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15
The Human Genome
Lecture Outline
I.
The study of human genetics requires alternative methods
A. Chromosomes are identified by karyotyping, analysis of inheritance patterns,
pedigree, DNA sequencing, and mapping of genes
B. Studies of pedigrees are problematic because human families are small
II.
Karyotyping is the analysis of chromosomes
A. Cytogenetics is the study of chromosomes and inheritance
1. Cytogenetics is based on studies of humans as well as Drosophila and
other organisms
B. A karyotype shows the composition of the chromosomes of an individual
1. The normal number of chromosomes in humans is 46: 44 autosomes and 2
sex chromosomes
2. In preparing a karyotype, harvested cells are first cultured
3. The cells are then treated with colchicine, which arrests the cells in
metaphase, then treated and stained to observe the chromosomes
4. Chromosomes can be photographed or visualized using a computer and
then analyzed, and are identified by size, position of the centromere,
banding, and staining regions
5. Chromosomes are also distinguished by FISH (fluorescent in situ
hybridization), which can show linkage and fusion of chromosomes, and
some genetic diseases and cancers
C. Family pedigrees can help identify some inherited conditions
1. A pedigree is a chart that shows the transmission of genetic traits in a
family over several generations
2. Studying pedigrees enables geneticists to learn more about Mendelian
traits
3. Pedigrees are only useful for studying traits with simple Mendelian
inheritance patterns
4. Characteristics, such as those with genomic imprinting, do not show
simple Mendelian patterns of genetics, such as Prader-Willi (PWS) and
Angelman (AS) syndromes
D. The Human Genome Project is sequencing the DNA on all human
chromosomes
1. In 1999, chromosome 22 (a small chromosome) was the first human
chromosome to be completely sequenced
2. In 2003, the final DNA sequencing of the human genome was completed;
the current estimate of the number of genes it contains is less than 30,000
3.
4.
a) What does it all mean?
The problem of sequencing the remaining human chromosomes is
complicated by the fact that 95% or more of the genome is noncoding or
has an unidentified functions to date
a) Many of these sections code for mRNAs, "potential" genes whose
products have never been identified
There are many exciting medical applications of the information that will
be obtained from the Human Genome Project
III.
The Human Genome Project stimulated the genome sequencing of other species
A. Mice and rats are dissimilar enough from humans that identical gene
sequences found in both are of functional and evolutionary significance
B. Other sequences that are being determined, or are already partially
determined, include the pufferfish (smallest known genome of all
vertebrates), the zebrafish, salmon, chickens, pigs, rice, Plasmodium,
Trypanosoma, and the chimpanzee
C. Bioinformatics (also called biological computing) is a new discipline involving
the storage, retrieval, and comparison of DNA sequences of various species
D. Pharmacogenics customizes drugs to match a patient’s genetic makeup
1. It is thought that soon a pharmacist will take a patient’s genetic screening
tests into account when prescribing a drug
2. DNA microarrays (DNA chips or gene chips), in which thousands of DNA
molecules are placed on a small chip, can be scanned; genes found with a
cDNA strand are amplified using PCR to yield information on that
individual (the actual process is much more involved!)
3. These gene chips can be used by physicians, pharmacogeneticists to
customize a treatment for a condition
4. The chips can also be used to show what conditions the patient may be
predisposed for—future diseases such as coronary artery disease or cancers
5. Proteomics, or functional genomics, is already the next wave or research
a) It is important to know what protein a gene is coding for
b) This is a close tie between the gene sequencers and the pharmaceutical
industry
E. Researchers use mouse models to study human genetic diseases
1. Gene targeting produces strains of mice that are homozygous or
heterozygous for a particular disease or disorder of interest
2. The cystic fibrosis gene has been highly studied in mice, and the gene has
been cloned, the protein has been studied, and the link to the disease
process is understood
IV.
Abnormalities in chromosome number cause certain human disorders
A. Polyploidy is the presence of additional sets of chromosomes
1. Polyploidy is common in plants
2. Polyploidy is typically lethal in animals
3. Polyploidy is due to nondisjunction, or multiple fertilizations of an egg
B. Aneuploidy is a condition of a single extra chromosome (e.g., trisomic for a
particular chromosome) or a missing chromosome (e.g., haploid for that
chromosome)
1. Aneuploidies result from nondisjunction during meiosis or mitosis
C. Persons with Down syndrome are usually trisomic for chromosome 21
1. Down syndrome is a relatively common chromosomal abnormality
2. Morphological characteristics include differences in the face, tongue, and
hands, and individuals are mentally retarded
3. Persons are also overly susceptible to diseases such as some cancers and
Alzheimer’s disease
4. Down syndrome is typically caused by a trisomy of chromosome 21,
usually caused by nondisjunction during oogenesis
5. Down syndrome is much more common in offspring from older mothers,
but explanations for this phenomenon vary
6. Affected individuals may vary in the severity of their symptoms
7. Other trisomies are typically inviable, as are monosomies
D. Most sex chromosome aneuploidies are less severe than autosome
abnormalities
1. Because mammals compensate for 2 X chromosomes by the single active X
hypothesis (the Barr body), these aneuploidies are less serious
a) The presence of a Barr body has often been used to screen for genetic
males and females, but has serious limitations
2. Individuals with Klinefelter syndrome have an XXY karyotype
a) Klinefelter males have small testes and are often sterile
b) Klinefelter males are often tall and have female-like breast
development; about half are mentally impaired
3. Persons with Turner syndrome have 1 one X chromosome and no Y
chromosome
a) Turner syndrome females are designated as XO, and have
undeveloped reproductive structures and are sterile
b) No Barr bodies are apparent in persons with Turner syndrome
4. Some essentially normal males have an XYY karyotype
a) Persons with an extra Y chromosome are fertile, phenotypically male,
often very tall, and have acne
E. Aneuploidies usually result in prenatal death
1. Chromosome abnormalities are relatively common at conception but
usually result in a miscarriage
2. Approximately 20% of all pregnancies may be spontaneously aborted,
often due to major chromosomal abnormalities early in gestation
F. Translocation is attachment of part of a chromosome to a nonhomologous
chromosome
1.
This is the cause of approximately 4% of cases of Down syndrome
G. A deletion is loss of part of a chromosome
1. Most large deletions are nonviable
2. An example of a deletion is the cri-du-chat syndrome
H. Fragile sites are weak points at specific sites in chromatids
1. Fragile sites appear to be held together by thin strands of chromatin
2. Fragile X syndrome is a relatively common cause of mental retardation,
particularly in males
V.
Genetic diseases caused by single-gene mutations and most genetic diseases are
inherited as autosomal recessive traits
A. Inborn errors of metabolism typically result in prenatal or early death
B. Phenylketonuria (PKU) is due to an enzyme deficiency and can be treated
with a special diet
1. Phenylketonurics convert phenylalanine into a toxic intermediate
2. Untreated PKU leads to severe mental retardation
3. Newborns are typically tested for PKU
4. Pregnant females should follow a strict diet to prevent maternal PKU from
affecting the fetus
C. Sickle cell anemia results from a hemoglobin defect
1. Sickle cell anemia is particularly common in persons of African descent
2. Sickled cells have abnormal hemoglobin (1 amino acid substitution), which
causes the red blood cells to take on a sickled shape
3. Sickled cells block small venous vessels and have shortened life spans,
resulting in anemia
4. Available treatments are limited, but gene therapy may someday be
possible
5. Heterozygote advantage is the cause for the disproportionately greater
number of persons with this disorder of African or Mediterranean descent,
as heterozygotes are resistant to falciparum malaria
D. Cystic fibrosis results from defective ion transport
1. CF is the most common serious autosomal recessive disorder in Caucasians
2. Due to an abnormal chloride transport protein, mucus builds up in the
respiratory system, pancreas, and reproductive system
3. Antibiotics, diet therapy, and new recombinant treatments allow affected
persons to live into their twenties and thirties
E. Tay-Sachs disease results from abnormal lipid metabolism in the brain
1. A lysosomal enzyme is missing, which results in improper lipid
metabolism in cells, particularly those of the nervous system
2. Tay-Sachs is particularly common among Ashkenazi Jews and their
descendants
a) This pattern of distribution may have been due to a population
bottleneck, or heterozygote advantage (resistance to tuberculosis)
3.
Recent research on mice indicates that an oral inhibitor may reduce the
lipid accumulation in the lysosomes which causes the disorder
VI.
Some genetic diseases are inherited as autosomal dominant traits
A. Huntington’s disease is an autosomal dominant disorder that affects the
nervous system
B. This is an unusual disease, as it is a dominant disorder, and 50% of the
offspring of an affected person may be also affected
1. Further, it is a late acting gene and often is diagnosed after the person has
reproduced
C. The gene causing Huntington’s disease was identified in 1993
1. The gene is a nucleotide triplet repeat (to over 100 times), and the degree of
the repeat appears to be related to severity and age of onset of symptoms
2. Now a genetic analysis can be run to see if a person has the HD allele
VII. Some genetic diseases are inherited as X-linked recessive traits
A. Hemophilia A is a classic example
B. This disorder is characterized by internal bleeding, which may lead to death if
untreated
C. Now, treatment is via transfusions of clotting factor VIII
1. Prior to 1992, blood transfusions for clotting factors were in jeopardy of
being infected with HIV (the virus that causes AIDS)
VIII. Many tools for genetic testing and counseling have been developed
A. Early detection of genetic abnormalities increases the possibility for
prevention or alleviation of effects
1. Amniocentesis involves sampling the fluid of the amniotic sac, which
contains shed epidermal cells of the fetus
a) Positioning of the needle is done via ultrasound imaging
b) After several weeks of laboratory culture, cells of the fetus can be
visualized
c) Karyotyping can indicate Down syndrome and other aneuploidies
d) The amniotic fluid may also be chemically analyzed to detect disorders
such as Tay-Sachs, sickle cell anemia, Huntington’s, cystic fibrosis, and
spina bifida
e) Other tests require the use of genetic engineering methods
f) The main drawback of amniocentesis is that it detects mostly incurable
defects and must be done relatively late in the pregnancy
2. Chorionic villus sampling (CVS) samples fetal cells of the placenta and can
be done earlier in pregnancy
3. PGD (pre-implantation genetic diagnosis) is recommended for parents at
high risk
a) This test can determine Tay Sachs, hemophilia A, sickle cell anemia,
and many other conditions
b)
B.
Conception occurs in vitro, then the embryos are screened before
implantation, allowing for sex determination
Genetic screening of a population looks for a genotype or karyotype
IX.
Genetic counselors educate people about genetic diseases
A. Genetic counselors can only give the probability of a certain condition
occurring in the offspring
B. The probabilities remain constant with each sequential pregnancy
X.
Human genetics, society, and ethics
A. Both human genetics and our beliefs about genetics affect society
B. All individuals have abnormal, potentially lethal alleles
1. Because of this, consanguineous matings are prohibited in many countries
C. Genetic discrimination provokes heated debate
1. Should information on genetic information be available to employers or
health insurance companies?
2. Various laws, research, referendums etc. regarding this issue are in place or
pending
D. Many ethical issues related to human genetics must be addressed
Research and Discussion Topics

What genetic disorders are currently identifiable through prenatal testing (such as
chorionic villus sampling and amniocentesis)? How are these procedures
accomplished?

Investigate the phenotypes of persons with Turner and Klinefelter syndrome, and
other sex chromosome abnormalities, such as XXX, XYY, and XXYY. How do these
different combinations arise? What gender are these persons?