Chapter 4 & 5

Single-gene diseases

A trait caused by a mutation in a single gene (monogenic)

• Also called Mendelian

• RARE

• Phenotypes of single genes are influenced by other genes and environmental factors

Modes of inheritance

Patterns in which single-gene traits and disorders occur in families

• Passing of trait: Gene is on an autosome (chromosomes 1-22) or on a

  sex chromosome (X and Y)

  
  

• Dominant

• Recessive

• Autosomal

• X or Y linked

Autosomal Dominant:

Autosomal Dominant: one autosomal allele causes a phenotype (Marfan Syndrome)

• Can affect both sexes

• Does NOT skip generations

• Affected individual has an affected parent, unless is a new mutation

• EX: Huntington Disease, Polydactyly (extra finger/toes)

Marfan Syndrome

EX for Autosomal Dominant Trait

• 1 in 10,000 people

• 25% have no family history = high mutation rate

• Fibrillin (gene FBN1) mutated: weaken connective tissue

• Affects: Skeletal system, cardiovascular system, heart and eyes

• Tall and thin with long arms, legs and thin fingers

• Weakened connected tissue at base of the aorta causes it to enlarge and rupture

Autosomal Recessive:

Autosomal Recessive: 2 autosomal alleles needed to cause a phenotype

• Can affect both sexes

• CAN skip generations

• Affected individual has parents who are affected or carriers (heterozygotes)

• EX: Cystic Fibrosis, Albinism (deficiency in melanin)

Cystic Fibrosis

Autosomal Recessive

• Fatal genetic disorder with abnormal secretions of the exocrine glands

• CFTR gene: encodes for the production of chloride membrane channel protein

  • Involved in secretion of sweat, mucus, and digestive juices

  • Mutation: Non-functional membrane protein that causes mucus build up in the lungs, causing infection

Consanguinity

Blood relatives having children together

• Autosomal Recessive conditions more likely to appear

  • Related parents may carry same alleles inherited from an ancestor

Monohybrid Cross

Follows one trait

• Dominant trait: observed

• Recessive trait: masked

Law of Segregation

Alleles of a gene are distributed into separate gametes during meiosis

Genotype

Organism’s alleles

Phenotype

Outward expression of an allele combination

Wild type

Most common phenotype in a population for a particular gene.

• recessive or dominant

Law of Independent Assortment

Two gene on different chromosomes, the inheritance of one gene does NOT influence the other gene

• Two gene far apart on the same chromosome: many crossovers happen between them

• Random alignment of chromosome pairs during metaphase 1 of meiosis

Hemizygous

Males only have one X chromosome, so hemizygous for x-linked traits

• Single copy of a gene instead of 2 copies

X-Linked Recessive

• More common than X-linked dominant

• Hemizygous males and homozygous recessive females are AFFECTED

• More COMMON in MALES, some are exclusive in males

  • Affected males: pass affected allele to ALL DAUGHTER, none to sons

Color Blindness

X-linked RECESSIVE

• Defective color vision from reduction or absence of visual pigments

  • 3 forms: red, green, blue blindness

    • 8% US Male affected

  • Defect in the Retina

Y chromosome

Only males have Y chromosomes

• Pass from father to son

• All y-linked genes are expressed (hemizygous for genes on Y chromosome)

  • Only 60 Y-linked traits identified

Pedigree Analysis

Diagram showing relationships in a family to show inheritance of a trait

• Proband (P): first person in a family to be identified with a genetic condition (seeks medical care)

Loss of Function

Recessive Traits: more severe, produce symptoms earlier than dominant disorders

• EX: No proteins made

Gain of Function

Dominant Traits

• Ex: Different (toxic) form of protein made (HD)

Lethal Allele

variant forms of a gene that cause the death of the organism that carries them

• EX: Achondroplasia- long trunk, short limbs, large head, flat face

  • New mutation

  • Gain of function (FGFR3) normally inhibits growth of the long bones of arms/legs

• Homozygous recessive lethal: 25% die or spontaneous abortion

• Removes expected progeny class from a specific cross

Multiple Alleles

Individual carries 2 alleles for each autosomal gene

• Gene can have multiple alleles

• Different allele combinations = variations in the phenotype

• Compound Heterozygote: 2 different recessive alleles for the same gene

• THREE OR MORE ALTERNATIVE FORMS

Incomplete dominance

Heterozygous phenotype is intermediate between those of the two

homozygotes

• EX: Familial Hypercholesterolemia (FH)

  • Heterozygote has approximately HALF the normal number of receptors

    in the liver to take up LDL cholesterol

  • Homozygous for the mutant allele totally lacks the receptor, and so

    their serum cholesterol level is very high

• EX: Hair follicle development

  • EDAR gene: develops hair follicles

  • “G” allele = East asian

  • “A” allele = European and African

  • GG = Thick hair, AA = very thin hair, AG = hair with diameter in between

Codominance

Heterozygous phenotype results from the expression of both

alleles

• ABO gene encodes a cell surface glycoprotein

  • I^A: A antigen

  • I^B: B antigen

  • i(I^o): no antigens

• I^A & I^B are codominant and both are dominant to i

• Blood type AB

Epistasis

A gene masking or affecting the expression of another gene

• EX: Bombay Phenotype

  • H gene is epistatic to the I gene

  • H protein: places a molecule at the cell surface to which the A or B antigens are attached

  • hh genotype = no H protein

  • no H protein → A or B antigens can NOT be attached to the surface of the RBC

• All hh genotypes = phenotype of type O, even though the ABO blood group can be anything (A, B, AB, or O)

Penetrance

All-or-none expression of a single gene. It tells us whether a person with the gene will show the trait.

• Percentage of individuals with a genotype who have an associated phenotype

• Incompletely penetrant: genotype where some people do NOT express the phenotype

Expressivity

Severity or degree of a phenotype

• Symptoms vary in intensity among different people

Pleiotropy

Single-gene disease with several symptoms or a gene that controls several functions (AFFECTS MORE THAN ONE TRAIT)

• Has more than one effect, causing different symptom subset in different people

• Influences 2 or more unrelated traits

• EX: Marfan Syndrome

  • fibrillin: Defect in elastic connective tissue

  • Lens dislocation, long limbs, spindly fingers, caved-in chest

  • Serious symptom = weakening of aorta, can suddenly burst

Genetic Heterogeneity

Different genes can produce identical phenotypes

• Genes encode enzymes that catalyze the same biochemical pathway, or different proteins that are part of the same pathway

EX:

• Osteogenesis imperfecta (abnormal collagen → weak bones): At least 18 genetically distinct forms are recognized

• Retinal dystrophies: caused by mutations in more than 270 genes (many routes to blindness)

Phenocopy

Trait that appears inherited but is caused by the environment

• Symptoms that resemble an inherited trait or occur within families

• EX: Infection (AIDS) - can be passed from mother to child, looks inherited

Mitochondrial Disorders

Mitochondrial genes encode proteins involved in protein

synthesis and energy production

• Mitochondrial Diseases (mutations in mtDNA)

  • Mitochondrial myopathies: weak and flaccid muscles

  • Leber optical atrophy: Impaired vision

• Woman with disease can avoid transmitting to children by replacing mitochondria from a donor

Mitochondrial DNA

Cell has thousands of mitochondria

• Each mitochondria has copies of it mini chromosome

• mtDNA does NOT cross over

• Mutates faster then DNA in nucleus

  • Fewer types of DNA repair and DNA-damaging oxygen free radicals are produced in the energy reaction

• Mitochondrial genes are NOT wrapped in proteins

• Mitochondrial gene are NOT interrupted in DNA sequences that do not encode protein

• Mitochondrial Genes are passed from mother to all of her offspring