genetics final

Genes provide

the basic blueprint for an organism.

The impact of a gene on the organism can be affected by

the environment

The impact of a gene on the organism can also be affected by

random events. Example: amount of UV light exposure.

Expression of a gene affected by:

– DNA sequence and regulatory effects

– Environment

– Noise (random)

What is a gene?

A segment of DNA that is transcribed into RNA

what is a Genotype

the collection of genes found in either an individual or a population of individuals.

what is a phenotype

the outward manifestation of the genotype.

what is an Allele

a specific instance of a given gene

what is a dominant trait

expressed if only one allele is required to generate the trait.

what is a recessive trait

only expressed when present in both alleles, or if the other allele is absent

Modes of Inheritance-Autosomal

linked to inheritance of regular chromosomes

Modes of Inheritance-sex linked

linked to inheritance of the sex determining chromosomes.

Modes of Inheritance-cytoplasmic

linked to the genomic material of cytoplasmic organelles (mitochondria & chloroplasts).

Inheritance of Traits- pure line

starting population that give rise to progeny showing no variation in the trait of interest.

Inheritance of Traits- Monohybrid Cross

single trait

Inheritance of Traits-Two pure lines

• Wrinkled peas

• Round peas

• Wild type R, mutant r

Mendel’s Model

• Particles inherited from parents controlled phenotypes of the progeny (now called genes).

• Genes exist in pairs (alleles).

• Gametes carry only one member of the pair.

• Alleles segregate during gamete formation.

• Fertilization is random.

Mendel’s First Law

• Equal Segregation: Two members of gene pair separate during gamete formation.

Homozygotes

pure breeding lines.

• Contain two copies of the same allele.

• YY -Homozygous dominant

• yy - Homozygous recessive

Heterozygote

contain two different alleles (such as Y/y)

Starch Synthesis

Glucose polymer

• In Wrinkled mutation, plants lack the enzyme for branching

• Mutant have a higher concentration of sucrose.

• Because of this, they absorb more water than wild type.

• When peas begin to dry, they become wrinkled

Mendel’s Second Law

• Different gene pairs assort independently during gamete formation.

• The two different genes must be far enough apart to segregate independently:

– Different chromosome

– Sufficient distance to insure recombination.

Product Rule

• Determines higher order distributions.

• The probability of independent events occurring together is the product of the probabilities of the individual events.

Temperature Determination

• Chromosomes of both sexes are identical.

• Sex is determined by temperature of development.

• Higher temperature favors one sex

• Turtles- warmer == female

• Alligators warmer == male

Comparative Genomics

• Gene functions have been conserved across evolution

• Nature solves a problem it typically continues to reuse the solution.

Elinor Crothers

-studying grasshoppers, found nonidentical pair of chromosomes along with an unpaired chromosome.

-Follow during meiosis and found that the two patterns assort independently.

Hershey-Chase Experiment

• Alfred Hershey & Martha Chase 1952

• Bacterial Virus (Phage) T2

• Two components: Protein Coat surrounding, DNA core

• Which component is found within bacteria during infection?

Label Components

Grow in Bacteria incubated with Radioactive Label

Label Protein with

radioactive Sulfur

Label DNA with

radioactive Phosphate

Radioactive protein

remains outside cell

Radioactive DNA

injected into cell

Chargaff’s Rules

• Amount of Purines = Amount of Pyrmidines

• Amount of Thymine = Amount of Adenine

• Amount of Guanine = Amount of Cytidine

• However A+T does not equal G + C

DNA is replicated by

a semiconservative mechanism

Centrifugation separates DNA by

density

Semiconservative Replication

• During replication both parent strands are used to generate a “daughter” strand

• Each cell gets a copy of the parental strand.

• Presumably, the parental strand is correct, because it had to survived selective pressure to be able to replicate.

• When DNA repair is needed, the DNA repair enzymes preferentially correct the error using the parent strand.

Allostery

Changes in protein structure due to interactions with another molecule

Bacterial Lactose Operon

• Three genes (lac z,y & a) coordinately regulated. These constitute the Lac operon

Lac z -

beta galactosidase

Lac y -

permease

Lac a-

acetylase

Negative Regulation

Induction of the ß-galactosidase operon in response to lactose.

in the absence of lactose

the operon is expressed at a very, very low level

Lactose -

Inducer of activity following conversion to allolactose.

Negative Regulation

• Synthesis of new protein: 1000 fold increase.

• In the absence of lactose, there is a mechanism to keep the operon off (negative regulation).

Lac I gene

• Mutants outside of Lac z,y,a that caused constitutive expression of the Lac z,y,a genes.

• Mutants in Lac I gene prevented the gene from being turned off in the absence of lactose.

• Negative regulation.

Repressor encoded by Lac I gene

-The product of the LacI gene is aof the LacI gene is a repressor protein.

• LacI+ is dominant to lacI-

• LacI gene product acts through the cytoplasm as a repressor.

• Exhibits Trans-dominance (across)

Repressor Action

• In absence of lactose, repressor binds DNA and blocks expression of lac zya genes

-Repressor no longer binds=genes can be active

Polycistronic mRNA

common in bacteria, rare in eukaryotes

Promoter -

region for binding of RNA polymerase

Operator -

region for binding of Repressor

Operator - cis acting

Only act upon genes directly linked on the same chromosome.

Catabolite Repression-

positive control

• Additional control mechanism prevents Lac operon expression when Glucose is present.

• Lactose + Glucose to E. coli-- Lac operon will remain off.

• Cells have a glucose sensor.

Repressor - trans acting

Exerts negative control, blocking expression of lac operon

cAMP-CAP - trans acting

Exerts positive control, promoting initiation by RNA polymerase

Genetics of Breast Cancer

Inherited susceptibility (germline)- Acquired tumor changes (somatic)- Breast tumor phenotype & evolution

-Breast cancer is genetic, but not always inherited.

-A person may inherit a BRCA1, BRCA2, or TP53 pathogenic variant, but the tumor still requires additional somatic events.

Germline variant

inherited; present in essentially all cells

Somatic mutation

Acquired; present in a tumor clone

Tumor suppressor

Cancer risk rises when protective function is lost

Oncogene

Cancer risk rises when activity is increased or activated

Expressivity

How strongly or variably the phenotype appears

Hereditary vs sporadic

inherited predisposition versus non-inherited tumor origin

Tumor heterogeneity

Different clones, subtypes, and molecular states

Germline variant

Variant is inherited from a parent- Present in eggs/sperm and most body cells- Can increase lifetime risk before a tumor exists

somatic mutation variant

Mutation arises in one cell- Expanded clone within the tumor- Shapes tumor behavior, subtype, or therapy response

Penetrance

How often a genotype produces a phenotype

-Example teaching lanuage: not every carrier develops the phenotype.

Expressivity

How strongly or variably the phenotype appears

-the same gene can be associated with different ages, severities, or cancer spectra.

Hereditary pathway

Inherited pathogenic variant- Second hit in breast cell- Tumor clone expands

Sporadic pathway

No inherited high-risk variant- Somatic events accumulate- Tumor clone expands

Tumor suppressor logic:

cancer risk increases when protective function is reduced or lost.

Oncogene logic:

cancer risk increases when signaling activity is amplified, activated, or misregulated.

Knudson-style tumor-suppressor logic

Genetic heterogeneity

Different clones can carry different mutations.

Phenotypic heterogeneity

Cells can differ in receptor status, proliferation, invasion, or therapy response.

Clinical consequence

A biopsy or treatment may sample or select only part of the evolving population.

Model for BRCA1-associated carcinogenesis

Central thesis: inherited or acquired loss of BRCA1 function can place breast epithelial cells on a genome-instability pathway that often converges with ER loss, TP53 mutation, and additional alterations before invasion.

Key distinction

inherited BRCA1 tumors begin with a germline pathogenic allele.

Sporadic BRCA1-deficient tumors may acquire epigenetic BRCA1 silencing.

Different starting mechanisms can converge on similar repair-deficient biology.