Chromosomal Basis of Inheritance

1
Chromosomal Basis of Inheritance
2
Mendel's work remained undiscovered until 1900's,
when others independently stumbled on similar
results.

• During 1875-1890's, work on cytogenetics led to
  discovery of chromosomes and their behavior
  during mitosis and meiosis.
  
• Led to a convergence in cytology and genetics.
• Several parallels noted between Mendel's 1st and
  2nd law and chromosome behavior

3
What we learned.

• 1. chromosomes and genes are both present in
  pairs in diploid cells
  
• 2. homologous chromosomes separate and alleles
  segregate during meiosis.
  
• 3. fertilization restores paired condition for
  both chromosomes and genes.
  

4
Mendels Laws
Law of Independent Assortment Alleles of ge
nes on non-homologous chromosomes assort Ind
ependently.
Law of Segregation Genes separate
5

• Chromosomal Basis of Mendels Laws
• Chromosome theory of inheritance mendelian
  genes have specific loci on chromosomes it is
  chromosomes that undergo segregation and
  independent assortment.
• See page 275

6
Thomas Hunt Morgan

• (Early 20th century) used genetic crosses
  involving the fruit fly, Drosophila melanogaster
  to prove Mendel's genes reside on chromosomes.
  
• He received the Nobel Prize for Physiology or
  Medicine in 1933.

7
Drosophila melanogaster

• Convenient study organism because
• prolific breeders
• small size
• 2-week generation time
• small chromosomes (n4)
• sex determined by XY system (as in mammals)

8
Morgan isolated single male fly with white eyes
(normally red).

• Genetic symbols
• gene takes the symbol from first mutant
• "" denotes most common allele (wildtype)
• upper and lower case denote dominant/recessive of
  mutant.
  

9
Discovery of sex-linked genes Morgan crossed
made the following cross
10
Sex - Linked Genes

• White eye male x red eye female all F1 with red
  eyes F2 show 31 ratio of red to white, BUT only
  males had white eyes, i.e eye color correlated
  with sex
• EXPLANATION of F2 results eye color present of X
  chromosome.
  
• Genes located on a sex-chromosome are called
  sex-linked genes
  

11
Linked genes tend to be inherited together
because they are located on the same chromosome

• Number of genes is much greater than the
  number of chromosomes. Each chromosomes has
  1000's of genes.
  
• When geneticists follow linked genes in
  breeding experiments, results deviate from those
  expected according to the mendelian principle of
  independent assortment.
• To show that linked genes are inherited
  together, Morgan did following cross (Fig 15.5)
  

12

• This is a testcrossif unlinked Expect 1111 of
  bb vgvgb b vg vgbb vgvgb b vg vg
  
• ACTUAL results were965 bb vgvg Largest class
  similar to944 b b vg vg parents (parental
  phenotypes)
  
• 206 bb vgvg Smallest class are 195 b b vg vg
  recombinants

13
Results restated

• Recombinants result from chromosome crossing over
  during prophase I of meiosis.
  
• Based on such results, concluded that these two
  genes are ordinarily on the same chromosome, but
  recombination unlinks them.
  
• When 1/2 of progeny are recombinant, we say that
  there is a 50 recombination frequency, and the
  genes in a cross behave as if on different
  chromosomes altogether.

14
Geneticists can use recombination data to map a
chromosome's genetic loci.

• Genetic map lists a sequence of genetic loci
  along a particular chromosome.
  
• Alfred Sturtevant Morgan's student reasoned that
  different recombination frequencies reflect
  different distances between genes on a chromosome
  ( Fig 15.6).
• the farther apart genes are, the greater
  likelyhood of X-over
  
• the closer together two genes are, the less
  likely of X-over occurring.
  
• Map unit 1 recombination frequency
  (centimorgan)
  
• recombination frequency ( recombinants) (100)
  /total offspring
  

15
Using crossover data to construct genetic maps

• Refer to Fig 15.7
• Suppose you know the distance between two
  genesSuppose also that another gene (cn) is
  known to be close to b. The question is how do
  you know to which side cn is of b with respect to
  the vg gene.

16

• (Fig 15.8)linkage map genetic map based on
  recombination frequencies
  
• cytological map actually pinpoints genes along
  on chromosomes
  
• NOTE because X-over frequency is not constant
  along all areas of the chromosome, 1 map unit
  does not actually correspond to a fixed length of
  chromosome.

17
Chromosomal basis of sex produces unique patterns
of inheritance

• In mammals, there are two types of sex
  chromosomes
  
• XX are female
• XY are male
• (Fig 15.9)

18
Sex-linked disorders in humans

• Not all genes on X chromosome are involved in
  sex determination
  
• (Fig 15.9).
• Genes on sex chromosomes are said to be
  sex-linked (X-linked or Y-linked)

19
Examples of Recessive X-linked disorders

• 1. Hemophilia
• defined by lack of a protein involved in blood
  clotting.
  
• plagued much of royal families of Europe
• 2. Duchene muscular dystrophy
• 1/3500 males in US
• more common in males than females
• characterized by progressive weakening of muscles
  and loss of coordination.
  
• lack a muscle protein known as dystrophin

20
Inactivation of X chromosome in females

• To compensate for dosage differences between male
  and female for X-linked genes, in females one of
  the X chromosomes is randomly inactivated early
  in development.
• The inactivated chromosome can be seen at the
  periphery of the nucleus and is called a Barr
  body.
  
• Females are a mosaic for X chromosome.

21
(No Transcript)
22
Alterations of chromosome number

• Alterations in chromosome number result from
  nondisjunction (pairs of chromosomes fail to
  separate at meiosis).
  (Fig 15.12)
• Aneuploidy having or - normal number
  chromosomes (monosomics vs trisomics).
  
• Chromosome deletions are usually lethal
• Other chromosome aberrations may be as lethal
  some survive (e.g trisomy 21)
  
• Polyploidy when organism has more than 2
  complete sets of chromosomes.
  
• Originate by genome doubling.
• (haploid, diploid, triploid, tetraploid)

23
Tetraploid Animals

• Studies of duplicate gene loci in tetraploid
  animals may reveal important general aspects of
  gene duplication, an important mode of gene
  evolution in metazoans.
• The common carp Cyprinus carpio has twice as many
  chromosomes as most other cyprinid fishes due to
  tetraploidization previously estimated to have
  occurred 50 Myr ago.

24
Human disorders due to chromosomal alterations

• Down syndrome 1/700 children affected extra
  chromosome 21 retardation to various degrees
  correlated with age of mother.
  
• Trisomy 13 1/500 rarely survive more than a
  year.
  
• XXY males (Klinefelters syndrome) 1/2000 have
  male sex organs, but are abnormally small breast
  enlargement and other female characteristics
  normal intelligence.
• XYY males taller than average
• XXX females 1/1000 indistinguishable from XX
• X females (Turner's syndrome) 1/1000
  phenotypically female but sex organs do not
  mature and are sterile.
  

25
Alteration of chromosome structure

• Deletions, duplications, inversions, reciprocal
  translocations.

26
Down Syndrome

• The presence of all or part of an extra 21st
  chromosome.
  
• It is named after John Langdon Down, the British
  doctor who first described it in1866.
  
• The condition is characterized by a combination
  of major and minor differences in body structure.
  
  
• Often Down syndrome is associated with some
  impairment of cognitive ability and physical
  growth as well as facial appearance.
  
• Down syndrome is usually identified at birth.

27
Aneuploidy of Sex Chromosomes

• XXY Klinefelter Syndrome
• Small male sex organs, sterile
• 1/2000 births
• Very small breasts
• Usually normal intelligence
• XYY
• Taller than average

• XXX
• Occurs 1/1000 births
• Cant tell from other girls physically
• X Turner Syndrome
• 1/5000 births
• Only viable human monosomy
• Sterile
• Estrogen
• Replacement
• helps

28
Structurally Altered Chromosomes

• Deletions
• Cri du chat syndrome
• Deletion of a number 5 chromosome
• Mentally retarded

• Translocations
• Some cancers
• Example
• Chronic Myelogenous Leukemia (CML)

29
Genomic Imprinting

• Believed to occur in gametogenesis.
• Genomic imprinting occurs when both maternal and
  paternal alleles are present, but one allele will
  be expressed while the other remains inactive.
  
• It is not completely evident why genes are
  imprinted.
  
• See figure 15.17

30
What exactly is genomic imprinting?

• A methyl groups (-CH3) added to cytosine
  nucleotides of one allele.
  
• May directly silence the other allele
• However in some cases it activates the allele
• Thought to affect only a small number of
  mammalian genes.
  
• Two active copies cause death.

31
Extra-nuclear Genes

• Not all of a eukaryotics genes are located on
  nuclear chromosomes
  
• Mitochondria, chloroplasts, and some plant
  plastids contain circular DNA molecules that
  carry genes encoded for proteins and RNA
  
• Do not distribute to offspring like in meiosis,
  so never exhibit mendelian genetics, however,
  mitochondria pass on via cytokinesis.
  
• Defects on these genes can cause protein
  malfunction which can cause mitochondrial
  Myopathy, diabetes, heart disease, Alzheimers.
  normal aging processes.