BIOL 106- Exam 3

What are the two functions of cell division?

* Single-celled organisms use cell division to reproduce


* Multicellular organisms use cell division for the growth, maintenance, and repair of cells and tissues

The cell’s DNA = its genome

* In prokaryotes, the genome consists of double-stranded, circular DNA molecules
* This resides in the nucleoid (=central part of prokaryotic cell where the chromosome is located)
* Additional smaller loops of DNA called plasmids may be present
* These are not necessary for normal growth but may have important info
* Exchange of plasmids with other cells allows gene transfer in prokaryotes

Eukaryotic Genomes

Consists of several double-stranded DNA molecules in the form of chromosomes 

Eukaryotic chromosomes

* The number of DNA molecules (chromosomes) in the cell nucleus varies among species (1-500 pairs; most have 10-50 pairs)
* Humans have 46 chromosomes in 23 nearly identical pairs
* Additional/missing (trisomy/monosomy) chromosomes usually fatal

Somatic Cells

Often have 2 matched sets of chromosomes which makes them diploid (2n)

Reproductive cells

Gametes (eggs and sperm cells) have half the number of chromosomes and are haploid (n)

Karyotype

* Particular array of chromosomes in an individual organism
* Arranged according to size, staining properties, location of centromere, etc.
* Humans are dipoid (2n)
* 2 complete sets of chromosomes
* 46 total chromosomes
* Haploid (n): 1 set of chromosomes
* 23 in humans
* Pair of chromosomes are homologous (“same knowledge”)
* Each one is a homologue

Chromosomes

* Typical human chromosomes 140 million nucleotides ling
* If pulled into a straight line \~ 2 inches in length
* Fitting into a cell nucleus is analogous to cramming a string the length of a football field into a baseball (x46 chromosomes)
* In the non-dividing nucleus
* Heterochromatin- not expresses (not “active”)
* Euchromatin- expresses (“active”)

Chromosome structure: Nucleosome

* Complex of DNA and histone proteins
* Promote and guide coiling of DNA
* DNA duplex coiled around 8 histone proteins every 200 nucleotides
* Histones are positively charged and strongly attracted to negatively charges phosphate groups of DNA

Chromosome structure: Solenoids

* Nucleosomes wrapped into higher-order coils
* Leads to a fiber 30 nm in diameter
* Usual state of non-dividing (interphase) chromatin
* During mitosis, chromatin in solenoid arranged around the scaffold of protein to achieve maximum compaction
* Radial looping aided by condensing proteins

Bacterial Cell division

* Bacterial divided by binary fission
* No sexual life cycle
* Reproduction is clinal
* Single, circular bacterial chromosome is replicated
* Replication begins at the Origin of replication and proceeds in two directions to site of termination
* New chromosomes are partitioned to opposite ends of the cell
* Septum forms to divide the cell into two cells

Septation

* Production of septum separates the cell’s other components
* Begins with the formation of a ring of FtsZ proteins
* Accumulation of other proteins follow
* Structure contracts radially to pinch cell in two
* FtsZ protein found in most prokaryotes

FtsZ protein has a structure similar to eukaryotic tubulin

* Cell division in different organisms involves protein assemblies
* Prokaryote protein assemblies involve FtsZ
* Eukaryotic protein assemblies involve microtubules formed from tubulin

Replication in Eukaryotes

* Prior to replication, each chromosome composed of a single DNA molecule
* After replication, each chromosome composed of 2 identical DNA molecules
* Held together by cohesion proteins
* Visible as 2 strands held together as chromosome becomes more condensed
* One chromosome composed of 2 sister chromatids

Eukaryotic cell cycle

1. G1 (gap phase 1)


1. Primary growth phase, longest phase
2. S (synthesis)


1. Replication of DNA
3. G2 (gap phase 2)


1. Organelles replicate, microtubules organize into a spindle
4. M (mitosis)


1. Subdivided into 5 phases
5. C (cytokinesis)


1. Separation of 2 new cells

Duration

* Time it takes to complete a cell cycle varies greatly
* Fruit fly embryos = 8 minutes
* Shortest known in animals
* Divide nuclei as quickly as replicate DNA, without cell growth (essentially no time spent in G1 and G2)
* Mature cells (vs embryos) take longer to grow
* Typical mammalian cell takes 24 hours
* Liver takes more than a year
* Growth occurs during G1, G2, and S phases
* M phase takes only about an hour
* Most variation in the length of G1
* Often pause in resting phase G0 before DNA replication- cells spend more or less time here
* At a given time most of the cells in an animal’s body are in the G0 phase- sometimes permanently (muscle and nerve cells)

Interphase

* G1, S, and G2 phases
* G1: cells undergo major portion of growth
* S: Replicate DNA & centrosome
* G2: Chromosomes coil more tightly using motor proteins; centrioles replicate; tubulin synthesis
* Centromere: point of constriction
* Kinetochore: attachment site for microtubules
* Each sister chromatid has a centromere
* Chromatids stay attached at the centromere by cohesion
* Replaced by condensing in metazoans

M phase

* Mitosis is divided into 5 phases
* Prophase
* Prometaphase
* Metaphase
* Anaphase
* Telophase

Prophase

* Individual condensed chromosomes first become with the light microscope
* Condensed continues throughout prophase
* Spindle apparatus assembles
* 2 centrioles move to opposite poles forming spindle apparatus (no centrioles in plants)
* Asters: radial array of microtubules in animals (not plants)
* Nuclear envelope breaks down

Prometaphase

* Transition occurs after the disassembly of the nuclear envelope
* Microtubules attachment
* 2nd group grows from poles and attaches to kinetochores
* Each sister chromatid connected to opposite poles
* Chromosomes begin to more to center of cell-congressional
* Assembly and disassembly of microtubules
* Motor proteins at kinetochores

Metaphase

* Alignment of chromosomes along metaphase plate
* Not an actual structure
* Future axis of cell division

Anaphase

* Begins with centromeres split
* Key event is removal of cohesion proteins from all chromosomes
* Sister chromatids pulled to opposite poles
* 2 forms of movements
* Anaphase A: Kinetochores pulled toward pulls
* Anaphase B: Poles move apart

Telophase

* Spindle apparatus dissembles
* Nuclear envelope forms around each set of sister chromatids
* Now called chromosomes
* Chromosomes begin to uncoil
* Nucleolus reappears in each new nucleus

Cytokinesis

* Cleavage divides the cell into equal halves
* Animal cells: constriction of actin filaments produces a cleavage furrow
* Plant cells: cell plate forms between the nuclei
* Fungi and some protists: nuclear membrane does not dissolve; mitosis occurs within the nucleus; division of the nucleus occurs with cytokinesis

Control of the cell cycle

* External triggers can initiate or inhibit the cell cycle
* Death of nearby cells
* Release of growth hormones
* Cell crowding
* Internal factors also regulate progress

Regulation at internal checkpoints

* New cell must duplicate the original
* Mistakes affecting function (such as mutated chromosomes or the wrong number of chromosomes) are regulated at 3 checkpoints in the cell cycle:
* Near the end of G1
* At the G2 to mitosis transition
* In metaphase of mitosis

G1 Checkpoint

* Determines whether all conditions are favorable for cell division
* External influence, adequate cell reserve and size are important
* There also is a check of genomic DNA damage
* A cell that does not meet all the requirements will not be allowed to enter the S phase
* The cell has 2 options if conditions aren’t met:
* Stop the cycle and try to fix the problem
* Enter G0 and wait for signs that conditions are better

G2 Checkpoint

* This checkpoint prevents entry into the mitosis phase if certain conditions are not met
* Cell size and protein reserves are checked again
* Most important role of this checkpoint is to ensure that all chromosomes have been replicated and that the replicated DNA is not damaged
* If any problems are detected, the cell cycle is halted while the cell attempts to either complete DNA replication or repair the damaged DNA

M Checkpoint

* Occurs near the end of metaphase
* Determines whether all sister chromatids are correctly attached to the spindle microtubules
* Also known as “spindle checkpoint”
* The cycle will not proceed until kinetochores of each pair of sister chromatids are firmly anchored to at least two spindle fibers
* Failure to correct this could lead to non-disjunction of chromatids

Two groups of intracellular molecules regulate the cell cycle

* Positive regulators promote movement to next step of the cell cycle
* Negative regulators stop advancement of the cell cycle

Positive Regulators: Cyclins and cyclin-dependent kinases (CDKS)

* Levels of these proteins fluctuate predictably over the cells cycle
* Internal and external signals can trigger increases in cyclin protein levels

How positive regulators work

* CDKS are protein kinases that can phosphorylate and activate other proteins that advance the cell cycle past a checkpoint
* To be fully activated, a CDK must bind to a cyclin protein and then be phosphorylated by another kinase
* The levels of CDKS are relatively stable throughout cell cycle; however, the concentration of cyclin fluctuates
* Different cyclins and CDKS bind at specific points in the cell cycle and thus regulate different checkpoints
* Without a specific concentration of fully activated cyclin/Cdk complexes, the cell cycle cannot proceed through the checkpoints

Negative Regulatory Molecules

* The best understood are retinoblastoma proteins (Rb), p53, and p21
* These act primarily at the G1 checkpoint
* Rib monitors cell size & influences other positive regulator proteins
* In its active state, binds E2F & production of proteins necessary for G1/S phase is stopped
* As cell increases in size, Rb is phosphorylated (inactivated)

Cancer and the Cell Cycle

* The term cancer covers may different diseases characterized by uncontrolled cell growth
* Begins with a gene mutation that results in a faulty protein that regulates cell reproduction
* Tumors result when reproduction of mutated cells surpasses growth of normal cells

Proto-oncogenes are normal genes that code for positive cell cycle regulators

When these genes mutate in certain ways, they become oncogenes

Proto-oncogenes

* Normal cellular genes that become oncogenes when mutated
* Oncogenes can cause cancer
* Example: mutation that allows cdk to be activated without cyclin, allows cell cycle to continue past a checkpoint- if cell is damaged my undergo further divisions & could result in cancer
* Some encode receptors for growth factors
* If receptor is mutated in “on,” cell no longer depends on growth factors
* Some encode signal transduction proteins
* Only one copy of a proto-oncogene needs to undergo this mutation for uncontrolled division to take place

Tumor suppressor genes are segments of DNA that code for negative regulator proteins

* When activated, these can prevent uncontrolled division
* Cells with a mutated form of a negative regulator might not be able to stop the cell cycle if there is a problem

Tumor-suppressor genes

* P53 plays a key role in G1 checkpoint 
* P53 protein monitors integrity of DNA 
* If DNA damaged, cell division halted, and repair enzymes stimulated  
* If DNA damage is irreparable, p53 directs cell to kill itself (apoptosis)  


* Prevent the development of mutated cells containing mutations  
* P53 is absent or damaged in many cancerous cells  
* P53 gene and many others  
* Both copies of the tumor-suppressor gene much lost function for the cancerous phenotype to develop  
* First tumor-suppressor identified was the retinoblastoma susceptibility gene (Rb)  
* Predisposes individuals for a rare form of cancer that affects the retina of the eye  


* Inheriting a single mutant copy of Rb means the individual has only one “good” copy left  
* During the hundreds of thousands of divisions that occur to produce the retina, any error that damages the remaining good copy leads to a cencerous cell  
* Single cancerous cell in the retina then leads to the formation of a retinoblastoma tumor 


* Rb protein integrates signals from growth factors 
* Role to bind important regulatory proteins and prevent stimulation of cyclin or CDK production  

Sexual life cycle

* Made up of meiosis and fertilization
* Diploid cells
* Somatic (non-reproductive) cells of adults have 2 sets of chromosomes
* Haploid cells
* Gametes (sperm and eggs) have only 1 set of chromosomes
* Offspring inherit genetic material from 2 parents
* Life cycles of sexually reproducing organisms involve the alternation of haploid and diploid stages
* Some lifecycles include longer diploid phases, some include longer haploid phases
* In most animals, diploid state dominates
* Zygote first undergoes mitosis to produce diploid cells
* Later in the life cycle, some of these diploid cells undergo meiosis to produce haploid gametes

Meiosis reduces the number of chromosomes by 1/2 to produce haploid (1n) cells

The process resembles mitosis but goes through two rounds of division: meiosis 1 and meiosis 2

Features of Meiosis

* Meiosis includes two rounds of division
* Meiosis 1 and Meiosis 2
* Each has prophase, metaphase, anaphase, and telophase stages
* Synapsis
* During early prophase 1
* Homologous chromosomes become closely associated
* Includes formation of synaptonemal complexes
* Formation also called tetrad or bivalents
* First meiotic division is termed the “reduction division”
* Results in daughter cells that contain one homologue from each chromosome pair
* No DNA replication between meiotic divisions
* Second meiotic division does not further reduce the number of chromosomes
* Separates the sister chromatids for each homologue

The process of Meiosis

* Meiotic cells have an interphase period that is similar to mitosis with G1, S, and G2 phases
* After interphase, germ-like cells enter meiosis 1
* Meiosis 1
* Prophase 1
* Metaphase 1
* Anaphase 1
* Telophase 1
* Meiosis 2
* Prophase 2
* Metaphase 2
* Anaphase 2
* Telophase 2

Prophase 1

* Chromosomes coil tighter and become visible, nuclear envelope disappears, spindle forms
* Each chromosome composed of 2 sister chromatids attached at the centromere
* Synapsis
* During interphase the ends of chromosomes are attached to the nuclear envelope at specific sites
* Homologous become closely associated
* Crossing over occurs between non-sister chromatids
* Remain attached to chiasmata (visible structures at cross over points)
* Chiasmata move to the end of the chromosome arm before metaphase 1

Crossing over

* Genetic recombination between non-sister chromatids


* Allows the homologues to exchange chromosomal material
* Alleles (“gene variants”) that were formerly on separate homologues can now be found on the same homologue
* Chiasmata maintained until anaphase 1

Metaphase 1

* Terminal chiasmata hold homologues together following crossing over


* Microtubules from opposite poles attach to each homologue
* Not each sister chromatid as in mitosis (sister chromatids act as a single unit)
* Homologues on the spindle is random

Anaphase 1

* Microtubules of the spindle shorten
* Chiasmata break
* Homologues are separated from each other and more to opposite poles
* Sister chromatids remain attached to each other at their centromere
* Each pole has a complete haploid set of chromosomes consisting of one member of each homologous pair
* Independent assortment of material and paternal chromosomes

Telophase 1

* Nuclear envelope re-forms around each daughter nucleus
* Sister chromatids are no longer identical because of crossing over (prophase 1)
* Cytokinesis may or may not occur after telophase 1
* Meiosis 2 occurs after an interval of variable length

Prophase II

Nuclear envelopes dissolve and new spindle apparatus form

Metaphase II

Chromosomes align on metaphase plate

Anaphase II

Sister chromatids are separated from each other

Telophase II

Nuclear envelope re-forms around 4 sets of daughter chromosomes; cytokinesis follows

Final results

* Four cells containing haploid sets of chromosomes
* In animals, develop directly into gametes
* In plants, fungi, and many protists, divide mitotically
* Produce greater number of gametes
* Adults with varying numbers of gametes

Errors in Meiosis

Nondisjunction: Failure of chromosomes to move to opposite poles during either meiotic division

Aneuploid gametes: gametes with missing or extra chromosome

Most common cause of spontaneous abortion in humans

Mystery of heredity

* Before the 20th century, 2 concepts were the basis for ideas about heredity
* Heredity occurs within species
* Traits are transmitted directly from parent to offspring
* Thought traits were born through fluid and blended in offspring (“bloodlines”)
* Paradox: if blending occurs why don’t all individuals look alike?

Josef Kolreuter

* 1760: crosses tobacco strains to produce hybrids that differed from both parents
* Additional variation observed in 2nd generation offspring contradicts direct transmission

T.A. Knight

* 1823: crosses 2 varieties of garden pea, Pisum sativa
* Crosses 2 true-breeding strains
* 1st generation resembled only 1 parent strain
* 2nd generation resembled both

Model system

* Chose to study pea plants because:
* Other research showed that pea hybrids could be produced
* Many pea varieties were available
* Peas are small plants and easy to grow
* Peas can self-fertilize or be cross-fertilized

Mendel’s experimental method

1. Produce true-breeding strains for each trait he was studying
2. Cross-fertilize true-breeding strains having alternate forms of a trait
3. Allow the hybrid offspring to self-fertilize for several generations and count the number of offspring showing each form of the trait

Monohybrid crosses

* Cross to study only 2 variations of a single trait
* Mendel produced true-breeding pea strains for different traits
* Each trait had 2 variants (e.g., round vs. Wrinkled seeds or yellow vs. green seeds

F1 generation

* First filial (“of or due from a son or daughter”) generation
* Offspring produced by crossing 2 true-breeding strains
* For every trait Mendel studied, all F1 plants resembled only 1 parent
* Referred to this trait as dominant
* Alternative trait was recessive
* No plants with characteristics intermediate between the 2 parents were produced

F2 generation

* Second filial generation
* Offspring resulting from the self-fertilization of F1 plants
* Although hidden in the F1 generation, the recessive trait has reappeared among some F2 individuals
* Counted proportions of traits
* Always found 3:1 ratio

3:1 is actually 1:2:1

* F2 plants
* 3/4 plants with the dominant form
* 1/4 plants with the recessive form
* The dominant-to-recessive ration was 3:1
* Mendel discovered the ration is actually:
* 1 true-breeding dominant plant
* 2 not true-breeding dominant plants
* 1 true-breeding recessive plant

Conclusions

* His plant did not show intermediate traits
* Each trait is intact, discrete
* For each pair, one trait was dominant, the other recessive
* Alternative traits were expressed in the F2 generation in the ratio of 3/4 dominant to 1/4 recessive

Mendel’s 5 element model

1. Parents transmit information for traits: Mendel called these traits “heritable factors”, now called genes
2. An organism inherits one copy of each gene parent


1. Mendel made this deduction without knowing about the role of chromosomes
2. The two alleles at the locus on a chromosome may be identical-homozygous


1. True-breeding plants of Mendel’s parental generation
2. Alternatively, the two alleles at a locus may differ-heterozygous


1. F1 hybrids
3. Alternative versions of gene account for variations in inherited characters


1. Example: gene for flower color in pea plants exists in two versions


1. These alternative versions for a gene are now called alleles
2. Each gene (information for a trait passed on from parent to offspring) resides at a specific locus on a specific locus on a specific chromosome
4. Two alleles for a heritable trait remain discrete and do not alter or blend with each other. During gamete, formation alleles segregate randomly in gametes
5. The presence of a particular allele does not ensure the trait encoded will be expressed


1. If the two alleles at the locus differ, then one (the dominant allele) determines the organism’s appearance, and the other (the recessive allele) has no noticeable effect on appearance

Genetics Vocabulary

* Because of the different effects of dominant & recessive alleles, and organism’s traits do not always reveal its genetic composition
* We distinguish between an organism’s phenotype (physical appearance), and its genotype (genetic makeup or a total set of alleles for an individual)
* Example of flower color in pea plants, PP and Pp plants have the same phenotype (purple) but different genotypes

Principle of Segregation

* Also known as Mendel’s First Law of Heredity
* Definition: Two alleles for a gene segregate during gametes formation and are rejoined at random during fertilization, one from each parent
* Segregation occurs due to behavior of chromosomes during meiosis

Punnet Square

* Tool used to show possible combinations of sperm & egg to predict results of a genetic cross between individuals of known genetic makeup
* Capital letters represent dominant alleles, & lowercase letters represent recessive alleles

Monohybrid cross

* Mendel derived the principle of segregation by following a single character
* The F1 offspring produced in this cross was monohybrids (individuals that are heterozygous for one character)
* A cross between such heterozygotes is called a monohybrid cross
* Genotype: total set of alleles of an individual
* PP= homozygous dominant
* Pp= heterozygous
* pp= homozygous recessive

Dihybrid Crosses

* Following two characters at the same time
* Crossing two true-breeding parents differing in two characters produces dihybrids in the F1 generation, heterozygous for both characters.
* A dihybrid cross, a cross between F1 dihybrids, can determine whether two characters are transmitted to offspring as a package or independently

Principle of Independent Assortment

* Mendel’s 2nd law of inheritance
* Principle of independent assortment is a dihybrid cross, alleles of each gene assort independently, segregation of different pairs of alleles is independent
* This law applies only to genes on different, non-homologous chromosomes
* Genes located near each other on the same chromosome tend to be inherited together
* Independent alignment of different homologous chromosome pairs during metaphase 1 leads to the independent segregation of the different allele pairs

Inheritance is governed by the Laws of Probability

* Probability allows us to predict the likelihood of the outcome of random events
* Because the behavior of different chromosomes during meiosis is independent, we can use probability to predict the outcome of crosses.
* When tossing a coin, the outcome of one toss has to impact on the outcome of the next toss
* In the same way, the alleles of one gene segregate into gametes independently of the allele when parent is heterozygote =0.5

Probability Rules

* Rule of multiplication: the probability of two independent events is equal to the product of probabilities of each event
* Rule of addition: the probability that either of two mutually exclusive (i.e., both cannot occur at the same time) events will occur is the sum of their individual probabilities

Extensions to Mendel

* Mendel’s Model of inheritance assumes that
* Each trait is controlled by a single gene
* Each gene has only 2 alleles
* There is a clear dominant-recessive relationship between the alleles
* There are no environmental effects
* Gene products act independently
* Most genes do not meet these criteria

Polygenic inheritance

* Occurs when multiple genes are involved in controlling the phenotype of a trait (true for most phenotypic traits)
* The phenotype is an accumulation of contributions by multiple genes
* These traits show continuous variation and are referred to as quantitative traits
* For example: human height
* Histogram shows normal distribution

Pleiotropy

* Refers to an allele which affects more than one phenotypic train
* Pleiotropic effects are difficult to predict, because a gene that affects one trait often performs other unknown functions
* This can be seen in human diseases such as cystic fibrosis or sickle cell anemia
* Multiple symptoms can be traced back to one defective allele

Multiple alleles

* Maybe more than 2 alleles for a gene in a population
* ABO blood types in humans
* 3 alleles
* Each individual can only have 2 alleles
* Number of alleles possible for any gene is constrained, but usually more than two alleles exist for any gene in an outbreeding population

Incomplete dominance

* Heterozygote is intermediate in phenotype between the 2 homozygotes (a new phenotype is produced)
* Red flowers x white flowers=pink flowers

Codominance

* Many times no single allele is dominant; instead, each allele has its own effect
* Heterozygote shows some aspect of the phenotypes of both homozygotes
* Distinguished from incomplete dominance by the appearance of the heterozygote

Human ABO blood group

* The system demonstrates both
* Multiple alleles
* 3 alleles of the I gene (IA, IB, and I)
* Codominance
* IA and IB and dominant to I but codominant to each other
* The gene that determines ABO blood types encodes an enzyme that adds sugar molecules to proteins on the surface of red blood cells (which act as a recognition marker for immune system)

Environmental influence

* Mendel also assumed that the environment did not affect the relationship between genotype and phenotype
* Coat color in Himalayan rabbits and Siamese cats
* Allele produces an enzyme that allows pigment production only at temperatures below 30 degrees celsius

Epistasis

* Mendel assumed that gene products do not interact, but this is not always true
* Behavior of gene products can change the ratio expected by independent assortment, even if the genes are on different chromosomes
* For example, gene that act in the same metabolic pathway should shows some form of dependence at the functional level
* Cannot assess whether later steps of the pathway are functional
* The interaction where one gene interferes with another is called epistasis
* The produce anthocyanin, must have at least one functional copy of each enzyme (in this case dominant allele)

Sex-linked traits

* In humans and many animals and plants, the sex of the individual organism is determined by sex chromosomes
* The sex chromosomes are non-homologous chromosomes (humans have 22 pairs of autosomes and one pair of sex chromosomes)
* In human females, the sex chromosomes are homologous “X” chromosomes. In males, the pair is “XY”
* The Y chromosome has a small region in common with the X chromosome. This allows them to pair during meiosis
* The Y chromosome is much shorter and contains fewer genes
* When a gene in question is present on the X chromosome, but not on the shorter Y chromosome, it is said to be X-linked
* Males, therefore, have only one allele for any x-linked gene. This is called Hemizygosity (males are hemizygous)

X-linked traits

* The Y chromosome will always be without an allele in monohybrid crosses involving X-linked traits
* X-linked alleles follow dominant/recessive patterns of inheritance in females
* In males, whatever allele is present on the single X chromosome is phenotypically expressed
* Some human disorders are x-linked recessive conditions
* Often we will refer to females heterozygous for the trait as “carriers”
* Males have a significantly higher change of having the disorder because a recessive allele cannot be masked by a second, dominant one
* Examples: color blindness, hemophilia, muscular dystrophy

Lethality

* Occasionally, in a population of organisms, a mutation will result in a non-functional allele for an essential gene
* The lethal allele may be transmitted through the population as long as the prescence of the wild-type (normal) allele functions well enough to sustain life. In other words, the wild-type much be sufficiently dominant over the lethal allele
*  Both males and females could be carriers of the trait  


* If two individuals heterozygous for a recessive lethal allele were to reproduce, what would be the outcome?  
* 25% normal offspring 
* 50% carriers 
* 25% lethal  


* Lethality does not necessarily occur in utero. Individuals may die later in life, depending on what life stage requires the gene  
* Dominant lethal inheritance patterns do exist 
* Both homozygous dominant and heterozygous individuals would have the lethality phenotype  
* Alleles of this type can only be transmitted if lethality occurs after reproductive age, when the allele may unknowingly be passed on  
* Example: Huntington’s disease 

Lethal alleles

* All Manx cats are heterozygotes for the ML allele  
* MM homozygotes are normal house cats  
* MML heterozygotes are Manx 
* MLML homozygotes all die 
* Crossing 2 manx cats produce an offspring ratio of 2 manx: 1 normal  

Human traits

* Some human traits are controlled by a single gene  
* Some of these exhibit dominant and recessive inheritance 


* Cannot do control crosses on humans- instead use pedigree analysis to track inheritance patterns in families  
* Graphical representation of matings and offspring over multiple generations for a particular trait  

Dominant Pedigree: Juvenile Glaucoma

* Disease causes degeneration of optic nerve leading to blindness  
* Diagnosed in childhood/early adulthood  
* Worldwide incidence is 1 in 50,000 
* Caused by mutations in a handful of different genes  
* The dominant trait appears in every generation (at least true for some families)  

Recessive Pedigree: Albinism

* Condition in which the pigment melanin is not produced  
* Pedigree for form of albinism due to a nonfunctional allele of the enzyme tyrosinaseae
* Males and females affected equally  


* Most affected individuals have unaffected parents  

Modern genetics began with the rediscovery of Gregor Mendel’s work in 1900

* Medel first published his work as a meeting paper titled Experiments on Plant hybridization in 1865 and as a paper in an obscure journal in 1866.  
* The work was largely ignored and no on recognized its significance towards understanding heredity until 1900  
* In that year 4 workers, Erich von Tschermak, Hugo de Vries, Caral Correns, and William Jasper Spillman, each independently trying to study heredity duplicated, then rediscovered Mendel’s work  
* \* Hugo de Vries coined the terms “gene” and “mutation”  

Shortly after the rediscovery of Mendel’s work a search for the physical basis of the gene began  

* Mendel’s findings were based in statistical results from numerous crosses and his “laws” were purely conceptual deductions  
* Mendel had no idea as to the actual physical nature of his conceptual “hereditary particles” (genes)  
* Rediscovery and recognition of the importance of his work triggered many into trying to fing the physical cause of Mendel’s observations  
* By 1900 microscopy of the cell was well known  
* Many microscopic studies of cells were undertaken to look for the physical gene 

Technological Advances  

Advances in microscopy and staining techniques allowed the visualization of chromosomes that appeared to behave in accordance with Mendel’s observations  

Chromosomes  

Today we know that chromosomes are threadlike nuclear structures consisting of DNA and proteins that serve the repositories for genetic information  

Chromosomal Theory of Inheritance  

* During meiosis, chromosome pairs migrate as discrete structures  
* Chromosome sorting from each homologous pair into gametes appears to be random  


* Each parent synthesizes gametes that contain only half their chromosomal complement 
* Even though male and female gametes (sperm and egg) differ in size and morphology, they have the same number of chromosomes, suggesting equal genetic contributions from each parent  
* The gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.  

Chromosome theory exceptions  

* Mitochondria and chloroplasts contain genes  
* Traits controlled by these genes do not follow the chromosomal theory of inheritance  
* Genes from mitochondria and chloroplasts are often passed to the offspring by only on parent (mother)  
* Maternal inheritance 

Genetic Mapping  

* Early geneticists realized that they could obtain information about the distance between genes on a chromosome  
* Based on genetic recombination (crossing over) between genes  
* If crossover occurs, parental allele are recombined producing recombinant gametes  
* As physical distance on a chromosome increases, so does the probability of recombination (crossover) occur between the gene loci 
* Sturtevant made two assumptions:  
* Genes are ordered serially (in a row) on thread-like chromosomes  
* The incidence of crossing-over between to homologous chromosomes could occur with equal likelihood anywhere along the length of the chromosome  


* He then hypothesized that 
* Alleles that were far apart on a chromosome were more likely to dissociate during meiosis simply because there was a larger region over which crossing-over could occur  
* Alleles that were close to each other on the chromosome were likely to be inherited together 


* Genes could range from being perfectly linked (cross-over frequency=0) to perfectly unlinked (cross-over frequency =0.5) when genes are on different chromosomes or are very far apart on one chromosome  
* Perfectly unlinked genes correspond to the hybrid frequencies predicted by Mendel to assort independently in a dihybrid cross 

Constructing maps  

* The distance between genes is proportional to the frequency of recombination events  
* Recombination frequency= recombinant progeny/ total progeny  
* 1% recombination= 1 map unit (m.u.)  
* 1 map unit= 1 centimorgan (cM)  

Wildtype

Typical form of a species as it occurs in nature

Multiple crossovers

* If homologues undergo two crossovers between loci, then the parental combination is restored  
* Leads to an underestimate of the true genetic distance  
* Relationship between true distance on a chromosome and the recombination of frequency is no linear  

Three-point testcross

* Uses 3 loci instead of 2 to construct maps
* Gene in the middle allows us to see recombination events on either side
* In any three-point cross, the class of offspring with two crossovers in the least frequent class

Human genome maps

* Data derived from historical pedigrees
* Difficult analysis
* Number of markers was not dense enough for mapping up to 1980s
* Disease-causing alleles rare
* Situation changed with the development of anonymous markers
* Detected using molecular techniques
* No detectable phenotype