Genetics Exam 1

comsumer genetics

-genetic analysis

-ancestory

-health

• genetic basis of traits

• predisposition- ex. to different diseases

• pharmacogenetics- ex. response to different drugs for treatment of diseases

Genes

-information bearing blueprints to make proteins

-DNA→ gene→ chromosome → genome (all chromosomes)

-human genome: about 3.2 billion base pairs in each 23 chromosomes

-humans are diploids- sets of identical chromosomes

Cells and Tissues

-chromosomes → nucleus → cells (eukaryotic) → tissues (multi-cellular) → organs → organ systems

Central Dogma of Molecular Biology

-flow of genetic information in a cell (gene expression)

-DNA (blueprint) — transcription→ mRNA (intermediate) —translation→ protein (machine/factory made)

-exome- part that is expressed (about 2% of genome)

• about 20k genes total- lot more proteins

DNA

-made of nucleic acids with building block of nucleotides

-nucleotides; phosphate (neg. charge), sugar (deoxyribose, nitrogenous base (A=T, C=G (3 bonds))

-double helix structure

-antiparallel strands

-Replication: DNA→ DNA

• info can be replicated, expressed, or changed/mutated

RNA

-made of nucleic acids and building blocks of nucleotides

-nucleotides: phosphate, sugar (ribose), and nitrogenous bases (A=U, C=G)

-(usually) single stranded helix

-transcription: DNA→ RNA

Protein

-translation: RNA→ proteins

• synthesized by ribosomes

-building block of amino acids

• 20 proteogenic amino acids

-proteins have acitivity (do nearly everything in cell)

• structural (ex. skin and hair)

• enzymes- catalyze reactions

• regulatory

  • lead to phenotypes and traits

Mutations

-changes in DNA sequences (therefore shape and function)- leads to…

• changes in mRNA

• changes in protein sequence

• change in activity

• change in phenotypes

• normal varitaion (mutation not always bad)

  • disease

Chromosomes

-23 pairs→ 46 total chromosomes

-22 pairs of autosomes (everything that is not a sex chromosomes and 1 pair of sex chromosome (X & Y)

-diploid- have two sets of chromosomes

-haploid- only one copy of each chromosome (seen in gametes: sperm/egg cells)

-germline cells- cells developing gametes (egg/sperm)

• somatic cells- everything else

Genotypes

-the actual genetic code for allele/organism

-allele (A, a)- form of a gene

• homozygous- same (AA, aa)

• heterozygous- different (Aa)

Phenotypes

-physical trait that can be seen

-can be dominant or recessive

-Mendelian- single gene (one gene change)

-Polygenic traits- where more than one gene influence phenotype

-genetic and envronmental factors

• considered complex/multifactoral traits if affected by both

Carbohydrates

-provide energy

-monosaccarhides

• sugars

• starches

• ex. glucose

Nucleic Acids

-provide information

-nucleotides

• DNA

• RNA

Proteins

-provide stucture and funciton

• enzymes

• receptors

• regulatory factors

• muscles

• antibodies

-amino acids

Lipids

-long term energy

• tyglycerides- glycerol backbone and 3 fatty acid tails

• phospholipids- membranes

-steroids

• hormones

• signaling

• regulation

-hyrdophobic

Prokaryotic vs. Eukaryotic

-Prokaryotic- “before” nucleus

• without memrabne bound organelles

-Eukaryotic- compartmentalization

• nucleus

• membrane bound organelles

Nucleus

-organelle than stores DNA processing

• DNA replicaiton, transcription, post-transcptional

-nucleolus- rRNA

-nuclear envelope- double membrane with nuclear pores

Endoplasmic Reticulum

-modifies proteins

-rER- protein synthesis and processing

• ribosomes, lysosome, ER-Golgi-Plasma membrane-secreted

• continuous with nuclear envelope

-sER- lipid synthesis

• phospholipids

-vesicles transport porteins to/from Golgi

Secretory Pathway in Cell

-pathway for proteins and exporting things through/out of the cell

1. Endoplasmic Reticulum

   1. smooth and rough

2. Golgi Apparatus

3. Two options

   1. Plasma Membrane

   2. Lysosome

Golgi Apparatus

-receives vesicles with proteins made in rER

-further processes/modifies proteins

• modify carbohydrate groups attached to proteins (glycoproteins)

-vesicles transport proteins to plasma membrane or lysosome

Plasma Membrane

-membrane proteins

• ex. membrane channels

-secretion (export)

• ex. caseins (milk proteins), antibodies

-leave golgi via vesicles and fuse with membrane

Lysosome

-”recylcing center”- digestion of biomolecules

-primary lysosome- has digestive enzymes to breakdown biomolecuels and cell components

• endoscopes- materials from outside cell

• autophagy- materials from inside cell

-lysosomal stoage diseases (LSD’s)- lysosomes do not work correctly

Peroxisomes

-detoxification

• break down H2O2 (hydrogen peroxide)

• without this, free radicals can lead to cellular damage/mutations

-fatty acid metabolism

Mitochondria

-energy production via cellular respiration

-gluscose → ATP

-has double membrane- makes 4 “compartments”

-motochonrial DNA and ribosomes

• has small # of genes to make small # of proteins for itself

  • not all mitochondrial proteins madein mitochondria, most come from/made in ER

Membranes

-semipermeable barrier

-phospholipid bilayer-

• hydrophilic head and hydrophobic tail

-fluid mosiac model

• inculdes proteins, carbohydrates, lipids, etc.

• shows PM is not a rigid structure

-transport:

• hydrophobic/non-polar molecules diffues

• ions through ion channels

• hydrophilic transported via carriers

-communication- singal transduction

• via receptors and ligands

-adhesion- cell adhesion molecules

• cells stick to each other and themselves in specific ways

Cytoskeleton

-filametous infastructure (proteins)

• microfilaments- actin (smallest)

• intermediate filaments- all other kinds

• microtubules- tubules (largest)

-dynamic system- moving and proteins continually being made

-play a role in: morphology (cell shape), locomotion, intracellular transport (vesicle movement), mitosis, & cytokinesis

Cell Cycle

-interphase (about 23 hours)

• G1- synthesis

• S- DNA replicaiton

• G2- more synthesis

-mitosis (about 1 hour)- produces identical clone cells

• Prophase- chromosomes condense

• Metaphase- move to middle (metaphase plate)

• Anaphase- sister chromatid segregation

• Telophase- feform nuclear envelope

-Cytokinesis- plasma membranes fully split

Control of Cell Cycle

-checkpoints- regulate progression through cycle

-cyclins and CDK’s- dimer (two proteins grouped into one together)

• cyclins are regulatory and levels oscillate

• CDK’s are kinases controlled by cyclins

  • phosphorylation

-disruptions to checkpoints can lead to cancer

-Environmental Factors can also influence mitosis and cell cycle

• contact inhibition

• hormones

Telomeres

-ends of chromosomes that shorten with each cell division

• because of this, many cells can undergo a finite number of divisions

• cells “clock” to count down cell’s lifespan

-telomerases- not all cells shorten telomeres

• extend telomeres in cells that express them so these cells can continue to divide

Apoptosis

-programmed cell death (implosion)

• a regulared process- DNA fragments (blebs) dissociate from other cells and are phagocytosed

• capases- proteases (protein digesting proteins) involved in apoptosis

-important in normal development

-too much mitosis or too little apoptosis can both lead to cancer

Stem Cells

-self-renewing w/ continual cell division

-maintain undifferentiated state

-stem cells vary along this:

• totipotent (all potential) → pluripotent (almost all) → multipotent → differentiated

• fertilized egg → progenitor cell → specialized cell

Differentiation and Cell Fate

-most cells (with a few exceptions) have same genomic content (23 chromosome pairs)

-increased differentiation and specialization of cell fate

• from differential gene expression, tissue specifics, “housekeeping” genes

-human differentiation is one-way → cells do not naturally go in reverse direction

Stem Cell Sources

-embryonic stem cells- ICM (inner cell mass)- from early embryo

-somateic cell nuclear transfer (SCNT)- nucleus of somatic cell transferred into egg with nucleus removed

• cloning (therapuetic vs. reproduction)

-own cells-

• reprogrammed- iPS (induced pluripotent)

• unaltered- “adult” stem cells- naturally occurring

  • tissue specific or somatic stem cells

  • limited mulipotency

Stem Cell Uses

-drug discovery

-study of dieases (early stages)

-culture tissues and organs for implant, transplant, infusions

-understand and use reporgramming proteins

Microbiome

-there are over 30 trillion cells inour body along with over 39 trillion other cells (bacteria, fungi, protozoa)

• microbes living in and on us

• dynamic “core microbiome”- depnds on other factors such as genetics, environment, age, diet, health, etc.

• human microboime project- studying microbiome of people and its affect on us

Meiosis and Sexual Reproduction

-reduction- 1 of each chromosome 1-23 (haploid)

• genetic stability

• continuity between generations

• highly specific

-Recombinaiton (variation)

• independent assortment

• crossing over (nearly infinite variation)

• variation between generations

  • sexual reproduction (fertilization)

Meiosis 1 & 2

-reduction, variation, diploid → 4 haploid gametes

-two rounds of division: reductional and equational

• based on ploidy number

Meiosis 1

-reductional

-crossing over in P1→ homologs line up in M1 → homologs separate in A1 (sister chromatids DO NOT separate)

-prophase 1- crossing over

• homogolous pairs of chromosomes align → synapsis and corssing over with non-sister chromatids → recombination

-anaphase 1- independent assortment

• M-A1- independent segregation of homologs

• segregation of 1 pair doesn’t influence segregation of any other pair

  • 2^n possible combinations

Meisosis 2

-equational

-no crossing over in P2

-individual chomosomes line up in M2

-sister chromatids segragate in A2

Meiosis Variation

-recombination via independent assortment of chromosomes

-recombination through crossing over

-fertilization

Spermatogenesis and Oogenesis

Spermatogenesis: meiosis in males

• starts at puberty

• diploid spermatogonium → haploid sperm (spermatozoa)

Oogenesis: meiosis in females

• starts in fetus

• arrests in P1

• about 1 mil. at birth, 400,000 @ puberty, about 400 released in ovulation

• Polar Bodies: assymetric cell division in Me1 and Me 2

  • assymetric partitioning of cellular material

  • after 2 rounds of Me., 1 hapliod ovum vs. 4 with sperm

Spermatogenesis vs. Oogenesis

-from each round of meiosis (1 & 2)

• spermatogenesis- 4 haploid sperm

  • oogenesis- 1 haploid ovum and 2-3 polar bodies

Developmental Arrests in Oogenesis

-P1 arrest in fetal development

-continues at puberty

-arrests at M2

-continues and complete M2 only with fertilization

Meiosis and Mutations

-inherited mutation present in parents or from their parents can be passed to gamates

-new spontaneous mutations can occur (in germline cells)

• more likely with age

• oocytes more often have chromosomal imbalances (non-disjunction

  • sperm more likely to have dominant single gene mutation

Fertilization

-corona radiate (follicle cells on ovum)

-only one sperm

-zona pellucida- acrosome enzyme

• allow sperm to break into ovum

Embyro Development

-early embyro development

• fertilization and zygote → cleavage → morula → blastocyte (inner cell mass) → implantation (hcG hormone about 1 week) → embryo (first 8 weeks) → fetus (9+ weeks)

-embyro

• primary germ layers: endoderm (skin), mesoderm (muscle), ectoderm (organs)

• chronionic villi: become placenta, chorionic villus sampling (can see large scale change in babies DNA)

• amnion and amniotic sac- aminocentesis

• -cell-free fetal DNA in material blood

• allantois- umbilical blood vessels and cord

Twins

-monozygotic (identical)- 1 fertilized egg

• genetically identical “natural clones”

-dyzygotic. (fraternal)- 2 different fertillized effs with 2 different sperm

-semi-identical- 2 sperm fertilize one egg

• share maternal genome but have different paternal genome

-conjoined twins- division occurs at 9-15 days

Birth Defects

-genetic abnormalities (mutations)

-toxic environmental exposure (tetratogens)

-critical period- when specific parts of the fetus are developing- will experience largest impact in this time if exposed to tetratogens

Tetratogens

-chemicals or other agents that cause birth defects

• cocaine

• cigarettes

• thalidomide

• alcohol

• nutrients

• viral infection

Mendel

-he is seen as the “father of genetics”

-experimented with pea plants

-universal laws of heredity- 7 traits

-characteristics ratios in F1 and F2 generations

Monohybrid Cross

-P1 generations- used 2 “true-breeding” parents

• phenotype: either tall (TT) or short (tt)

• genotype: homozygous (TT/tt)

-F1 generation

• phenotype: all tall

• genotype: all heterozygous (Tt)- “monohybrid”

-F2 generation

• phenotype: ¼ short (tt), ¾ Tall (TT or Tt)

  • 3:1 Tall:Short

• genotype: ¼ tt, ½ Tt, ¼ TT 1:2:1

-Pattern: 3:1 ratio for all monohybrid crosses

Mendel’s Postulates

-unit factors (genes) occur in pairs

-unit factor segragate (law of segregation)

• corresponds to Me1 phase in cells

-dominance/recessiveness

Punnett Squares

-used to solve Mendelian crosses

• monohybrid or dihybrid

-predict genotypes, phenotypes, and their ratios in the next generation

Test Cross

-Test on a phenotypically dominant individual when one wants to find the genotype (it could be TT or Tt)

-test cross with a homozygous recessive

-ratio of progeny will tell you:

• if all offspring dominant, TT

  • if there is 50/50 in offspring, Tt

Autosomal Recessive Genes

-for example, cycstic fibrosis

-both parents carriers, but not affected by disease themselves (BbxBb)

• each offspring has 25% chance of having CF (bb)

• 50% chance of having Bb (unaffected carrier

-can appear to skip a generation sometimes

Autosomal Dominant Genes

-for example Huntingdon disease

-early (childhood) vs. late (after puberty) onset

-each offspring of affected individual has 50% chance of inheriting allele (and therefore the condition)

-has no carriers

-usually present in every generation

-de novo (spontaneous mutation)- you can get a dominant condition even without parents having it

Consanguinity

-marriage between relatives

-mutant alleles rare in population, but increased risk of rare mutant alleles coming together in consanguineous matings

Loss or Gain of Function Mutations

-molecular basis for recessive or dominant mutations

-often rescessive alleles are loss of function mutation

• more common

• need two mutant copies to give phenotype

-often dominant alleles are gain of function mutation

• only one mutant copy needed to give phenotype

Inheritance of More than One Gene: Dihybrid Cross

-follow inheritenxe of two traits sumultaneously

• governed by two different genes

-P1- two true bredding (homozygoudparents and two traits

• RRYY x rryy

• RRyy x rrYY

-F1- both phenotypically dominant for both traits

• all double heterozygous (RrYy) genotypically

  • dihybrid

-F2- 9:3:3:1- classic Mendelian F2 dihybrid ratio

Higher Order Mendelian Problems

-ex. trihyrid, tetrahybrid, etc.

-Be able to andwer questions about them:

• How big are the Punnett squares?

• How many gametes can each F1 parent make?

  • 2^n where n is number of heterozygous genes

Calculating Probability

-product rule- “and”

• get blank and blank

• ex. heads on a penny and heads on a quarter

  • ½ x ½ = ¼

-sum rule- “or”

• ex. get two coins to land on same side

  • ¼ + ¼ = ½

-you can also make a Punnett Square and calculate probability

• use this for 3+ genes squares- make each gene (letter) a 2×2 Punnett square

Pedigree Analysis

-autosomal dominant trait

• characteristics: affected individuals in all generations, affects male/female equally (autosomal)

-autosomal recessive

• characteristics: can skip generations, affects males/females equally (autosomal

-consanguinity- increases probability to see rare recessive conditions

-sometimes pedigrees are inconclusive due to not having enough information

Conditional Probability

-probability of some event (A) given some condition (B) is true

-changes probability (of A) from what it is without condition (B)

-narrows and restricts possible options available

Trios Sequencing: Inherited vs. de novo

-scenario: unaffected parents with affected child

-what is the basis for child’s condition?

• parents could both be carriers: recessive mutation

  • if so, 25% chance child gets a disease 50% carriers

• new spontaneous (de novo): dominant mutation arose

  • from sperm/egg or early development of child

  • if de novo, no siblings affected, child has 50% passing disease on

-can distinguish which it is with trios sequencing

• genomes and exomes

• look at mutation in parents and child: if only in child then de novo dominant mutation

Incomplete Dominance

-one allele not dominant over the other and heterozygous have phenotype in-between (intermediate) between homozygous parents

• ex. Red flower (RR) x white flower (rr) = pink flower (Rr)

• ex. famial hypercholesterolemia (FH)

-dosage dependency: idea that the effect of a gene depends on number of alleles or variant present in the genome

Codominance

-sometimes one allele is not dominant over others and heterozygous express both parental phenotypes

-ex. ABO blood typing

• A

• B

  • AB- I^A I^B- both fully A and fully B

Multiple Alleles

-some genes can have more than two alleles available in a population

-still considered diploid as each individual only holds 2 alleles at a time

-different mutant allele combinations lead to increased range of possible phenotypes

-ex. ABO blood typing has 3 alleles available in population

• 4 phenotypes instead of two

• increased range of diploid phenotypes/genotypes

Lethal Alleles

-genotypes/alleles that cause death

• example of conditional probability

• early lethals can skew apparent ratios and numbers

-can be dominant or recessive

-onset time:

• early- ex. Tays Sachs Disease- 3-4 yrs

• late- ex. Huntingdon’s- middle age

Epistasis

-some traits are governed by more than one gene and those genes interact with each other (gene interaction)

-one gene controls expression (phenotype) of another: control gene = modifier gene

-examples:

• eye color

• Bombay phenotype (ABO)

Expressivity

-sometimes if you have an allele, it doesn’t always express fully

-variability of expression/intensity of phenotype in individuals with same genotype

-ex. polydactyly- people can express varaible number of extra digits

Penetrance

-all individuals in population with the same genotype should have the same phenotype, but sometimes they don’t (incoplete penetrance)

-refers to proportion (%) of population with given phenotype expressing the expected phenotype

-ex. Huntingdon disease- usually completely penetrant

-ex. polydactyly- not all with genotype have extra digits

**traits can have both expressivity and incomplete penetrance

Pleiotrophy

-when genes impact more than one trait

-ex. Marfan syndrome- autosomal dominant mutation in fibrillin gene

Genetic Heterogeneity

-when mutations in different genes produce the same phenotypes

-can occur when multiple genes encode proteins in the same pathway or when proteins affect same parts of the body

-ex. Osteogeneis imperfecta- affected by 8+ genes

-ex. Retinal dystrophy- affected by 20+ genes

Phenocopy

-environmental factors leading to phenotypes that mimic inherited ones

-ex. teratogen thalidomide phenocopies rare inherited condition phocomelia

Mitochondrial Disease/Myopathies

-conditions resulting from mutations in mitochondrial genes (37 mitochondiral genes)

-often affect high energy demand tissues (muscle) -fatigued, weak

-maternally inherited

Heteroplasmy

-cells have many mitochondria- may not all be the same genetically because of mutations

-propotions of different mitochondira in a cell will vary

• various pehontypes, variability, tissue dependent

Linkage

-sometimes genes are not assorted independently because they are on the same chromosome

-these do not produce Mendelian ratios because the do not independently assort (physically linked on same chromosome

-recombinant chromosome- crossing over between linked genes produces this non-parental combination of alleles

-linkage analysis wiht genetic maps can tell you relative distance between genes on a chromosome

• expressed in cM