and blue light.

• Each receptor is made by a gene. The blue receptor is on an autosome, while the red and green receptors are on the X chromosome (sex-linked).

• Most colorblind people are males, who have mutated, inactive versions of either the red or the green (sometimes both) color receptors. Most females with a mutant receptor gene are heterozygous: the normal version of the receptor genes gives them normal color vision.

Inheritance of Colorblindness• A heterozygous female has

normal color vision. Sons get their only X from their mother. So, ½ of the sons of a heterozygous mother are colorblind, and ½ are normal.

• A colorblind male will give his X to his daughters only. If the mother is homozygous normal, all of the children will be normal. However, the daughters will heterozygous carriers of the trait, and ½ of their sons will be colorblind.

Hemophilia• Hemophilia is a disease in which the blood does not clot when exposed to air.

People with hemophilia can easily bleed to death from very minor wounds. Hemophilia is another sex-linked trait.

• Hemophilia is treated by injecting the proper clotting proteins, isolated from the blood of normal people. In the early 1980’s, the blood supply was contaminated by HIV, the AIDS virus, and many hemophiliacs contracted AIDS at that time.

• Queen Victoria of England, who lived through most of the 1800’s, apparently had a mutation on one of her X chromosomes that caused many of her descendants to have hemophilia. Most importantly, Alexis, son of the Czar of Russia had it, which contributed to the Russian Revolution and the rise of communism.

Sex-Influenced Traits• Some traits appear to be specific to

one sex, but are not sex-linked: their genes are not on the X chromosome.

• Such a trait is called sex-influenced. More specifically, a trait that is dominant in one sex but recessive in the other is a sex-influenced trait.

• The best human example is male pattern baldness.

• Baldness is dominant in males: heterozygotes and homozygotes both become bald. In females, baldness is recessive: only homozygotes (which are relatively rare) become bald. Also, females tend to lose hair more evenly than men, giving a sparse hair pattern rather than completely baldness.

• BUT: this may be an oversimplification.

Types of Chromosomal Mutations1. Variations in chromosome structure or number can arise

spontaneously or be induced by chemicals or radiation. Chromosomal mutation can be detected by:a. Genetic analysis (observing changes in linkage).

b. Microscopic examination of eukaryotic chromosomes at mitosis and meiosis (karyotype analysis).

2. Chromosomal aberrations contribute significantly to human miscarriages, stillbirths and genetic disorders.a. About 1⁄2 of spontaneous abortions result from major

chromosomal mutations.

b. Visible chromosomal mutations occur in about 6/1,000 live births.

c. About 11% of men with fertility problems, and 6% of those institutionalized with mental deficiencies have chromosomal mutations.

Variations in Chromosome Structure1. Mutations involving changes in chromosome structure occur in

four common types:a. Deletions.

b. Duplications.

c. Inversions (changing orientation of a DNA segment).

d. Translocations (moving a DNA segment).

2. All chromosome structure mutations begin with a break in the DNA, leaving ends that are not protected by telomeres, but are “sticky” and may adhere to other broken ends.

3. Polytene chromosomes (bundles of chromatids produced by DNA synthesis without mitosis or meiosis) are useful for studying chromosome structure mutations (Figure 17.1).a. Polytene chromosomes are easily detectable microscopically.

b. Homologs are tightly paired, joined at the centromeres by a proteinaceous chromocenter.

c. Detailed banding patterns are characterized for the four polytene chromosomes, with each band averaging 30 kb of DNA, enough to encode several genes.

台大農藝系遺傳學 601 20000

Fig. 17.1 Diagram of the complete set of Drosophila polytene chromosomes in a single salivary gland cell

Deletion1. In a deletion, part of a chromosome is missing.

a. Deletions start with chromosomal breaks induced by:

i. Heat or radiation (especially ionizing).

ii. Viruses.

iii. Chemicals.

iv.Transposable elements.

v. Errors in recombination.

b. Deletions do not revert, because the DNA is missing.

2. The effect of a deletion depends on what was deleted.

a. A deletion in one allele of a homozygous wild-type organism may give a normal phenotype, while the same deletion in the wild-type allele of a heterozygote would produce a mutant phenotype.

b. Deletion of the centromere results in an acentric chromosome that is lost, usually with serious or lethal consequences. (No known living human has an entire autosome deleted from the genome.)

c. Large deletions can be detected by unpaired loops seen in karyotype analysis (Figure 17.2).

Fig. 17.2 A deletion of a chromosome segment

Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Duplication

1. Duplications result from doubling of chromosomal segments, and occur in a range of sizes and locations (Figure 17.5).

a. Tandem duplications are adjacent to each other.

b. Reverse tandem duplications result in genes arranged in the opposite order of the original.

c. Tandem duplication at the end of a chromosome is a terminal tandem duplication (Figure 17.6).

d. Heterozygous duplications result in unpaired loops, and may be detected cytologically.

Fig. 17.5 Duplication, with a chromosome segment repeated


Fig. 17.6 Forms of chromosome duplications are tandem, reverse tandem, and

terminal tandem duplications


Fig. 17.7 Chromosome constitutions of Drosophila strains

台大農藝系遺傳學 601 20000 Chapter 21 slide 25Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Multigene families result from duplications. Hemoglobin (Hb) is an example: a. Each Hb contains two copies of two subunits (e.g., 2 α-globins and

2 β-globins), and the identity of the subunits changes with the organism’s developmental stage.

b. Genes for the α-type polypeptides are clustered together on 1 chromosome, and those for β-type polypeptides are clustered on another.

c. α-type genes have similar sequences, as do β-type. They probably result from duplication and subsequent sequence divergence.

Fig. 17.8 Inversions


Different recombinant chromosomes are produced by crossover in a heterozygote, depending on centromere involvement: a. Paracentric inversions (no centromere) result in visible inversion loops between

homologous chromosomes (Figures 17.9).

i. Crossover in the inversion region results in unbalanced sets of genes, and gametes or zygotes derived from recombined chromatids may be inviable due to abnormal gene dose.

ii. Without crossover in the looped region, gametes receive complete sets of genes (two gametes with normal and two with inversions) and are viable.

iii. Effects of a single crossover within an inverted segment in a heterozygote include (Figure 17.10):

(1) Joining of homologous regions of two chromatids to produce a dicentric bridge, and corresponding loss of an acentric fragment.

(2) During anaphase the two centromeres of the dicentric chromosome migrate towards opposite poles, causing the bridge to break, and producing two chromatids with deletions.

(3) The second meiotic division distributes one chromatid to each gamete:

(a) Two gametes carry normal sets of genes (one in the normal order and the other in inverted order).

(b) Two gametes are missing many genes, and are inviable.

(4) Female mammals often shunt dicentric chromosomes or acentric fragments to the polar bodies, so fertility may not be so reduced.

Fig. 17.9 Consequences of crossing-over in a paracentric inversion


Fig. 17.10 Meiotic products resulting from a single crossover within a heterozygous,

pericentric inversion loop


Fig. 17.11 Translocations


Fig. 17.12 Meiosis in a translocation heterozygote in which no crossover occurs

Chapter 21 slide 32Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Chromosomal Mutations and Human Tumors1. Most human malignant tumors have chromosomal mutations.

a. The most common are translocationsb. There is much variation in chromosome abnormalities, however, and they include

simple rearrangements to complex changes in chromosome structure and number.c. Many tumor types show a variety of mutations.d. Some, however, are associated with specific chromosomal abnormalities.

2. Examples of specific abnormalities associated with tumors:a. Chronic myelogenous leukemia (CML; OMIM 151410) involves a reciprocal

translocation of chromosomes 9 and 22 (Figure 17.13).i. Myeloblasts (stem cells of white blood cells) replicate uncontrollably.ii. 90% of CML patients have the Philadelphia chromosome (Ph1) reciprocal translocation.iii. The reciprocal translocation causes transition from a differentiated cell to a tumor cell, by translocating a proto-oncogene from chromosome 9 to chromosome 22, and probably converting it to the ABL oncogene.iv. The hybrid gene arrangement causes expression of a leukemia-producing gene product.

Fig. 17.13 Origin of the Philadelphia chromosome in chronic myelogenous leukemia

(CML) by a reciprocal translocation involving chromosomes 9 and 22


b.Burkitt lymphoma (BL) involves a reciprocal translocation of chromosomes 8 and 14.i. Induced by a virus, this disease is common in Africa.ii. B cells are affected, and secrete antibodies as they proliferate.iii. The reciprocal translocation positions the MYC proto-oncogene next to an active immunoglobulin gene, resulting in over-expression of MYC and development of the lymphoma.

台大農藝系遺傳學 601 20000 Chapter 21 slide 35

Position Effect 1. Sometimes inversions or translocations change phenotypic expression of

genes by the position effect, for example, by moving a gene from euchromatin to heterochromatin (transcription generally occurs in euchromatin but not in heterochromatin).

2. This is an example of an epigenetic effect since the DNA sequence of the gene is not affected.

3. An example is the white-eye (w) locus in Drosophila:a. An inversion moves the w+ gene from a euchromatin region of the X

chromosome to a position in heterochromatin.b. In a w+ male, or a w+/w female, where w+ is involved in the inversion, the eyes

will have white spots resulting from the cells where the w+ allele was moved and inactivated.

4. Position effects are associated with some human diseases. Aniridia (“without iris,” OMIM 106210) is an example.

a. Aniridia is severe hypoplasia of the iris, usually associated with cataracts and clouding of the cornea.

b. The cause of aniridia is early termination of eye development, resulting from lost function of the PAX6 gene by deletion, mutation, or translocation.

Fragile Sites and Fragile X Syndrome1. Chromosomes in cultured human cells develop narrowings or unstained

areas (gaps) called fragile sites; over 40 human fragile sites are known.

2. A well-known example is fragile X syndrome, in which a region at position Xq27.3 is prone to breakage and mental retardation may result (Figure 17.14).a. Fragile X syndrome has an incidence in the U.S. of about 1/1,250 in males,

and 1/2,500 in females (heterozygotes) (Figure 17.15).

b. Inheritance follows Mendelian patterns, but only 80% of males with a fragile X chromosome are mentally retarded. The 20% with fragile X chromosome but a normal phenotype are called normal transmitting males.

i. A normal transmitting male can pass the chromosome to his daughter(s).

ii. Sons of those daughters frequently show mental retardation.

c. About 33% of carrier (heterozygous) females show mild mental retardation.

i. Sons of carrier females have a 50% chance of inheriting the fragile X.

ii. Daughters of carrier females have a 50% chance of being carriers.

Fig. 17.14 Diagram of a human X chromosome showing the location of the fragile site

responsible for fragile X syndrome


Variations in Chromosome Number

1. An organism or cell is euploid when it has one complete set of chromosomes, or exact multiples of complete sets. Eukaryotes that are normally haploid or diploid are euploid, as are organisms with variable numbers of chromosome sets.

2. Aneuploidy results from variations in the number of individual chromosomes (not sets), so that the chromosome number is not an exact multiple of the haploid set of chromosomes.

Changes in One or a Few Chromosomes1. Aneuploidy can occur due to nondisjunction during meiosis.

a. Nondisjunction during meiosis I will produce four gametes, two with a chromosome duplicated, and two that are missing that chromosome.

i. Fusion of a normal gamete with one containing a chromosomal duplication will produce a zygote with three copies of that chromosome, and two of all others.

ii. Fusion of a normal gamete with one missing a chromosome will result in a zygote with only one copy of that chromosome, and two of all others.

b. Nondisjunction during meiosis II produces two normal gametes and two that are abnormal (one with two sibling chromosomes, and one with that chromosome missing).

i. Fusion of abnormal gametes with normal ones will produce the genotypes discussed above.

ii. Normal gametes are also produced, and when fertilized will produce normal zygotes.

c. More complex gametic chromosome composition can result when:

i. 1 chromosome is involved.

ii. Nondisjunction occurs in both meiotic divisions.

iii. Nondisjunction occurs in mitosis (result is somatic cells with unusual chromosome complements).

2. Autosomal aneuploidy is not well tolerated in animals, and in mammals is detected mainly after spontaneous abortion. Aneuploidy is much better tolerated in plants. There are four main types of aneuploidy (Figure 17.16):

a. Nullisomy involves loss of 1 homologous chromosome pair (the cell is 2N - 2).

b. Monosomy involves loss of a single chromosome (2N - 1).

c. Trisomy involves one extra chromosome, so the cell has three copies of one, and two of all the others (2N + 1).

d. Tetrasomy involves an extra chromosome pair, so the cell has four copies of one, and two of all the others (2N + 2).

3. More than one chromosome or chromosome pair may be lost or added. Examples:

a. A double monosomic aneuploidy has two separate chromosomes present in only one copy each (2N - 1 - 1).

b. A double tetrasomic aneuploidy has two chromosomes present in four copies each (2N + 2 + 2).

Fig. 17.16 Normal (theoretical) set of metaphase chromosomes in a diploid (2N)

organism (top) and examples of aneuploidy (bottom)


Fig. 17.17 Meiotic segregation possibilities in a trisomic individual


5. Human examples of aneuploidy in autosomes and sex chromosomes are summarized in Table 17.1.

a. Sex chromosome aneuploidy is found more often than autosome aneuploidy, because lyonization compensates for chromosome dosage.

b. Autosomal monosomies are rarely found in humans, presumably because they are lost early in pregnancy.

c. Autosomal trisomies account for about half of fetal deaths, and only a few are seen in live births. Most (trisomy-8, -13 and -18) result in early death, with only trisomy-21 (Down syndrome) surviving to adulthood.


e. Trisomy-13 (Patau syndrome) occurs in 2/104 live births, and most die within the first 3 months. Characteristics include (Figure 17.21):

i. Cleft lip and palate.

ii. Small eyes.

iii. Polydactyly (extra fingers and toes).

iv. Mental and developmental retardation.

v. Cardiac and other abnormalities.


f. Trisomy-18 (Edwards syndrome) occurs in 2.5/104 live births, and 90% die within 6 months. About 80% of Edwards syndrome infants are female. Characteristics include (Figure 17.22):

i. Small size with multiple congenital malformations throughout the body.

ii. Clenched fists.

iii. Elongated skull.

iv. Low-set ears.

v. Mental and developmental retardation.


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Human Chromosomes We have 46 chromosomes, or 23 pairs. 44 of them are called autosomes and are numbered 1 through 22. Chromosome 1 is the longest, 22 is