CHAPTER 4 GENES AND GENETIC DISEASES

Transcription

• Process by which RNA is synthesized from a DNA template, forming messenger RNA (mRNA)
• Initiated when RNA polymerase binds to a promoter site on DNA, which specifies the beginning of a gene
• Regulated by transcription factors that activate or repress gene expression, and can be up-regulated by enhancers
• RNA polymerase separates DNA strands, exposing bases
• One DNA strand becomes the template for mRNA nucleotide sequence
• mRNA base sequence is complementary to the template strand, identical to the other DNA strand (except uracil replaces thymine)
• Process continues until a termination sequence is reached, releasing mRNA into the cytoplasm

Polyploidy

• Euploid cells have multiples of the normal chromosome number
• Normal gametes are haploid (23 chromosomes), somatic cells are diploid
• Polyploid cells have more than the diploid number of chromosomes and exist normally in liver, bronchial, and epithelial tissues
• Triploidy involves a zygote with three copies of each chromosome
• Tetraploidy involves euploid cells with 92 chromosomes
• Triploidy and tetraploidy account for 10% of miscarriages

Aneuploidy

• Aneuploid cells do not contain a multiple of 23 chromosomes
• Trisomy: An aneuploid cell containing three copies of one chromosome
• Newborns with trisomy of chromosomes 13, 18, and 21 can survive
• Monosomy: An aneuploid cell with only one copy of a given chromosome in a diploid cell
• Monosomy of any chromosome is lethal
• Loss of a chromosome material has more serious consequences than duplication of chromosome material
• Aneuploidy of sex chromosomes is less severe than that of autosomes, particularly for the Y chromosome
• A zygote bearing no X chromosome cannot survive

Nondisjunction

• Error in meiosis or mitosis where homologous chromosomes or sister chromatids fail to separate normally
• Results in gametes with either two copies or no copies of a chromosome
• Leads to aneuploidy when these gametes unite with normal haploid gametes, resulting in monosomic or trisomic zygotes

Translocation

• Interchanging of genetic material between non-homologous chromosomes
• Robertsonian translocation: fusion of long arms of two non-homologous chromosomes at the centromere
• Confined to chromosomes 13, 14, 15, 21, and 22
• Carriers have 45 chromosomes but are normal because they lose no essential genetic material
• Offspring may have deletions or duplications, like Down syndrome if the long arms of chromosomes 21 and 14 fuse
• Responsible for 3-5% of Down syndrome cases
• Reciprocal translocation: breaks in two chromosomes with material exchange; carriers are normal but gametes can have duplications/deletions

Causes of Intellectual Disability

• Chromosome abnormalities are a leading cause of intellectual disability and miscarriage
• Aneuploidy: cells that do not contain a multiple of 32 chromosomes (e.g., Down, Turner, Klinefelter Syndromes)
• Chromosome breakage: deletions result in missing genes (e.g., cri du chat syndrome)
• Translocation: interchanging of genetic material between nonhomologous chromosomes (e.g., Robertsonian translocation)
• Fragile sites: observable breaks/gaps on chromosomes; fragile X syndrome causes cognitive impairment
• Polyploidy: cells with more than the diploid number of chromosomes; nearly all triploid and tetraploid conceptions are spontaneously aborted
• Monosomy is lethal, but trisomy of chromosomes 13, 18, or 21 can be survived
• Examples include Down syndrome, Trisomy X, Cri du chat syndrome, Fragile X syndrome, Klinefelter syndrome, untreated phenylketonuria (PKU), Wilms tumor, Angelman Syndrome, Prader-Willi Syndrome, and Sturge-Weber syndrome

Down Syndrome

• Trisomy of the 21st chromosome
• Life expectancy is 60 years for those who survive infancy
• Usually caused by nondisjunction during gamete formation/embryonic development
• Risk increases with maternal age

Turner Syndrome

• Sex chromosome aneuploidy with a single X chromosome (45, X)
• Affects females, causing sterility and gonadal streaks instead of ovaries
• Features: short stature, webbing of the neck, widely spaced nipples, coarctation of the aorta, edema of the feet, sparse body hair
• IQ is typically normal, but spatial and mathematical reasoning may be impaired

Klinefelter Syndrome

• Individuals with at least two X chromosomes and a Y chromosome (47, XXY karyotype)
• Male appearance, usually sterile, may develop gynecomastia
• Small testes, sparse body hair, high-pitched voice, elevated stature, possible mental impairment in some cases

Cri du Chat Syndrome

• Disease caused by a deletion of part of the short arm of chromosome 5
• Symptoms: low birth weight, severe mental retardation, microcephaly, heart defects, characteristic "cry of the cat"

Dominance and Recessiveness

• Dominant allele masks effects of another
• Recessive allele's effects are hidden
• Heterozygote genotype Aa has same phenotype as dominant homozygote AA
• Recessive allele must be in homozygous form, aa, to be expressed

Recessive Gene Inheritance

• Recessive disease-causing alleles occur in heterozygotes (carriers) who don't express the disease
• Recessive genes survive by "hiding" in carriers
• Cystic fibrosis is the most common lethal recessive disease in white children
• Males and females are affected equally
• Consanguinity is often present
• Disease is seen in siblings but not parents usually
• 25% of offspring of carrier parents will be affected
• Recurrence risk for offspring of carrier parents is 25%
• If both parents have the disease, all children must be affected

Penetrance and Expressivity

• Penetrance: percentage of individuals with a specific genotype who show the expected phenotype; incomplete penetrance means some individuals with the allele do not express the phenotype
• Expressivity: variation in phenotype associated with a particular genotype; severity of the disease can vary greatly

Autosomal Dominant Inheritance

• Condition is expressed equally in males and females
• Males and females equally likely to pass the gene to offspring
• Union of normal parent and affected heterozygous parent produces affected offspring
• 50% of children of affected heterozygous parent will express the condition
• No generational skipping
• Each birth is independent
• Examples include Von Recklinghausen Disease, Huntington Disease, Retinoblastoma, and Achondroplasia

Autosomal Recessive Inheritance

• Rare; many individuals are carriers
• Affected individual must be homozygous
• Trait appears in children, not parents
• Condition expressed equally in males and females
• Observed in siblings but not parents
• 25% of offspring are affected
• Consanguinity may be present
• Examples include Cystic Fibrosis, Sickle Cell Anemia, Fanconi Anemia, and Bloom Syndrome

X-Linked Inheritance

• Disorders involve X and Y chromosomes
• Y-linked disorders are rare
• Males have one X chromosome, thus are always hemizygous
• Females have two X chromosomes and can be homozygous or heterozygous
• X-Inactivation: one X chromosome in female somatic cells is inactivated (Barr body)
• X-linked recessive occurs significantly more often in males; no father-to-son transmission; Duchenne Muscular Dystrophy, Hemophilia A, Fabry Disease, and Fragile X Syndrome are examples
• X-linked dominant affects both males and females but can be more severe in males; no male-to-male transmission

X-Linked Dominant Inheritance

• Caused by mutations in genes located on the X chromosome
• Females (XX): mutation in only one of the two gene copies is sufficient to cause the disorder; usually less severe symptoms compared to males
• Males (XY): mutation in this single copy will cause the disorder; symptoms are often more severe
• No male-to-male transmission as fathers cannot pass an X-linked dominant disorder to their sons (since sons inherit the Y chromosome from the father)
• Example: Fragile X Syndrome

Hemophilia Inheritance

• Base substitution (missense mutation) usually produces a mild form of hemophilia A
• Nonsense mutation (premature termination of translation) produces a more severe form of hemophilia A

Recessive Disease Inheritance

• When both parents are heterozygous carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%; one-quarter of the offspring are normal, and 1/2 are carriers
• For the recessive allele to be expressed, it must exist in the homozygote form
• Abnormal allele is recessive, and the person must be homozygous to express the disease
• Approximately one-quarter of the offspring of carrier parents will be affected
• Is rare, but many individuals are carriers
• Condition is expressed equally in males and females
• The disease is seen I siblings but usually not in their parents
• Consanguinity is sometimes present; marriage between related individuals
• Often a factor in producing children with recessive diseases because related individuals are more likely to share the same recessive disease-causing alleles

Inheritance of Blood Types

• Codominance occurs when a heterozygote is distinguishable from both homozygotes
• Both alleles are expressed simultaneously and equally
• MN Blood Group: Both M and N alleles are detectable
• ABO Blood Group: A and B alleles are codominant; individuals with both alleles (heterozygotes) express both A and B antigens on red blood cells (blood type AB)
• Four Primary Common Blood Types: O (Most common), A, B, AB (Least common)
• Blood type is determined by three common alleles: A, B, O Each person inherits two alleles, one from each parent can be OO, AO, BO, AB, AA, or BB.
• Codominance vs. Recessiveness: A and B alleles are codominant, and the O allele is recessive; A codominant allele is expressed even with just one copy and a recessive allele is only expressed if two copies are present

Gene Abnormality Causes Cystic Fibrosis

• Cystic fibrosis (CF) is a multiorgan disease affecting airways, digestive tract, and reproductive organs
• Caused by a mutation in the CFTR gene: Cystic Fibrosis Transmembrane Conductance Regulator gene
• Leads to abnormal expression of the CFTR protein: chloride channel present on epithelial cells in airway lining, bile ducts, pancreas, sweat ducts, paranasal sinuses, and vas deferens
• Most Common Mutation: F508delCFTR
• The lungs are the most seriously affected and respiratory failure is almost always the cause of death

Incidence, Prevalence, Risk

• Incidence Rate: the number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population
• Prevalence Rate: the proportion of the population affected by a disease at a specific point in time and is determined by both the incidence rate and the length of the survival period in affected individuals
• Relative Risk: the increased rate of a disease among individuals exposed to a risk factor divided by the incidence rate among individuals not exposed
• Influenced by age, gender, diet, exercise, and family history

Familial Hypercholesterolemia

• Common autosomal dominant disorder affecting 1 in 500 people
• Causes heart disease
• Plasma cholesterol levels are ~2x higher than normal (300-400 mg/dL), leading to atherosclerosis and cholesterol deposits
• Homozygotes (1 in 1 million) are more severely affected, with cholesterol levels of 600-1200 mg/dL, and may have MI before age 20
• Caused by reduction in the number of functional LDL receptors on cell surfaces, reducing cellular cholesterol uptake and increasing circulating cholesterol
• There are 5 classes of LDL Receptor Gene Mutations (Class 1: No detectable protein product; Class 2: Receptor can't leave the endoplasmic reticulum and is degraded; Class 3: Receptor reaches surface but can't bind normally to LDL; Class 4: Normal receptor but doesn't migrate to coated pits thus can't internalize LDL; Class 5: Receptor can't dissociate from LDL particle after cell entry)
• Heterozygotes are treated with dietary cholesterol reduction, bile acid-absorbing resins, and statins, while homozygotes need liver transplants, plasma exchange, and somatic gene therapy
• Also caused by mutations in apolipoprotein B and PCSK9 genes

Cancers That Cluster in Families

• Many cancers (breast, colon, prostate, ovarian) cluster in families due to inherited genes and shared environmental factors
• Breast Cancer is autosomal dominant and can be caused by BRCA1 and BRCA2 (BRCA1 → increased risk of ovarian, prostate, and colon cancer while BRCA2 → increased risk of ovarian cancer; up to 6% of males with BRCA mutations also develop breast cancer)
• Colorectal Cancer has a familial aggregation in some single-gene trait cases (APC gene → familial adenomatous polyposis), and hereditary nonpolyposis colorectal cancer → mutations in six genes
• Prostate Cancer has heterozygosity in tumors

Type II Diabetes Risk Factors and Obesity

• Type II DM: >90% of diabetes cases
• Caused by insulin resistance
• More common in those >40 years old and obese individuals
• Genes that cause Type II DM variants include TCF7L2 gene or PPAR-γ
• Top Risk Factors include positive family history and obesity, but can be reduced with exercise (lowers risk even with family history and helps with obesity risk factor)
• MODY (Maturity-Onset Diabetes of the Young): very rare form of diabetes