Lectures Clinical Genetics

Dr. Aneela Javed

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.

• 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 clear-cut

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.

MULTIFACTORIAL 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 (OMIM107400), 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.

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..

POLYGENIC MULTIFACTORIAL CONDITION

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

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. Single-

gene traits are instead discrete or qualitative, often providing an “all-or-none”

phenotype such as “normal” versus “affected.”

POLYGENIC TRAITS ARE CONTINUOUSLY VARYING

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.

A BELL-SHAPED CURVE

During weeks 6 through 13 ofprenatal development, the ridge pattern canbe altered as the fetus touches the finger andtoe pads to the wall of the amniotic sac. Thisearly environmental effect explains why thefingerprints of identical twins, who share allgenes, are in some cases not exactly alike.

FINGERPRINT PATTERNS

Height

EYE COLOUR

SKIN COLOUR

Skin color is one trait used to distinguish race

In one telling investigation, 100 studentsin a sociology class in “Race and EthnicRelations” at Pennsylvania State Universitydemonstrated that skin color does not necessarilyreflect ancestry. The students hadtheir DNA tested for percent contributionfrom “European white,” “black African,”“Asian,” and “Native American” genevariants that are more common in thesegroups. No student was pure anything, and

CHANGING MYTHS

many were quite surprised at what theirDNA revealed about their ancestry. Onestudent, a light-skinned black, learned thatgenetically he is 52 percent black Africanand 48 percent European white: approximately half black, half white. Anotherstudent who considered herself black wasactually 58 percent white European. TheU.S. census, in recognition of the complexityof classifying people into races based onskin color, began to allow “mixed race” as acategory in 2000. Many of us fall into thiscategory.

Offering medical treatments based onskin color may make sense on a populationlevel, but on the individual level it maylead 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 percentof 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.