Mendel died in 1884
1882 Flemming observed chromosomes in cell nuclei/mitosis
1887  Weismann special division process during gamete formation (meiosis)
It was not until 1900 that biology caught up with Gregor Mendel
    3 botanists repeated Mendel's experiments
1902 Walter Sutton, Theodor Boveri and others noted parallels between meiosis/fertilization and Mendelian genetics =        Chromosomal theory of inheritance

Morgan and the Drosophila school

    Thomas Hunt Morgan - first associated a specific gene with a particular chromosome

    Used fruit flies (Drosophila melanogaster) as model system
        only 4 paris of chromosomes - 3 paris of autosomes and 1 pair of sex chromosomes

    Terminology:
        Wild type - normal found phenotype in the population
        Mutant phenotype - alternative form of wild type

        Notation:  Allele takes symbol from the first mutant found

            ex.  white eyes is the mutant phenotype in Drosophila = w
                the "⁺" symbol indicates the wild type, so w⁺ = red eyes

                If the first mutant trait discovered is dominant, the symbol for the allele begins with a capitol letter
                    ex. Cy stands for curly wing mutant (wings curl up).
                    Flies with normal straight wings are homozygous recessive = Cy⁺
 
 

Tracing a gene to a specific chromosome

    white eyed male  is crossed with a red eyed female    P1
            (X^wY)            X                  (XX)

    all offspring have red eyes (suggesting wild type was dominant)

            X^w          Y

    X      XX^w      XY

    X     XX^w       XY
 
 
 

F1  X  F1 -> 3:1 ratio among F2 progeny.  All F2 females had red eyes, 1/2 males had red eyes and 1/2 had white eyes.
        All white eyes showe up in males
        Therefore, the fly eye color is linked to its sex

        Genes located on sex chromosomes are called sex-linked genes

                    X            X^w

        X         XX         XX^w

        Y         XY         X^wY
 

Chromosome maps (maps for Drosophila, human, mouse)
    Hundreds of genes on each and every chromosome
    Genes on the same chromosome usually inherited together = linked genes

Thomas Morgan did the following experiment
 
    Wild type fly = grey body, normal wings
    mutant = black body, vestigial wings

    Body color            Wing size
        b⁺ = grey            vg⁺ = normal wings
        b  = black            vg  = vestigial wings
 

Morgan crossed

    female                X        male
    grey-normal wings        black-vestigial wings
    b⁺bvg⁺vg                      bbvgvg

    Expected: 1/4 grey normal
                    1/4 black vestigial
                    1/4 grey vestigial
                    1/4 black normal

    Observed disproportionate numbers of progeny that looked like parents
        wild type (grey-normal) and double mutants (black vestigial)
        also got a few grey-vestigial and black normal (due to crossing over)
 

If linked genes do not assort independently and

    tend to move together through meiosis and fertilization,

    on would expect to observe phenotypes like the parents
 
 

But in the experimental cross just described, one does also observe phenotypes unlike either parent

    In other words, get neither the 1:1:1:1 ratio from independent assortment,
    nor the 1:1 expected ration if genes are completely linked.
 

Experimental data:

Morgan explained the results by crossing over/exchange of genetic material must have occurred.

Recombination - exchange of genetic material of linked genes, crossing over
        Recombination by crossing over in prophase I of meiosis I - change of genetic material
        Recombinants - phenotype unlike either parent

    Recombination frequency reflects distance between genes.  In other words, the higher the recombination frequency, the further apart the genes are located on the chromosome.

Probability of crossing over between 2 genes is directly proportional to the distance between them.

    If genes on separate chromosome, the recombination frequency = 50%

    1 map unit - 1% recombination frequency = 1 centimorgan

    map distance in % = # recombinants (100)/total # progeny

 
Example:

    There is another gene on chromosome containing b and vg.  Gene for eye color = cinnabar (cn)

    If recombination experiment performed again looking at b, vg and cn,
    Sturtevant obtained the following data:

        cinnabar to b locus = 9% recombination frequency

        v and vg = 17% recombination frequency

            so to draw may, cn -  b -  vg        or   b -  cn -  vg,
 
            need to find recombination frequency of cn to vg   =  9.5%

        Map must look like b - cn - vg

Alterations in chromosome number
    aneuploidy - abnormal number of chromosomes
                        occurs as a result of non-disjunction
                        resulting in trisomic or monosomic chromosome #

    polyploidy - more than 2 sets of chromosomes
                    triploid (3N), tetraploid (4N)

Alterations in chromosome structure
    Determined from differential staining techniques

    Deletion - fragment loss from a chromosome (can be caused by viral attack, irradiation or chemical action)

    Duplication - repeat gene sequence improperly aligned during meiosis

    Inversion

    Translocation - a segment from one chromosome is permanently transferred to a non-homologous chromosome

    Polytene chromosomes - unusually large chromosomes from insect larvae.  Each chromosome copied over and over

    Deletion of particular portion of chromosome 15

    Syndrome                            Defective chromosome inherited from:

Prader-Willi syndrome                father
    mental retardation
    obesity
    short stature
    unusually small hands and feet

Angelman syndrome                    mother
    spontaneous uncontrollable laughter
    jerky movement
    other mental and motor symptoms
 

Explanation:  Genomic imprinting - certain genes are imprinted in some way each generation.  Imprint is different depending on whether gene in male or female.  May be related to DNA methlyation
 

Fragile X syndrome

    Abnormal X chromosome - arm hangs by "thread" along side of chromosome

    Aflicted individuals have mental retardation

    Disease more likely to occur if abnormal chromosome is inherited from the mother.  Disease is more common in males than females  (1:1000 males and 1:2000 females)
 

Extranuclear inheritance

    DNA in plastids, mitochondria