Transcript Lctures Clinical genetics – 6

Lectures Clinical Genetics
Dr. Aneela Javed
MULTIFACTORIAL DISORDERS
Conditions caused by many contributing factors are called complex or
multifactorial disorders.
•
sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene.
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heart disease, diabetes, and obesity do not have a single genetic cause—
likely associated with the effects of multiple genes in combination with
lifestyle and environmental factors
Although complex disorders often cluster in families, they do not have a clearcut pattern of inheritance. This makes it difficult to determine a person’s risk of
inheriting or passing on these 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.
Researchers continue to look for major contributing genes for many common
complex disorders.
On the first page of the first chapter of On the Origin of Species,
Charles Darwin noted that two factors are responsible for biological
variation—“the nature of the organism and the nature of the
conditions.”
genes and the environment are actually two forces that interact, and
they do so in ways that mold many of our characteristics.
A trait can be described as either
1. Single gene (or Mendelian or monogenic)
2. Polygenic, reflects the activities of more than one gene
Both single-gene and polygenic traits can also be
multifactorial, which means they are influenced by the
environment.
Pure polygenic traits—those not influenced by the environment—
are very rare.
Up to 10% of newborn children will express a multifactorial disease at some
time in their life. Atopic reactions, diabetes, cancer, spina
bifida/anencephaly, pyloric stenosis, cleft lip, cleft palate, congenital hip
dysplasia, club foot, and a host of other diseases all result from
multifactorial inheritance. Some of these diseases occur more frequently in
males. Others occur more frequently in females. Environmental factors as
well as genetic factors are involved.
Multifactorial inheritance was first studied by Galton, a close relative of
Darwin and a contemporary of Mendel. Galton established the principle of
what he termed "regression to mediocrity." Mendel studied discontinuous
characters, green peas vs. yellow peas, tall vs. dwarf, etc. There was no
overlap of phenotype. Galton studied the inheritance of continuous
characters, height in humans, intelligence in humans, etc. Galton noticed that
extremely tall fathers tended to have sons shorter than themselves, and
extremely short fathers tended to have sons taller than themselves. "Tallness"
or "shortness" didn't breed true like they did in Mendel's pea experiments.
The offspring seemed to regress to the median, or "mediocrity.”
Multifactorial traits affect more than 1 in 1,000 individuals and include
height, skin color, body weight, illnesses, and behavioral conditions and
tendencies.
The genes of a multifactorial trait are not inherently more
complicated than others. They follow Mendel’s laws, but expression
of the genes is more difficult to predict because of the combined
actions of genes and the environment.
An example of a single-gene trait that is influenced by the
environment is alpha-1 antitrypsin (AAT) deficiency (OMIM
107400), which causes an inherited form of the lung disease
emphysema. Although some individuals who inherit AAT
deficiency develop lung problems early in life even if they never
smoke or encounter pollution, others require exposure to an
irritant to become ill.
People with AAT deficiency were overrepresented among the
rescue workers from the World Trade Center site on September
11, 2001 who developed persistent lung problems. Exposure to
the particle-laden air at the site triggered or hastened their
inherited lung disease.
POLYGENIC MULTIFACTORIAL CONDITION
A polygenic multifactorial condition reflects additive
contributions of several genes. Each gene confers a degree of
susceptibility, but the input of these genes is not necessarily
equal.
For example, three genes contribute to the risk of developing type
2 diabetes mellitus.
Different genes may contribute different aspects of a phenotype
that was once thought to be due to the actions of a single gene..
Consider migraine, a condition for which many a sufferer will
attest is more than just a headache. Studies have found that a
gene on chromosome 1 contributes sensitivity to sound; a gene
on chromosome 5 produces the pulsating headache and
sensitivity to light; and a gene on chromosome 8 is associated
with nausea and vomiting. In addition, certain environmental
influences are well known to trigger migraine in some people
POLYGENIC TRAITS ARE CONTINUOUSLY VARYING
For a polygenic trait, the combined action of many genes often produces a “shades of
grey” or “continuously varying” phenotype, also called a quantitative trait. DNA
sequences that contribute to polygenic traits are called quantitative trait loci, or
QTLs. The individual
genes that confer a polygenic trait follow Mendel’s laws, but together they do not
produce single-gene phenotypic ratios. They all contribute to the phenotype, but
without being dominant or recessive to each other. For example, the multiple genes
that regulate height and skin color result in continuously varying phenotypes. Singlegene traits are instead discrete or qualitative, often providing an “all-or-none”
phenotype such as “normal” versus “affected.”
A BELL-SHAPED CURVE
A polygenic trait varies in populations, Although the
expression of a polygenic trait is continuous, we can
categorize individuals into classes and calculate the
frequencies of the classes. When we do this and plot the
frequency for each phenotype class, a bell-shaped curve
results. Even when different numbers of genes affect the
trait, the curve takes the same shape.
FINGERPRINT PATTERNS
During weeks 6 through 13 of
prenatal development, the ridge pattern can
be altered as the fetus touches the finger and
toe pads to the wall of the amniotic sac. This
early environmental effect explains why the
fingerprints of identical twins, who share all
genes, are in some cases not exactly alike.
Height
EYE COLOUR
SKIN COLOUR
CHANGING MYTHS
Skin color is one trait used to distinguish race
In one telling investigation, 100 students
many were quite surprised at what th
in a sociology class in “Race and Ethnic
DNA revealed about their ancestry. O
Relations” at Pennsylvania State
student, a light-skinned black, learne
University
genetically he is 52 percent black Afri
demonstrated that skin color does not
and 48 percent European white:
necessarily
approximately half black, half white.
reflect ancestry. The students had
student who considered herself black
their DNA tested for percent contribution
actually 58 percent white European. T
from “European white,” “black African,”
U.S. census, in recognition of the com
“Asian,” and “Native American” gene
of classifying people into races based o
variants that are more common in these
skin color, began to allow “mixed race
groups. No student was pure anything, and
category in 2000. Many of us fall into
category.
Offering medical treatments based on
skin color may make sense on a population
level, but on the individual level it may
lead to errors,
in one study, researchers identified variants of a gene called MDR (for
multidrug resistance) in four population groups. This gene encodes a
protein that pumps poisons out of certain white blood cells and
intestinal lining cells. When a gene variant results in a pump that works
too well, the protein recognizes drugs used to treat cancer, AIDS, and other
conditions as toxins, sending them out of the cell. Researchers have found this
protein variant in 83 percent
of West Africans, 61 percent of African Americans, 26 percent of Caucasians,
and 34 percent of Japanese. MDR genotype could be used to prescribe certain
drugs only for individuals whose cells would not pump the drugs out. Thus,
MDR genotype is a more biologically meaningful basis for prescribing a drug
than skin color.