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Human Genetics
Concepts and Applications
Ninth Edition
RICKI LEWIS
22
Genomics
PowerPoint® Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
Introduction
• Biotechnology is the use or alteration of
cells or biological molecules for specific
applications
• A transgenic organism has DNA from
different species
• Recombinant DNA comes from more
than one type of organism
• Both are possible because of the
universality of the genetic code
Introduction
Figure 19.1
Mice containing the jellyfish gene for
green fluorescent protein (GFP)
What is Patentable?
• To qualify for patent protection, a
transgenic organism must be new, useful,
and non-obvious
• Patent law has had to evolve to keep up
with modern biotechnology
• A DNA sequence alone does not warrant
patent protection
•
- It must be useful as a tool for
research or as a novel or improved
product, such as a diagnostic test or drug
What is Patentable?
• A new problem for patenting DNA stems
from the shift in focus of the entire field
from a single-gene to a genome-wide
approach
• Especially problematic are:
•
- “Panels” of tests
•
- “Direct-to-consumer” genetic tests
that scan client’s DNA for many
thousands of SNPs
The “Patent Thicket”
• Term used to describe the need to license
patents for every SNP or snippet of DNA
• Suggested ways around this:
•
- Allow DNA to be patented only for
use in diagnostic tests
•
- Exempt individuals from litigation if
they use patented DNA sequences
• A broader action is to ban patenting any
DNA or its encoded proteins
Horses vs. Zebras
Figure 20.1
Horses vs. Zebras
• Medical students are told early on,
“When you hear hoofbeats, think horses,
not zebras.”
• Single-gene disorders, however, are
often zebras
• Medical geneticists are trained to see the
big picture
•
- Can solve a medical mystery by
putting together the pieces
Genetic Counseling
• Addresses medical, psychological,
sociological, and ethical issues
• A genetic counselor has medical,
scientific, and communication skills
• Genetic counseling began in pediatrics,
and prenatal care, and has become
specialized
• The field has even infiltrated public policy
as genetic testing has become widespread
Genetic Counselors
• The US only has about 3,000
• Provide information to individuals,
couples expecting children, and families
about:
•
- Modes of inheritance
•
- Disease risks and symptoms
•
- Available tests and treatments
• Interpret direct-to-consumer genetic tests
and assist other health care professionals
with genetic information in their practices
Genetic Counselors
• When genetic counseling began, it was
“nondirective”
•
- The practitioner did not offer an
opinion or suggest a course of action, but
presented options
• A more recent definition of the role of the
genetic counselor is “shared deliberation
and decision making between the
counselor and client”
Figure 20.2
Genetic Testing
• Genetic tests diagnose and predict the
course of a disease and predict and
monitor response to treatment
• Using them widely must balance two
traits
•
1) Genetic determinism: our tendency
to blame all ills on our genes
•
2) Identifying ways to change our
lifestyles to compensate for factors that
we cannot control
Newborn Screening
• Usually tests for inborn errors of
metabolism
• Are not genetic tests, but instead they use
tandem mass spectrometry to identify
unusual metabolites or chemical
imbalances that indicate a certain disease
• The American College of Medical Genetics
recommends testing for 29 disorders
•
- However, the actual number of tests
varies by state
• The field of newborn screening began in
1961 with the Guthrie test for
phenylketonuria (PKU)
•
- It detects phenylalanine, which builds
up in affected individuals
• In 1963, a specialized diet became
available
• The diet is difficult to follow, but does
prevent mental retardation
• After diet’s success, genetic tests expanded
• Some states perform DNA tests on
newborns as well as biochemical tests
Direct-To-Consumer Genetic Testing
• Companies market DNA-based tests for
traits, susceptibilities, and genetic diseases
to the general public
• The Clinical Laboratory Improvement
Amendments (CLIA) control genetic testing
• DTC tests presented as information, not
diagnoses, may not be regulated
• Unawareness of incomplete penetrance is
one complication of DTC genetic testing
Nutrigenetics Testing
• Some DTC testing company websites offer
genetic tests along with questionnaires
about diet, exercise, and lifestyle habits
• The company then sends a “nutrigenetics”
profile with dietary suggestions and
pitches to purchase supplements
• However, many of these companies
provide inaccurate information
•
- Some suggestions are even
dangerous
Matching Patient to Drug
• A pharmacogenetic test detects a variant
of a single gene that affects drug
metabolism
• A pharmacogenomic test detects variants
of multiple genes or gene expression
patterns that affect drug metabolism
• These are often considered together under
the umbrella term “personalized medicine”
•
- Help physicians to select the best
drugs for individual patients
Treating Genetic Disease
• Treatments have evolved through stages
•
1) Removing an affected body part
•
2) Replacing an affected body part or
biochemical with material from a donor
•
3) Delivering pure, human proteins
derived from recombinant DNA technology
to compensate for the effects of a mutation
•
4) Gene therapy, to replace mutant
alleles
Treating The Phenotype
• Lysosomal storage diseases are a
subclass of inborn errors of metabolism
• Treatments are based on understanding
metabolic pathways
•
- If any enzyme is deficient or its activity
blocked, the substrate builds up and the
product is deficient
• There are three general approaches for
counteracting these diseases
Figure 20.3
Gene Therapy
• Altering genes theoretically can provide
a longer-lasting effect than treating
symptoms
• The first efforts focused on inherited
disorders with a known mechanism,
even though the conditions are rare
• Gene therapy now is targeting more
common illnesses, such as heart
disease and cancers
Gene Therapy
• Germline gene therapy
•
- Gamete or zygote alteration;
heritable; not done in humans; creates
transgenic organisms
• Somatic gene therapy
•
- Corrects only the cells that a
disease affects; not heritable
Table 20.7
Table 20.8
Invasiveness of Gene Therapy
• Ex vivo gene therapy is applied to cells
outside of body that are then returned
• In situ gene therapy occurs directly on
accessible body parts
• In vivo gene therapy is applied directly
to an interior body part
•
- The most invasive
Gene Therapy: OTC,
Ornithine Transcarbamylase
• Deficiency of OTC is inherited as an Xlinked recessive mutation
• OTC normally breaks down amino acids
present in protein
• Lack of OTC allows buildup of ammonia,
which damages brain function
• Low-protein diets and ammonia-binding
drugs are used to treat OTC deficiency
Gene Therapy: OTC,
Ornithine Transcarbamylase
Clinical trials to treat OTC deficiency were
established using adenovirus as a vector
for the normal OTC gene
Jesse Gelsinger (18 yrs old)had a mild OTC
deficiency, volunteered for the OTC gene
therapy trial and was accepted
Four days after gene therapy Jesse died
from an overwhelming immune reaction
and associated complications ( he had a
virus in his body and was asymptomatic)
OTC Gene Therapy
Figure 20.7
• This led to a suspension of several gene
therapy trials.
• The death drew particular attention to
safety since Jesse had not been very ill..
• Should gene therapy continue?
• What about those disorders without any
cure or treatment?
Gene Therapy:
Leber’s Congenital Amaurosis II
•
•
•
•
Most severe form of blindness
Inherited as autosomal recessive disease
Mutation is in a gene called RPE64
Gene therapy first tried on Briard dogs,
who have the same mutation as humans
•
- It was then tried on four young
adults, and later on 8-year old Corey
Haas
•
- So far it is working! He can see!
Gene Therapy:
Leber’s Congenital Amaurosis II
Figure 20.9
Perspective on Gene Therapy
• Great promise, but slower than expected
• More complex than expected
•
- Gene interactions
•
- Appropriate vectors
•
- Adequately targeting and sustaining
therapeutic effects
•
- Safety issues
Savior Siblings and More
• Innovative ways to conceive offspring:
•
1) Couple in search of an oocyte donor
advertises for an attractive, athletic woman
•
2) Cancer patient stores her oocytes
before therapy; becomes a mother two
years later
•
3) A paralyzed man has sperm removed
and injected into his partner’s oocyte
Savior Siblings and More
• Lisa and Jack Nash sought to have a child
for a different reason
• They conceived and selected Adam to save
his sister’s life
•
- She was suffering from Fanconi
anemia
• A month after his birth, physicians infused
Adam’ umbilical cord stem cells into Molly
Adam and Molly Nash
Figure 21.1
Assisted Reproductive
Technologies
• ARTs are methods that replace the source
of a male or female gamete, aid fertilization
or provide a uterus
• Developed to treat infertility but are
becoming part of genetic screening
• The US Government does not regulate
ARTs
•
- However, the British Government does
Infertility and Subfertility
• Infertility is the inability to conceive a
child after a year of frequent intercourse
without contraceptives
• Subfertility distinguishes couples who
can conceive, but require longer time than
usual
• Affect one in six couples
• A physical cause can be identified in 90%
of cases: 30% in males, 60% in females
Male Infertility
• One in 25 men are infertile
• Easier to detect, but often harder to treat
than female infertility
• Most cases of male infertility are genetic
• Causes of infertility include:
•
- Low sperm count (oligospermia)
•
- A malfunctioning immune system
•
- A varicose vein in the scrotum
•
- Structural sperm defects
Male Infertility
Box Figure 1
• Most cases of male infertility are genetic
•
- Due to small deletions of Y
chromosome that remove genes important
for spermatogenesis
•
- Mutations in genes for androgen
receptors or other hormones promoting
sperm development
• In cases of low sperm count, sperm can
be stored frozen, then pooled
• Lack of motility in sperm prevents
movement in the female reproductive tract
Female Infertility
• Many women with subfertility or infertility
have irregular menstrual cycles
•
- This makes it difficult to pinpoint
when conception is most likely
• Tracking ovulation cycles aids in
determination of the most likely days for
conception
• Abnormalities in any part of the female
reproductive system can cause infertility
Figure 21.2
Female Infertility
• Fertility drugs stimulate ovulation but
may induce release of multiple oocytes
• Blocked fallopian tubes can result in
ectopic pregnancy (tubal pregnancy).
• Excess tissue growth in uterine lining
may make it inhospitable for an embryo
•
- Fibroids: benign tumors
•
- Endometriosis: buildup of uterine
lining
Female Infertility
• Secretions in the vagina and cervix may
be hostile to sperm
• Infertility may also result if the oocyte
fails to release sperm-attracting
chemicals
• Early pregnancy loss due to an abnormal
chromosome number is more common in
older female
•
- May appear as infertility because
bleeding resembles a heavy menstrual
flow
Infertility Tests
• The man is checked first, because it is
easier, less costly and less painful to
obtain sperm than oocytes
•
- Sperm are checked for number
(sperm count) motility and morphology
(shape)
• A gynecologist can then check the
female to see if reproductive organs are
present and functioning
• Psychological factors may also be at
Assisted Reproductive
Technologies (ARTs)
• Many people with fertility problems use
alternative ways to conceive
• In the US, about 1% of the 4 million
births each year are from ARTs
• Several of the ARTs were developed in
nonhuman animals
Assisted Reproductive
Technologies (ARTs)
• Examples
•
- Intrauterine insemination
•
- Surrogate motherhood
•
- In vitro fertilization (IVF)
•
- Gamete intrafallopian transfer
(GIFT)
•
- Zygote intrafallopian transfer (ZIFT)
•
- Oocyte banking and donation
•
- Preimplantation genetic diagnosis
Intrauterine Insemination
• Donated sperm is placed in a woman’s
reproductive tract, typically at the cervix or
in uterus
• Success rate is 5-15%
• 1790: first reported pregnancy from
artificial insemination
• 1953: methods for freezing and storing
sperm were developed
• Sperm catalogs list personal
characteristics
Surrogate Motherhood
• In surrogate motherhood, a woman
carries a pregnancy to term for another
woman who cannot conceive and/or
carry the pregnancy
• Custody rights are given up at birth
• A surrogate mother may or may not have
contributed an oocyte
• Complex legal and emotional issues
must be considered
In vitro Fertilization (IVF)
• For in vitro fertilization, a sperm fertilizes
an oocyte in a culture dish
• Embryos are transferred to the oocyte
donor’s uterus (or a surrogate’s uterus) for
implantation
• 1978: First IVF child born (Louise Joy
Brown)
•
- Since then, 4 million IVF children
• Intracytoplasmic sperm injection (ICSI) is
more effective than IVF alone
Intracytoplasmic Sperm Injection
• For cases in which sperm cannot
penetrate the oocyte, IVF can be
accompanied by ICSI which injects
sperm directly into the oocyte
• ICSI allows conception in cases of low
sperm count, abnormal sperm shape,
sperm motility problems,
•
- And in cases where male has spinal
cord injuries and cannot ejaculate
Intracytoplasmic Sperm Injection
Figure 21.4
Gamete Intrafallopian Transfer
(GIFT)
• GIFT is a method in which superovulated
oocytes from a woman and sperm from
her partner are placed together in her
uterine (fallopian) tube
• Fertilization occurs in the woman’s body
• Allows conception in cases of fallopian
tube blockage
• 22% success rate and costs less than IVF
Zygote Intrafallopian Transfer
(ZIFT)
• IVF ovum is introduced into the uterine
tube and allowed to move to the uterus
for implantation
• Also about 22% successful
• GIFT and ZIFT are done much less
frequently than IVF
•
- They often will not work for women
with scarred uterine tubes
From Genetics To Genomics
• Genetics is a young science, genomics
is younger still
• The term genome was coined in 1920,
to refer to a complete set of
chromosomes and its genes
•
- Now it refers to all the DNA in a
haploid set of chromosomes
• The term genomics was coined in 1986
•
- Indicates the study of genomes
Positional Cloning
• A gene-by-gene approach that matches
single genes to specific diseases
• Begins with a phenotype, and gradually
identifies a causative gene, localizing it to
a part of a chromosome
• In the 1980s and 1990s, yielded
discoveries of genes that cause such
diseases as Duchenne muscular
dystrophy, cystic fibrosis and Huntington
disease
Huntington Disease Pedigree
Box Figure 1
The Human Genome Project
• The idea to sequence the human genome
emerged in the 1980s with several goals
• Officially started in 1990
•
- $3 billion, 15-year project
•
- Under the direction of the DOE and
NIH
• Draft of the human genome in 2001
• Finished sequence in 2003
• Represents the work of thousands of
researchers in an international collaboration
Human Genome Project (ELSI)
• Recognizing the impact of the human
genome project on public policy
• 3% of the government-sponsored budget
was set aside for Ethical, Legal, and
Social Issues
• To prevent misuse of information and
genotypic discrimination
Sequencing Methods
DNA Sequence Data
Figure 22.5
Sequencing Methods
• Newer approaches to DNA sequencing
use a microfluidics environment
•
- A method called 454 sequencing,
can sequence 20 million bases in 4.5
hours!
• Even newer approaches use
nanomaterials to distinguish how each of
the four bases disrupts an electrical field
Comparative Genomics
• Hundreds of species have had their
genomes sequenced
•
- First, viruses and bacteria
•
- Then, our closest relatives (rats and
chimps), and our favorites (cats and dogs)
•
A
Sampling
of Animal
Genomes
Figure 22.8
Comparative Genomics May Help Us
Answer Important Questions
• Minimal set of genes for life
• Distinctions between three domains of
life
• Genes for the simplest eukaryote
• Basic blueprint for an animal
• Genes for terrestrial living
• Birds to mammals
• Chimps to humans
Personal Genome Sequencing
• Comparing the genomes of healthy people
to those with certain diseases will reveal
how gene combinations affect health
•
- This permits recognition of controllable
environmental factors
• Sequencing personal genomes is under
way
•
- The information can be used in
several ways