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Gene And Disease
基因与疾病
Deqiao Sheng PhD
[email protected]
Biochemistry Department
Basic concept and classification

Genes transmit inherited traits (including
mutations that cause disease) from one generation
to the next
 Genetic factors play a major role in the
development and severity of many, if not most,
diseases.
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Cancer
Alzheimer's
Diabetes
Infections
Damage to the genes by radiation, chemicals and
the like may accumulate over a lifetime and
contribute to the changes associated with aging.

What are genes?
– A gene is a molecular unit of heredity of a living
organism. It is a name given to some stretches
of DNA and RNA that code for a polypeptide or
for an RNA chain that has a function in the
organism.
– Genes are specific lengths of DNA that
determine the order of amino acids used to
make protein.
– Alternative forms of the same gene are called
alleles.
Useful definitions

Locus: a unique chromosomal
location defining the position of
an individual gene or DNA
sequence
 Allele : one of several
alternative forms of a gene
existing at a locus (Homologous
chromosome)
 Mutation: sequence variation
resulting in a phenotypic
difference

Genotype
– The genotype is the genetic makeup of a cell, an
organism, or an individual (i.e. the specific
allele makeup of the individual) usually with
reference to a specific character under
consideration.

Phenotype
– A phenotype is the composite of an organism's
observable characteristics or traits: such as its
morphology, development, biochemical or
physiological properties, phenology, behavior,
and products of behavior (such as a bird's nest).

An organism's genotype is a major (the largest by
far for morphology) influencing factor in the
development of its phenotype, but it is not the only
one.
– Even two organisms with identical genotypes normally
differ in their phenotypes. One experiences this in
everyday life with monozygous (i.e. identical) twins.
Identical twins share the same genotype, since their
genomes are identical; but they never have the same
phenotype, although their phenotypes may be very
similar.

Phenotypes result from the expression of an
organism's genes as well as the influence of
environmental factors and the interactions
between the two!!!
What is a gene mutation and
how do mutations occur?

A gene mutation is a permanent change in the
DNA sequence that makes up a gene. Mutations
range in size from a single DNA building block
(DNA base) to a large segment of a chromosome.
 Gene mutations can occur for a variety of reasons,
and have a range of effects, from benign to
malignant.
 Benign mutations in genetic material explain why
people look very different, for example, while
cancer is caused by malignant genetic mutations.

Hereditary or germline mutations occur when eggs
or sperm develop mutations which are passed on
to the baby. These mutations often occur because
of errors in the generation of eggs and sperm,
although they can also be errors which have been
passed down over generations.
 If a gene mutation occurs after fertilization, as
might occur when some of the rapidly dividing
cells in a developing fetus mutate, it is a new or de
novo mutation.
 Both types of mutation can lead to congenital
disabilities, or they may be so minimal that they
are not evident.
Hereditary Mutations
Egg
Sperm
Mutation Occurs
Fertilized Egg
Reproductive
Bone
Mutation
Pancreas
Body Cells of Offspring
Brain
Acquired Mutations
Normal Bone Cell
Mutation Occurs
Altered Gene
Altered Bone Cells
Normal Bone Cells

Two classes of mutations are spontaneous
mutations (molecular decay) and induced
mutations caused by mutagens.
– Spontaneous mutation
• Depurination, Deamination , Slipped strand
mispairing
– Induced mutation (by mutagens):
• Chemicals: Base analogs , DNA intercalating agents
(e.g. ethidium bromide), DNA crosslinkers, Oxidative
damage
• Radiation :Ultraviolet radiation
– pyrimidine dimer

Mutation can result in several different
types of change in sequences; these can
either have no effect, alter the product of a
gene, or prevent the gene from functioning
properly or completely.
Classification of mutation types
By effect on structure
– Point mutations (Silent mutations/Missense
mutations/Nonsense mutations)
– Insertions
– Deletions (remove one or more nucleotides or
large chromosomal regions from the DNA)
Insertion
Deletion
By effect on function
– Loss-of-function mutations
– Gain-of-function mutations
– Dominant negative mutations
– Lethal mutations
– back mutation or reversion
DNA
Cell
membrane
Nucleus
DNA
bases
mRNA
Chain of
amino
acids
Gene
Protein
Ribosome
Altered DNA→Altered Protein
Genes and Disease

Categories of Human disease
 Single-gene
disorders (Monogenic disease)
 Multifactorial disorders (Polygenic disease)
 Chromosomal disorders
 Mitochondrial disorders
 Acquired genetic disease (infectious diseases)
Monogenic diseases

Caused by the inheritance of a single
defective gene
 Scientists currently estimate that over
10,000 of human diseases are known to be
monogenic.
 Pure genetic diseases are caused by a single
error in a single gene in the human DNA.
The nature of disease depends on the
functions performed by the modified gene.

The single-gene or monogenic diseases can
be classified into three main categories:
– Dominant（显性）
– Recessive （隐性）
– X-linked （X-连锁）

All human beings have two sets or copies of each
gene called “allele”; one copy on each side of the
chromosome pair.
– Recessive diseases are monogenic disorders that occur
due to damages in both copies or allele.
– Dominant diseases are monogenic disorders that involve
damage to only one gene copy.
– X linked diseases are monogenic disorders that are
linked to defective genes on the X chromosome which is
the sex chromosome. The X linked alleles can also be
dominant or recessive. These alleles are expressed
equally in men and women, more so in men as they
carry only one copy of X chromosome (XY) whereas
women carry two (XX).
Monogenic diseases

Hundreds of different monogenic diseases, caused
by errors in hundreds of different genes, have
been discovered.
 Most of these disorders are very rare; however a
few are relatively common. Well known
monogenic diseases include cystic fibrosis, sickle
cell anemia and Tay Sachs disease, which are
recessive diseases, and myotonic dystrophy and
Marfan syndrome, which are dominant.
Type or protein from
mutant gene
Example
Clinical disorder
Enzyme
Phenylalanine hydroxylase
Adenosine deaminase
Phenylketonuria
Severe combined
immune deficiency
(SCID)
Enzyme inhibitor
Alpha-1-antitrypsin
Emphysema and liver
disease
Membrane receptor
Low-density lipo-protein receptor
Familial
hypercholesterolemia
Membrane ion channel
Cystic fibrosis transmembrane
conductance regulator
Cystic Fibrosis
Structural protein
Hemoglobin
Fibrillin
Dystrophin
Sickle cell disease
Marfan’s syndrome
Muscular dystrophy
Cell growth inhibitor
NF-1
Neurofibromatosis
Tumor suppressor
Rb protein
Retinoblastoma
Clotting factor
Factor VIII
Hemophilia
Sickle-cell anaemia
镰状红细胞贫血

Sickle cell anemia is a disease of red blood cells. It
is caused by a mutation in the hemoglobin gene.
 A single base change results in a single amino acid
substitution. This mutation causes the hemoglobin
to change its conformation to a more elongated
form under certain conditions, distorting the red
blood cells and impairing their ability to carry
oxygen.

Normal hemoglobins in the red cell consist of Hb A, Hb F,
and Hb A2. The protein sequences are DNA coded on
Chromosome 11 for the beta, delta and gamma chains. The
alpha chains are coded on Chromosome 16. The beta
variants such as Hb S, Hb C, and Hb D all occur from a
mutation on Chromosome 11.

SCA is an autosomal recessive disease caused by a
point mutation in the hemoglobin beta gene (HBB)
found on chromosome 11p15.4.
 Single base mutation in the 6th codon (CTC to
CAC) of the beta-hemoglobin gene
 Results in substitution of valine for glutamic acid
in beta chain

Hemoglobin S is an inherited variant of
normal adult hemoglobin (hemoglobin A). It
results from a substitution of valine for
glutamic acid in the sixth position of the β
globin chain.

Normal Hemoglobin
– Hemoglobin AA (adult)
– Hemoglobin F (fetal)

Sickle Cell Hemoglobin
– Hemoglobin AS (trait)
– Hemoglobin SS (disease)

In sickle cell trait (Hgb AS) 35-45% of
hemoglobin is affected
Pathophysiology

Sickled cells have shortened lifespan (16-20
days compared to 120) resulting in chronic
anemia
 Microvascular occlusion leads to impaired
delivery of oxygen to tissues and chronic
tissue damage
 Sickled cells also cause endothelial damage
to larger vessels resulting in thickened walls,
stenosis, occlusion and thrombus formation
Fragile X syndrome

The Fragile X syndrome is caused by a
"fragile" site at the end of the long arm of
the X-chromosome.
 It is a genetic disorder that manifests itself
through a complex range of behavioral and
cognitive phenotypes. It is the result of
genetic mutation which varies considerably
in severity among patients.

Fragile X syndrome is the most common
cause of inherited mental retardation.
Although it is a X-linked recessive trait with
variable expression and incomplete
penetrance, 30% of all carrier women are
affected.
Multifactorial disorders

Common medical problems such as heart disease,
diabetes, and obesity do not have a single genetic
cause—they are likely associated with the effects
of multiple genes in combination with lifestyle and
environmental factors. Conditions caused by many
contributing factors are called complex or
multifactorial disorders.
 Complex disorders are also difficult to study and
treat because the specific factors that cause most
of these disorders have not yet been identified.
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Asthma(哮喘 )
autoimmune diseases
cancers
ciliopathies
cleft palate
diabetes
heart disease
hypertension
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inflammatory bowel
disease
mental retardation
mood disorder
obesity
refractive error
infertility
Cancer

Cancer is ultimately the result of cells that
uncontrollably grow and do not die. Normal
cells in the body follow an orderly path of
growth, division, and death. Programmed
cell death is called apoptosis, and when this
process breaks down, cancer begins to form.
Unlike regular cells, cancer cells do not
experience programmatic death and instead
continue to grow and divide. This leads to a
mass of abnormal cells that grows out of
control.

Cancer is a leading cause of death
worldwide, accounting for 7.6 million deaths
(around 13% of all deaths) in 2008
 Lung, stomach, liver, colon and breast
cancer cause the most cancer deaths each
year.
 About 30% of cancer deaths are due to the
five leading behavioral and dietary risks:
high body mass index, low fruit and
vegetable intake, lack of physical activity,
tobacco use, alcohol use.

Tobacco use is the most important risk
factor for cancer causing 22% of global
cancer deaths and 71% of global lung
cancer deaths.
 Cancer causing viral infections such as
HBV/HCV and HPV are responsible for up
to 20% of cancer deaths in low- and middleincome countries.

The main types of cancer are:
– lung (1.37 million deaths)
– stomach (736 000 deaths)
– liver (695 000 deaths)
– colorectal (608 000 deaths)
– breast (458 000 deaths)
– cervical cancer (275 000 deaths)
What causes cancer?

Cancer arises from one single cell. The
transformation from a normal cell into a
tumor cell is a multistage process, typically
a progression from a pre-cancerous lesion to
malignant tumors. These changes are the
result of the interaction between a person's
genetic factors and three categories of
external agents, including:
– physical carcinogens, such as ultraviolet
and ionizing radiation;
– chemical carcinogens, such as asbestos,
components of tobacco smoke, aflatoxin
(a food contaminant) and arsenic (a
drinking water contaminant); and
– biological carcinogens, such as infections
from certain viruses, bacteria or parasites.

There are many different kinds of cancers. Cancer
can develop in almost any organ or tissue, such as
the lung, colon, breast, skin, bones, or nerve tissue.
 There are many causes of cancers, including:
– Benzene and other chemicals
– Drinking excess alcohol
– Environmental toxins, such as certain poisonous
mushrooms and a type of poison that can grow on
peanut plants (aflatoxins)
– Excessive sunlight exposure
– Genetic problems
– Obesity
– Radiation
– Viruses

Ageing is another fundamental factor for
the development of cancer. The incidence of
cancer rises dramatically with age, most
likely due to a build up of risks for specific
cancers that increase with age.

Determining what causes cancer is complex.
– Many things are known to increase the risk of
cancer, including tobacco use, certain infections,
radiation, lack of physical activity, obesity, and
environmental pollutants.
– These can directly damage genes or combine
with existing genetic faults within cells to cause
the disease. Approximately five to ten percent of
cancers are entirely hereditary.

Cancers are primarily an environmental disease
with 90-95% of cases attributed to environmental
factors and 5-10% due to genetics.
 Environmental, as used by cancer researchers,
means any cause that is not inherited genetically,
not merely pollution. Common environmental
factors that contribute to cancer death include
tobacco (25-30%), diet and obesity (30-35%),
infections (15-20%), radiation (both ionizing and
non-ionizing, up to 10%), stress, lack of physical
activity, and environmental pollutants.

Studies have shown that the primary determinants
of most cancers are lifestyle factors, such as
tobacco, dietary and exercise habits, environment
carcinogens and infectious agents, rather than
inherited genetic factors.
 In fact, inherited cancer syndromes caused by
high penetrance genes transmitted In fact, the
proportion of cancers caused by high penetrance
genes is low, about less than 5% for breast cancer
and less for most other cancer types except
retinoblastoma in children.
Pathophysiology

Cancer is fundamentally a disease of failure
of regulation of tissue growth. In order for a
normal cell to transform into a cancer cell,
the genes which regulate cell growth and
differentiation must be altered.
 Cancer occurs because of mutations in the
genes responsible for cell multiplication and
repair.
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The affected genes are divided into two broad
categories.
– Oncogenes are genes which promote cell growth and
reproduction.
– Tumor suppressor genes are genes which inhibit cell
division and survival. Malignant transformation can
occur through the formation of novel oncogenes, the
inappropriate over-expression of normal oncogenes, or
by the under-expression or disabling of tumor
suppressor genes.

Typically, changes in many genes are required to
transform a normal cell into a cancer cell.

Genetic changes can occur at different levels
and by different mechanisms. The gain or
loss of an entire chromosome can occur
through errors in mitosis. More common
are mutations, which are changes in the
nucleotide sequence of genomic DNA.

The mutation of critical genes, including
supressor genes, oncogenes and genes
involved in DNA repair, leads to genetic
instability and to progressive loss of
differentiation.
Global status report on noncommunicable
diseases 2010 (WHO)
Cancer is second leading cause of death
Estimated annual number of new cases and deaths for the 10 most common
cancers, by World Bank income groups and by sex, 2008
Cardiovascular disease

Major cardiovascular diseases (CVD) include
coronary heart disease, cerebrovascular disease,
heart failure, rheumatic heart disease and
congenital heart disease. The major risk factors
associated with cardiovascular diseases are
cigarette smoking, unhealthy diet, physical
inactivity, hypertension, diabetes and high blood
cholesterol.

CVD may also result from a variety of genetic
causes, including single-gene mutations, the
interaction of multiple genes and environmental
factors. Economic transition, urbanisation,
industrialization and globalisation bring about
lifestyle changes that promote heart disease. Life
expectancy in developing countries is rising
sharply and people are exposed to these risk
factors for longer periods

Of the estimated 16.6 million deaths
attributed to CVD worldwide, 80% is in
developing countries. By 2010, CVD is
estimated to be the leading cause of death in
developing countries.

Cardiovascular disease is a class of diseases that
involve the heart or blood vessels (arteries,
capillaries and veins). Cardiovascular disease
refers to any disease that affects the
cardiovascular system, principally cardiac disease,
vascular diseases of the brain and kidney, and
peripheral arterial disease. The causes of
cardiovascular disease are diverse but
atherosclerosis and/or hypertension are the most
common.

Almost all cardiovascular disease in a population
can be explained in terms of a limited number of
risk factors: age, gender, high blood pressure, high
serum cholesterol levels, tobacco smoking,
excessive alcohol consumption, family history,
obesity, lack of physical activity, psychosocial
factors, diabetes mellitus, air pollution. While the
individual contribution of each risk factor varies
between different communities or ethnic groups
the consistency of the overall contribution of these
risk factors is remarkably strong.
Chromosomal Disorders

Numerical (aneuploidy)
– Monosomies (loss of one copy of chromosome)
• If autosome affected, usually incompatible with life
• Sex chromosome monosomies are compatible with
life
– Trisomies (extra copy of chromosome)

Structural
– Result form chromosome breakage followed by loss or
rearrangement of genetic material
Chromosomal Disorders

Loss of chromosomal material produces
more severe defects than does gain
 Excess chromosomal material may result
for complete chromosome (trisomy) or part
of a chromosome
 Imbalances of sex chromosomes are better
tolerated than imbalances of autosomes
Chromosomal Disorders

Aneuploidy of Sex Chromosomes
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Turner’s Syndrome (45, X0)
Poly X Female (45 XXX)
Kleinfelter’s Syndrome (47, XXY)
XYY Males
Trisomy of Autosomes
– Trisomy 21 (Down Syndrome)
– Trisomy 13 (Patau’s Syndrome)
– Trisomy 18 (Edward’s Syndrome)
Down Syndrome

Down Syndrome is a type of mental
retardation caused by extra genetic material
in chromosome 21. This can be due to a
process called nondisjunction, in which
genetic materials fail to separate during a
crucial part of the formation of gametes,
resulting in an extra chromosome (called
trisomy 21).
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Common physical signs include:
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Decreased muscle tone at birth
Excess skin at the nape of the neck
Flattened nose
Separated joints between the bones of the skull (sutures)
Single crease in the palm of the hand
Small ears
Small mouth
Upward slanting eyes
Wide, short hands with short fingers
White spots on the colored part of the eye (Brushfield
spots)
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Children may also have delayed mental and
social development. Common problems may
include:
– Impulsive behavior
– Poor judgment
– Short attention span
– Slow learning
Mitochondrial disorders

Mitochondrial disorders: are rare disorders
caused by mutations in non-chromosomal
DNA located within the mitochondria. (The
mitochondria are subcellular organelles.)
These disorders can be found to affect any
part of the body including the brain and the
muscles.
 Mitochondria DNA (mtDNA)

Mitochondrial diseases are a group of
disorders caused by dysfunctional
mitochondria, the organelles that generate
energy for the cell.
– Mitochondria are found in every cell of the
human body except red blood cells.
– Mitochondria convert the energy of food
molecules into the ATP that powers most cell
functions.

Mitochondrial DNA can be regarded as the
smallest chromosome. Human
mitochondrial DNA was the first significant
part of the human genome to be sequenced.
In most species, including humans, mtDNA
is inherited solely from the mother.

Depending on which cells are affected,
symptoms may include loss of motor control,
muscle weakness and pain, gastro-intestinal
disorders and swallowing difficulties, poor
growth, cardiac disease, liver disease,
diabetes, respiratory complications, seizures,
visual/hearing problems, lactic acidosis,
developmental delays and susceptibility to
infection

Mitochondrial diseases are the result of
either inherited or spontaneous mutations in
mtDNA or nDNA which lead to altered
functions of the proteins or RNA molecules
that normally reside in mitochondria.
 Diseases of the mitochondria appear to
cause the most damage to cells of the brain,
heart, liver, skeletal muscles, kidney and the
endocrine and respiratory systems.

The unique features of mitochondrial
genetics are essential for the understanding
of the etiology and pathogenesis of
mitochondrial disorders.
 Normally, all mitochondria of a human
subject contain genetically identical mtDNA
copies (homoplasmy). However, the mtDNA
has a mutation rate approximately 10–20
times higher than that of the nuclear DNA.