Lectures Clinical Genetics

1. Lectures Clinical Genetics Dr. AneelaJaved

2. 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. • 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.

3. 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 Single gene (or Mendelian or monogenic) 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.

5. 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.

6. 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.”

8. 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.

9. 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.

10. 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..

11. 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

12. POLYGENIC TRAITS ARECONTINUOUSLY VARYING For a polygenic trait, the combined actionof many genes often produces a “shadesof grey” or “continuously varying” phenotype,also called aquantitative trait.DNA sequences that contribute to polygenictraits are called quantitative traitloci, or QTLs. The individual genes that confer a polygenic traitfollow Mendel’s laws, but together theydo not produce single-gene phenotypicratios. They all contribute tothe phenotype,but without being dominant orrecessive to each other. For example, themultiple genes that regulate height andskin color result in continuously varyingphenotypes. Single-gene traits are insteaddiscrete or qualitative, often providing an“all-or-none” phenotype such as “normal”versus “affected.”

13. 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.

14. 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.

15. Height

16. EYE COLOUR

17. SKIN COLOUR

18. CHANGING MYTHS Skin color is one trait used to distinguish race In one telling investigation, 100 students in a sociology class in “Race and Ethnic Relations” at Pennsylvania State University demonstrated that skin color does not necessarily reflect ancestry. The students had their DNA tested for percent contribution from “European white,” “black African,” “Asian,” and “Native American” gene variants that are more common in these groups. No student was pure anything, and many were quite surprised at what their DNA revealed about their ancestry. One student, a light-skinned black, learned that genetically he is 52 percent black African and 48 percent European white: approximately half black, half white. Another student who considered herself black was actually 58 percent white European. The U.S. census, in recognition of the complexity of classifying people into races based on skin color, began to allow “mixed race” as a category in 2000. Many of us fall into this category.

19. Offering medical treatments based on skin color may make sense on a population level, but on the individual level it may lead to errors,

20. 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.