Ch. 15

• Define NOW:
• Linkage √ translocation
• Deletion √ duplition
• Nondisjunction √ autosome
• Aneuploidy
• Triplet repeats
• Genomic imprinting
• inversion

• Mendelian inheritance has its physical basis in the behavior of chromosomes during sexual life styles.
• 1860s: Mendel proposed that discrete inherited factors segregate & assort independently during gamete formation
• 1875: Cytologists worked out process of mitosis
• 1890: Cytologists worked out process of meiosis
• 1900: 3 botanists (Correns, deVries, von Seysenegg) independently rediscovered Mendel’s principles of segregation & independent assortment
• 1902: cytology & genetics converged

• 1902: Walter Sutton, Theodor Boveri et al noticed parallels between the behavior of Mendel’s factors and the behavior of chromosomes
• Chromosomes & genes are both paired in diploid cells
• Homologous chromosomes separate & allele pairs segregate during meiosis
• Fertilization restores the paired condition for both chromosomes & genes
• Based on these observations: chromosomal theory of inheritance:
• Mendelian factors or genes are located on chromosomes
• Is is the chromosomes that segregate & independently assort
• Morgan traced a gene to a specific chromosome
• Experiments in early 1900s at Columbia University
• Used the fruit fly, Drosophila melanogaster,
• Easily cultured, prolific breeders, short generation time, only 4 pairs of chromosomes

• Drosophila chromosomes:
• 3 autosomes (I, II, III)
• One pair of sex chromosomes
• Female = XX
• Males = XY
• A note on genetic symbols:
• For a particular character:
• A gene’s symbol is based on the 1st mutant, wild-type discovered
• If the mutant is recessive, the 1st letter is lowercase (w= white)
• If the mutant is dominant, the 1st letter is capitalized (C= curly)
• Wild-type trait designated by superscript +
• Normal or most frequently observed phenotype
• Mutant phenotypes = phenotypes that are alternatives to the wild type & which are due to mutations in the wild-type gene
• Sex-linked genes = genes located on sex chromosomes. The term commonly applied only to the genes on the X chromosome

• Discovery of a Sex-linked Gene
• After a year of breeding Drosophila to find variant phenotypes, Morgan discovered a single male fly with white eyes instead of the wild-type red
• Morgan mated this mutant white-eyed male with a red-eyed female
• Results:

• a disproportionaly large # of flies had the phenotypes of the parents: gray with normal wings, or black with vestigial wings
• Morgan proposed that these unusual ratios were due to linkage.
• The genes for body color & wing size are on the same chromosome & are usually inherited together

• Independent assortment of chromosomes & crossing over cause genetic recombination
• Genetic recombination = the production of offspring with new combinations of traits different from those combinations found in the parents; results from the events of meiosis & random fertilization

• The recombination of unlinked genes: independent assortment of chromosomes
• Mendel discovered that some offspring from dihybrid crosses have phenotypes unlike either parent
• Parental types = progeny that have same phenotype as 1 or the other of the parents
• Recombinants = progeny whose phenotypes differ from wither parent

• 1/4 of the progeny have round, yellow seeds & 1/4 have wrinkled green seeds
• So 1/2 are parental types
• The remaining 1/2 of the progeny are recombinants.
• 1/4 are round, green & 1/4 are wrinkled yellow
• Phenotypes not found in either parent
• When 1/2 the progeny are recombinants, there is a 50% frequency of recombination
• A 50% frequency of recombination usually indicates that the 2 genes are on different chromosomes
• This is the expected result if the 2 genes assort randomly
• Genes for seed shape & seed color assort independently
• The recombination of Linked Genes:Crossing Over
• If genes are totally linked, some possible phnotypic combinations should NOT appear
• Sometimes, they do
• Using Morgan’s crossing of:

• black body, normal wings

• Gray body, normal wings

• black body, vestigial wings

• gray body, vestigial wings

• Recombination frequency =

• If wing type & body color genes were unlinked, they would assort independently & the progeny would show a 1:1:1:1 ratio of all possible phenotypic combinations
• If the genes were completely linked, espected results from the testcross would be a 1:1 phenotypic ratio of parental types only
• Morgan’s testcross did not produce results consistent with unlinkage or total linkage
• The high proportion of parental phenotypes suggested linkage between the 2 genes
• Since 17% of the progeny were recombinants, the linkage must be incomplete
• Morgan proposed that there must be some mechanism that occasionally breaks the linkage between the 2 genes
• Crossing over during meiosis accounts for the recombination of linked genes
• The exchange of parts between homologous chromosomes breaks linkages in parental chromosomes
• Forms recombinants with new allelic combinations
• Geneticists can use recombination data to map a chromosome’s genetic loci
• A.H. Sturtevant (Morgan’s student) assumed that if crossing over occurs randomly, the probability of crossing over between 2 genes is directly proportional to the distance between them
• Sturtevant used recombination frequencies between genes to assign them a linear position on a chromosome map
• He defined 1 map unit as 1% recombination frequency (now called centimorgans)
• Crossover data is used to construct a map:

• If linked genes are so far apart on a chromosome that the recombination frequency is 50%, they are indistinguishable from unlinked genes that assort independently
• Linked genes that are far apart can be mapped, if additional recombination frequencies can be determined between intermediate genes & each of the distant genes
• Sturtevant extended this method to map other Drosophila genes in linear arrays
• crossover data allowed them to cluster the known mutations into 4 major linkage groups
• Drosophila has 4 sets of chromosomes, so clustering of genes into 4 linkage groups was evidence that genes are on chromosomes
• Maps based on crossover data only give info about relative position of linked genes on a chromosome
• Cytological mapping pinpoints the actual location of genes & the real distance between them
• Involves screening offspring for mutant phenotypes & associating mutants with microscopically visual chromosomal defects
• The location of loci derived from maps based on crossover data differs from the spacing derived from cytological mapping
• Because the frequency of crosssing over is not the same for all chromosomal regions
• The chromosomal basis of sex produces unique patterns of inheritance
• In most species, sex is determined by the presence, or absence, of special chromosomes
• as a result of meiosis, each gamete has 1 sex chromosome to contribute at fertilization

• Heterogametic sex = the sex that produces 2 kinds of gametes & determines the sex of the offspring
• Homogametic sex = the sex that produces 1 kind of gamete
• In Humans
• Mammals have an X-Y mechanism that determines sex at fertilization
• Males are heterogametic
• Females are homogametic
• male or female depends upon the presence of a Y chromosome
• A single gene, Sry, on the Y chromosome triggers the complex series of events which leads to testicular development
• Codes for a protein
• some genes on sex chromosomes play a role in sex determination, but these chromosomes also contain genes for other traits
• Sex-linked traits refers to X-linked traits (in humans)
• X much larger than Y
• Most X-linked traits have no homologous loci on Y
• Most genes on Y have no counterpart on X (encode only masculine traits)
• Color-blindness, Duchenne muscular dystrophy, hemophilia = X-linked
• Fathers pass X-linked alleles to only and all of their daughters
• Males get X from Mom
• Fathers CAN NOT pass sex-linked traits to their sons
• Mothers can pass sex-linked alleles to both sons & daughters
• Females get an X from each parent
• Mothers pass 1 X to every child
• If a sex-linked trait is due to a recessive allele, females will express the trait only if homozygous recessive
• Females can be homozygous or heterozygous for X-linked traits
• Fewer affected females
• Carrier mates with normal male may pass on mutation to half of sons & half of daughters
• Carrier mates with a male with the trait, 50% of offspring will have trait
• Because males have only 1 X-linked locus, any male receiving a mutant allele from his mother will express the trait
• Far more males than females have sex-linked disorders
• males are said to be hemizygous
• A condition where only 1 copy of a gene is present in diploid beings
• How does an organism compensate for the fact that some individuals have a double dosage of sex-linked genes while others have only one?
• In female mammals, most diploid cells have only 1 fully functional X chromosome
• Lyon hypothesis (Mary Lyon)=
• In females, each of the embryonic cells inactivates 1 X
• Inactive X contracts into a dense object called a Barr body
• Inside the nuclear envelope, a densely staining object that is an inactivated X chromosome in female mammalian cells
• Most Barr body genes not expressed
• Are reactivated in gonadal cells that undergo meiosis

• female mammals are a mosaic of 2 types of cells - those with active maternal X and those with active paternal X
• Which is inactivated determined randomly
• After X inactivated, all mitotic descendants will have same inactive X

• Examples= coloration in calico cats & normal sweat gland development in humans
• X chromosome deactivation associated with DNA methylation
• methyl groups (-CH3) attach to cytosine (DNA nitrogenous base)
• Barr bodies are highly methylated compared to actively transcribed DNA
• What determines which of the 2 Xs will be methylated?
• XIST gene only active on Barr Bodies
• Its product, X-inactive specific transcript, is an RNA that interacts with the X chromosome & keeps it inactive
• Lots of ???

• Alternations of chromosome # or structure cause some genetic disorders
• Meiotic errors & mutagens can cause major chromosomal changes
• Alterations of chromosome Number
• Nondisjunction - meiotic or mitotic error during which certain homologous chromosomes or sister chromatids fail to separate
• Meiotic nondisjunction
• May occur during Meiosis I - homologous pair does not separate
• May occur during Meiosis II - sister chromatids do not separate
• Results in 1 gamete with 2 of the same type of chromosome & another with none
• Remaining chromosomes may be ok
• Mitotic nondisjunction
• Also results in abnormal # of certain chromosomes
• If occurs in embryonic cells, mitotic division passes this abnormal chromosome # to a large # of cells
• Can affect may cells

• Aneuploidy
• Condition of having an abnormal # of certain chromosomes
• May result if normal gamete unites with aberrant one produced as a result of nondisjunction
• Triplicate chromosome - trisomic
• Missing chromosome - monosomic

• Aneuploid zygote divides by mitosis, transmits chromosomal anomaly to all subsequent cells
• Causes characteristic symptoms
• Down’s Syndrome, trisomy of chromosome 21
• Polyploidy
• A chromosome # that is more than 2 complete chromosome sets
• Triploidy - 3 haploid chromosome sets (3N)
• May be produced by fertilization of an abnormal diploid egg produced by nondisjunction of all chromosomes
• Tetraploidy - 4 haploid chromosome sets (4N)
• Diploid zygote undergoes mitosis without cytokinesis
• Subsequent normal mitosis would produce a 4N embryo
• Polyploidy common in plants
• Occur rarely in animals, but they are more normal in appearance than aneuploids
• Mosaic polyploids (with patches of polyploid cells) more common than complete polyploids

• Alterations of Chromosome Structure
• Chromosomes which lose a fragment lacking a centromere will have a deficiency or deletion
• Framents without centromeres are usually lost when cell divides, OR
• May join to a homologous chromosome = duplication, OR
• Join to a nonhomologous chromosome = translocation
• Reattach to the original chromosome in reverse order = inversion
• Crossing over error is another source of deletions & duplications
• Are normally reciprocal, but sometimes 1 sister chromatid gives up more genes than it receives
• A nonreciprocal crossover results in 1 chromosome with a deletion & 1 chromosome with a duplication
• Alternations of chromosome structure can have various effects
• Homozygous deletions, including a single X in a male, are usually lethal
• Duplication & translocations tend to have deleterious effects
• Even if all genes are present in normal dosages, reciprocal translocations between nonhomologous chromosomes & inversions can alter phenotype because of subtle position effects
• Influence on a gene’s expression because of its location among neighboring genes

• Human Disorders Due to Chromosomal Alterations
• Aneuploidy, resulting from meiotic nondisjunction during gamete formation, usually prevents normal embryonic development
• Results in spontaneous abortion
• Some cases do survive
• Can be screened by fetal testing

• Down’s Syndrome
• Aneuploid condition affecting 1/700
• Trisomy 21
• Includes characteristic facial features, short stature, heart defects, mental retardation, susceptibility to respiratory infections, proneness to leukemia & Alzheimer’s disease
• Most sexually underdeveloped & sterile, some females can have children
• Some correlation between Down’s & maternal age
• Result of long time lag between 1st meiotic division during mom’s fetal life & completion of meiosis at ovulation OR
• Older women less likely to miscarry trisomic embryo
• Rarer disorders caused by autosomal aneuploidy
• Patau syndrome (trisomy 13)
• Edwards syndrome (trisomy 18)
• Sex chromosomes aneuploidies result in less severe conditions than autosomal ones
• Because y chromosome carries few genes
• Copies of X chromosome become inactivated as Barr bodies
• The basis of sex determination in humans is illustrated by sex chromosome aneuploidies
• A single Y is sufficient to produce maleness
• The absence of Y is required for femaleness
• Sex chromosme aneuploidy in males:
• Klinefelter Syndrome

• Extra Y

• Abnormalities of sex chromosome # in females
• Triple X syndrome

• Turner Syndrome:

• Structural chromosomal alterations (deletions, translocations) can also cause human disorders
• Deletions can cause severe defects even in heterozygous state:
• Cri du chat syndrome: deletion on chromosome 5
• Mental retardation, small head, unusual facial features, mewing cry

• Translocations:
• Certain cancers such as chronic myelogenous leukemia (CML)
• Portion of chromosome 22 switches places with fragment of chromosome 9
• Some cases of Down’s:
• 3rd # 21 translocates to 15, results in 2 normal 21s + translocation

• The phenotypic effects of some genes depend on whether they were inherited from Mom or Dad
• Genomic Imprinting
• Prader-Willi syndrome & Angelman syndrome caused by same deletion on #15.
• Symptomes differ depending on whether inherited from mother or father

• Prader- Willi: paternal deletion
• Mental retardation, obesity, short stature, very small hands & feet
• Angelman syndrome: maternal deletion
• Uncontrollable spontaneous laughter, jerky movements, motor & mental symptoms

• This implies that the deleted genes normally behave differently in offspring, depending on whether they belong to the maternal or parental homologue
• Homologous chromosomes inherited from males & females are somehow differently imprinted, which causes them to function differently

• Genomic Imprinting = process that induces intrinsic changes in chromosomes inherited from males & females;

• According to this hypothesis: certain genes are imprinted in some way each generation
• The imprint is different depending upon whether the genes reside in females or males
• Same alleles may have different effects on offspring depending on whether they are inherited from Mom or Dad

• In the new generation, both maternal & patenal imprints can be reversed in gamete-producing cells
• All the chromosomes are re-coded according to the sex of the individual in which they now reside
• DNA methylation may be 1 mechaism for genomic imprinting

• Fragile X & Triplet Repeats
• Triplet Repeats = sections of DNA where a specific triplet of nucleotides is repeated many times
• Occur normally in areas of human genome
• Progressive addition of triplets can lead to genetic disorders: Fragile X & Huntington’s disease

• Fragile X: 1/1500 boys, 1/2500 girls
• Most common genetic cause of mental retardation
• Fragile X is an abnormal X, the tip of which hangs on the rest of the chromosome by a thin DNA thread
• This altered region (as well as the comparable region on a normal X) contains triplet repeats

• Triplet repeat (CGG) is repeated up to 50x on 1 tip of a normal X, but more than 200x on a fragile X
• Abnormal addition of triplet repeats occurs incrementally over generations:
• Pre-fragile X: 50 to 200 CGG repeats (phenotyoically normal)
• As repeats accrue, symptoms appear

• Fragile X’s complex expression may be a consequence of maternal genomic imprinting
• More likely to appear if the abnormal X inherited from Mom
• Pre-fragile X in ova producing cells more likely to acquire new CGG triplets than those in sperm

• In the female parent, the site of triplet repeats on the X is imprinted by DNA methylation
• Excessive methylation may inactivate 1 or more gees & prevent normal expression in offspring
• Maternal imprinting explains why fragile X more common in males
• Males inherit fragile X from Mom

• Females can inherit fragile X from either parent, but only maternal version is imprinted & causes expression of syndrome
• Heterozygous carriers: have partial protection from normal X
• Usually only mildly retarded
• Huntington’s Disease another example

• Huntington loci, near tip of #4, has a CAG extended triplet repeat
• Genomic imprinting influences expression of the gene
• Triplet repeat at the Huntington’s loci more likely to extend if allele inherited from Dad
• Extranuclear genes exhibit a non-mendelian pattern of inheritance

• Exceptions to chromosomal theory of inheritance
• Extranuclear genes are found in cytoplasmic organelles such as plastids & mitochondria
• Not inherited in Mendelian fashion, because they are not distributed by segregating chromosomes during meiosis

• In plants, zygote receives its plastids from the ovum, not pollen
• Offspring receive only maternal cytoplasmic genes
• Cytoplasmic genes in plants 1st described by Corens (1909)
• Noticed plant coloration determined by seed bearing plants not pollen producing plants

• Now known that maternal plastid genes control variegation of leaves
• In mammals, inheritance of mitochondrial DNA is exclusively maternal
• Since the ovum contributes most of the cytoplasm to the zygote, the mitochondria are all maternal in origin