Gen Two

Be able to explain the two possible reasons for incomplete penetrance and variable expressivity.

(1) If some individuals in a population don't express a trait, even though they have the corresponding genotype, the trait is said to exhibit incomplete penetrance in that population. When using the term penetrance, therefore, think of populations. Polydactyly (extra fingers and toes) exhibits incomplete penetrance in human populations. (2) Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype.[1] For example, individuals with the same allele for a gene involved in a quantitative trait like body height might have large variance (some are taller than others), making prediction of the phenotype from a particular genotype alone difficult. The expression of a phenotype may be modified by the effects of aging, other genetic loci, or environmental factors. Another example is neurofibromatosis, where patients with the same genetic mutation show different signs and symptoms of the disease.[1]

Locus Heterogenenity

A disease can be caused by mutations in 2 or more different genes; hemophilia involves several different proteins

Albinism

Absence/partial deficiency of melanin in the skin, eye, hair, occurs in animals

Tay-Sachs Disease

Appear healthy at birth, then develop neurodegeneration symptoms @ 4 to 6 months -Cerebral degeneration, blindness and loss of motor function-usually die @ 3/4 years -Result of mutation in gene that encodes the enzyme hexosaminidase A (hex A)- Hex A breaks down lipids called GM2-ganglisosides; excessive accumulation of this lipid in cells of CNS cause the neurodegenerative symptoms

Enumerate a few important ways in which genetics can help us deal with diseases in a better manner.

Appx. 12000 genetic diseases afflict people, our genes underline every aspect of our health both function and dysfunction Genetic testing to detect predisposition to certain forms of cancer, sickle cell, huntington example; analyzing people with hemophilia researchers have identified genes that participate in blood clotting.

Androgen Insensitivity Syndrome

Gene product-Androgen receptor--effect--missing male steroid hormone receptor; XY individuals have external fts that are feminine but internally have undescended testes and no uterus

Duchenne Muscular Dystrophy

Gene product-Dystrophin--effect--progressive degeneration of muscles that begins in early childhood

explain why it is important to understand genes and the interaction of genes with environment both for normal health and disease. Also, be able to explain that under healthy conditions, genes encode proteins that play important roles and perform important functions to maintain normal cellular processes. Mutations in genes (leading to loss of function, gain of function, etc) may lead to diseased states

Have a profound impact on the way many diseases are diagnosed and treated, prevented. º Mutagenes- Pollutants that are in the environment that alter your DNA sequence: chemicals in change smoke to cancer. ºGene-Gene interaction- don't change your sequence, but cause a chain reaction and affects the function of the other gene ºTranscription Factors: Pollutants in environment can indirectly affect DNA sequence by altering transcription factors responsible for starting the process of using genes to make proteins that are needed for functions of the body. º Epigenetics can alter your health by affecting the proteins that turn genes on/off. ºº EXAMPLE ºº The height reached by a tree at maturity is a phenotype that is strongly influenced by environmental factors, such as the availability of water, sunlight, and nutrients. Nevertheless, the tree's genotype still imposes some limits on its height: an oak tree will never grow to be 300 meters tall no matter how much sunlight, water, and fertilizer are provided.

Why are males termed hemizygous?

Hemizygous is a condition in which only one copy of a gene or DNA sequence is present in diploid cells. Males are hemizygous for most genes on sex chromosomes, having only one X and one Y chromosome. When an X-linked gene is said to express dominant inheritance, it means that a single dose of the mutant allele will affect the phenotype of the female. A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype. The following are the hallmarks of X-linked dominant inheritance: 1. The trait is never passed from father to son. 2. All daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. 3. Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. 4. Males are usually more severely affected than females. The trait may be lethal in males. 5. In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.

Haploinsufficiency

Heterozygote has 50% of the normal protein; not sufficient for normal phenotype. º Polydactyly º Brachydactyly

Multi-Genetic or Polygenic disorders

Locus heterogeneity refers to that a disease can be caused by mutations in 2 or more different genes combination of lifestyle and environmental factors; Example Hemophilia you have A, B and C

Why does red-green color blindness often affect males. why X-linked recessive disorders affect males very easily.

Men are affected more to color-blindess because the genes responsible for the most common inherited color blindness are on the X chromosome, Males only have one X while females 2, in females a function gene on only of the x chromosome is enough to compensate for loss of the other --Males have only a single copy of most x-linked gene are termed hemizygous female heterosygous gene will pass trait half her sons

Cystic Fibrosis (CF)

Most common lethal genetic disease amongst caucasians 3% are carriers -Gene encodes a protein called the Cystic Fibrosis transmembrane conductance regulator (CTFR) -CTFR protein regulates ion transport across the cell membrane (normal process) -mutant allele creates an altered CFTR protein that ultimately causes ion imbalance -Serious digestive and respiratory problems -Life expectancy 38 yrs

Gain-Of-Function Mutation

Mutation changes protein, will then gain a new function is overactive than normal protein. º Huntington Disease º Achondroplasia

Of the x-linked dominant disorders listed in table 24.4, which of these are fatal in males before they may be born so that there are no viable males seen among the affected population.

Rett Syndrome Aicardi syndrome; gene product unkwn, partial or complete absence of a key structural in brain called the corpus callosum and presence of retinal abnormalities

Dominant Negative Mutations

The altered gene product acts antagonistically to normal product

Phenylketonuria

an autosomal recessive disorder defect in gene that encodes phenylalanine hydroxylase -Affected cannot metabolize phenylalanine will accumulate and be converted to phenylpyruvic acid, toxic and will cause mental and physical abnormalities -can put on strict dietary regimen new borns are routinely screened -Low phenylalanine tend to develop normally

Define the terms penetrance and expressivity. Be able to quote the examples studied in class. Give an example, be able to choose which of the two is being referred to.

º % penetrance =# of indiv. with correct phenotype/# of indviduals with genotype coding for phenotype. ºº penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype. For example, an organism may have a particular genotype but may not express the corresponding phenotype, because of modifiers, epistatic genes, or suppressors in the rest of the genome or because of a modifying effect of the environment. Alternatively, absence of a gene function may intrinsically have very subtle effects that are difficult to measure in a laboratory situation. º Another measure for describing the range of phenotypic expression is called expressivity. Expressivity measures the extent to which a given genotype is expressed at the phenotypic level. Different degrees of expression in different individuals may be due to variation in the allelic constitution of the rest of the genome or to environmental factors. Figure 4-23 illustrates the distinction between penetrance and expressivity.(The effects of penetrance and expressivity through a hypothetical character "pigment intensity." In each row, all individuals have the same allele—say, P—giving them the same "potential to produce pigment." However, effects deriving from the rest of the genome and from the environment may suppress or modify pigment production in an individual.) Like penetrance, expressivity is integral to the concept of the norm of reaction. º The ABO blood group genes show almost complete penetrance º Neurofibromatosis shows 50-80% penetrance º Polydactyly also show incomplete penetrance ºº May cause a phenotype to skip a generation ºº Expressivity; (Beagle piebald spotting allele) --both incomplete penetrance and variable expressivity indicated That the pathway between a genotype and phenotype can have considerable variation due to both health and genetic factors.

Autosomal Recessive

º Albinism (11q)Tyrosinase inability to synthesize melanin resulting in white skin/hair, etc º Cystic Fibrosis (7q) Transmembrane conductance regulator (CFTR) Water imbalance in tissue of pancreas, intestine sweat glands and lungs due to impaired ion transport= lung damage º Tay-Sachs Disease (15q) Hexosaminidase A; Progressive neurodegeneration º PKU (12q) Phenyalanine hydroxylase; foul smelling urine- cannont metabolize phenylalanine will accumulate and be converted to acid to cause mental/physical abnormalities Disorders that involve defective enzymes typically have an autosomal recessive mode of inheritance HETEROZYGOTE has 50% of the normal enzyme (sufficient for a normal phenotype)

Be able to list the five major inheritance patterns of traits or diseases controlled by single genes.

º Autosomal Dominant º Autosomal Recessive º X-Linked Dominant º X-Linked Recessive º Y-Linked

explain factors that make study of inheritance of human diseases difficult. How is inheritance of genetic disease best studied currently.

º Controlled matings are not possible º Sibship sizes are relatively small º Complete penetrance is sometimes lacking º degrees of expressivity sometimes vary - Pedigree diagrams that show the relationship among members of a family, as well as their status w/ respect to a particular hereditary condition

explain how screening for phenylketonuria helps in preventing the development of phenylketonuria.

º Guthrie Test (heel-prick) º The mother's body is able to break down phenylalanine during pregnancy. Blood test reveals raised phenylalanine levels after 1 - 2 days of normal infant feeding.

Hemophilia

º Hemophilia A is a defect in clotting (factor VIII) º Hemophilia B defect in clotting (factor IX) º Hemophilia C found on chromosomal 4; Factor XI º Hemophilia blood cannot clot properly severe internal or external bleeding, infected royal family

X-Linked Recessive

º Hemophilia B (factor IX) º Hemophilia A (Factor VIII) º Duchenne Muscular dystrophy (Dystrophin) progressive degeneration of muscles that begin in early childhood º Androgen Insensitivity Syndrome (Androgen Receptor) Missing male steroid hormone receptor; XY individuals have external ft that are feminine but internally have undescended testes and no uterus -They pose a special problem for males -Males have only a single copy of most X-Linked genes termed hemizygous -Female heterozygous for an x-linked recessive gene will pass this trait to half her sons

Autosomal Dominant

º Huntington Disease (4p) º Polydactyly (5q) º Achondroplasia (FGFR3) º Brachydactyly (HDAC4) º Syndactyly

For a genetic disease (assuming full penetrance and if given the assumption that in the set of twins under study, new mutations did not arise in germline or postfertilization) be able to assign the possible appropriate concordance values for monozygotic and dizygotic twins.

º Monozygote- share the disease more often than fraternal (dizygotic) twins º Concordance which is the degree to which it is inherited; it refers to the % of twin paris in which BOTH twins exhibit the disorder/trait --Degree to which a disorder is inherited by calculating the % of twins pairs in which both twins exhibit the disorders relative to pairs where only one twin shows disorder --Theoretically, diseases caused by a single gene amongst identical (monozygote) twins should be 100% -DIZYGOTE expected to 50% assuming only one parent is HETEROZYGOUS *Recessive disease with fraternal twins would be 25% if both are HETEROZYGOTES

explain the term phenocopy. Which genetic disorder does Thalidomide syndrome phenocopy? How were toxicity studies of this drug in model animals useful for the FDA to block the use of this drug in the United states. What accounts for the useful effects of the drug thalidomide and its teratogenic effects.

º Phenocopy; an individual showing features characteristic of a genotype other than its own, but produced environmentally rather than genetically. ºº Sedative, between 1959-1962 children with shortened limbs were born to mothers who took the drug early in their pregnancy - Thalidomide is an over the counter sedative used in the early 1950s outside the US. - It was tested for toxicity in rodents, and no LD50 was found, and no teratology studies were done at the time. - Despite the seemingly unremarkable results in rodents, about 12,000 "thadomide babies" were born between 1956 and 1962, expressing "flipper-like" limbs (phocomelia) or missing all limbs altogether (quadruple amelia). - 50% of children died within 4-5 years of life, the other half are still living. - Thalidomide was removed from the market in 1961, having been found in rabbits and primates to be a teratogen. - The drug returned to the market around the 1990s because it does do a pretty good job in treating leprosy, cancer, and certain types of blindness. - Thalidomide and other teratogenic drugs come with a warning label.

explain the inheritance pattern of Phenylketonuria, the exact molecular nature of the defect and consequence of taking a diet rich in proteins vs the consequence of taking a diet that is well controlled for phenylalanine during childhood.

º Phenylketonuria-Congenital genetic condition where phenylalanine accumulates. º caused by Mutations in the gene for hepatic enzyme Phenylalanine Hydroxylase (PAH) º normal function Metabolises the amino acids phenylalanine into tyrosine. º left untreated= intellectual disability and seizures. º Treated by Phenylalanine restricted diet. Supplemented medical formula that contains amino acids. º untreated children Failure to reach early milestones, microcephaly, progressive impairment of cognitive function. º life without treatment= hyperactivity e.g. ADHD, EEG abnormalities, seizures, severe learning disabilities, tendency to eczema. º foods contain phenylalanine=Aspartame (sweeter), protein rich foods.

single gene disorders

º Single Gene º -Autosomal Recessive --Trait skip generations --Both sexes affected equally --Unaffected parents can have an affected child --Two affected parents cannot have an unaffected child --More likely to occur in consanguineous marriages

single gene disorders

º Single Gene º -X-Linked Recessive --Trait may skip generations --Males are mostly affected --Affected males result from affected mothers or mothers who are carries --Affected females come from affected fathers and affected or carrier mothers --Affected females will have affected sons --Trait can never be transmitted directly from father to son

single gene disorders

º Single Gene º -Y-Linked --Trait only affects male --Affected males get it from their fathers and give it to their sons

X-Linked Dominant

º Vitamin D-Resistant Rickets; (PHEX gene) Typical rickets but resistant to vitamin D supplementation º Faulty Tooth Enamel (GJB1 gene) motor and sensory neuropathy, muscle weakness, sensory impairment º Rett syndrome gene (MECP2 gene); Regression of psychomotor development during 2nd year of life, severe mental retardation, involuntary hand movements, microcephaly

Seven characteristics that are associated with diseases that have a genetic basis

º When an individual exhibit a disease the disorder is more likely to occur in blood relatives than in the general population º Identical twins share the disease more often than fraternal twins º Disease does not spread to individuals sharing similar environmental situations º Different populations tend to have different frequencies of the disease º Disease tends to develop @ a character age º Human disorder may resemble a genetic disorder that is already known to have a genetic basis in an animal º Correlation is observed between a disease and a mutant human gene or a chromosomal alteration

single gene disorders

ºSingle Gene º -Autosomal Dominant --Present in every generation --both sexes are equally affected --Unaffected parents produce unaffected offspring --Two affected can produce unaffected --half of children of affected parent will be affected --HOMOZYGOTE allele is more SEVERELY affected than HETEROZYGOTE

single gene disorders

ºSingle Gene º -X-linked Dominant --Trait does not skip generations --Affected males must come from affected mothers --Affected females come from affected mothers/fathers --Affected males have no normal daughters and no affected sons --Affected HETEROZYGOUS females transmit the trait to appox. half of their children of either sex --Affected HOMOZYGOUS females transmit the trait to all their children --Males are often more severely affected