Genetics of Chromosomes:
Introduction to Cytogenetics

In Principle:

Genes occupy physical locations (loci) in linear arrays on chromosomes
    Alterations in the number of chromosomes or relative order of genes affect expression

Chromosomes occur in species-specific sets
    Chromosomes within sets have  characteristic size & morphology
Chromosome irregularities are associated with particular medical syndromes
       These are some of the major classes of genetic disorders in humans

Chromosomes each comprise a single, continuous DNA molecule
       DNA is systematically packaged into chromosomes through several levels of coiling
       Most DNA does not code for proteins
       Non-coding DNA occurs in several classes

Chromosome morphology at the microscopic level

Chromosomes occur in sets: haploid number = n
    Eukaryotic chromosomes have arms (short p & long q) & a centromere (IG1 11.12,14)
= # arms
        metacentric (q ~ p)
        acrocentric (q > p)
        telocentric (q >> p ~ 0 )
        Ex.: Karyotype of Homo sapiens: 2n = 46 = 44 + XX or 44 + XY
                   Metaphase karyotype has seven groups A - G (IG1 11.15smc, 11.15smc2)
                   autosomes vs sex chromosomes (XY system in mammals)
                         Alternative sex-determination systems (WZ) in birds (Aves)

       Cytological appearance of chromosomes
            euchromatin  - non-staining [GC]-rich, genetically active
            heterochromatin - staining [AT]-rich, geneticvally inactive
                  Barr Body - an inactive X chromosome
                      dosage compensation between XX & XY karyotypes
                      effect on semi-dominant X-linked expression:
                           the genetics of tortoiseshell & calico cats

           chromosome banding  (IG1 11.Tab3)
                G-banding       - (G)iemsa bands = proteolytic enzyme treatment + Giemsa stain
                                                                            chromosome-specific banding patterns
                FISH banding - (fluorescent in situ hybridization) identifies translocations
                polytene chromosomes - endoreplication in Drosophila (2n = 8)
[iGen3 16.01]
                Lampbrush chromosomes in Triturus salamanders (Amphibia)

Variations in chromosome number

Number of n sets: euploidy
[iGen3 16-22]
        diploid number (2n)
= two haploid sets
            haploid (monoploid) species: male bees & wasps Hymenoptera
            triploid (3n) - typically sterile (Ex.: seedless watermelon)

                autopolyploid - formed by duplication of set within species
                     tetraploid (4n) plants often larger than parents
                allopolyploid - formed by mating of different species:
2n x 2n = 4n'
                      Raphanobrassica cabbage x radish hybrid
                      Xenopus frogs evolve by polyploidization: 2n = 20 ~ 108
                      Triticum wheat is a diploidized hexaploid (6n)

    Number of chromosomes per set: aneuploidy
[iGen3 16-15]
         Human cytogenetic disorders: 7.5% of spontaneous abortions
                                                                    0.6% of live births 
[iGen3 16-Table 01]

        monosomy: one chromosome missing -  non-disjunction in meiosis
[iGen3 16-16]
            X humans: Turner Syndrome ( 2n = 45, X)
        trisomy: one chromosome duplicated (2n = 47, +21)
            XXX: standard female
            XXY: Klinefelter Syndrome ( 2n=47, XXY )
            XYY: 'supermale' syndrome (misnomer)
            Trisomy-21: Down Syndrome
( 2n=47, +21 ) [iGen3 16-17]
                most common, ~ 1 / 2000 live births
                Associated with later maternal age [iGen3 16-Table 02]
            Rarer trisomies: Patau Syndrome (Trisomy-13) ( 2n=47, +13 ) [iGen3 16-20]
                                         Edward Syndrome (Trisomy-18) ( 2n=47, +18 ) [iGen3 16-18]

Variations in chromosome arrangement
     Loss / duplication / transfer of partial chromosomes: segmental aneuploidy
: small part of long arm of Chromosome 7 in Williams Syndrome (2n=46, 7q11.23-) [HOMEWORK]
             reciprocal translocations )
[iGen3 16-11]
                  duplication / deletion gametes heritable Down Syndrome
                  Philadelphia Chromosome
(2n=46, t 9q,22q Chronic Myologenous Leukemia (CML [iGen3 16-12] (IG1 20.19)
                  balanced translocations new species ?
             Unbalanced translocations:

Cri-du-Chat Syndrome: loss of short arm of Chromosome 5 (2n = 46, 5p-) [iGen3 16-04]

             pericentric inversions include centromere
[iGen3 16-09]
             paracentric inversions occur within one arm  [iGen3 16-08]
                   Inversion polymorphism  in Drosophila shows intra-specific evolution
             Synteny among species shows inter-specific evolution
             Robertsonian fusions / fissions: # arms constant, 2n varies [# centromeres]
                       Ex.: Homo has 2n = 46 vs Chimp, Gorilla, & Orangutan with  2n=48

Chromosome architecture at the molecular level
             OR: Whatcha gonna do with all that junk inside your genes?

How is DNA packed into chromosomes?
        1o coiling of DNA helix
        2o coiling of DNA + histone core = nucleosome
              histone octamer: (H2A, H2B, H3, H4) x 2
              histone H1 + linker DNA
        3o coiling of core + linker forms Solenoid
                six H1 subunits
        4o coiling of solenoid loops to non-histone Scaffold

     scaffold supercoil chromatin thread chromosome

Fine-scale DNA structure of chromosomes [Chromosome 11 CSHL Animation]

     Protein-coding genes have introns, exons, promoters, enhancers
         'exon shuffling' hypothesis 
               exons as protein domains
               exon recombination occurs via transposable elements
        Human genomes include ~20,050 protein-coding "genes" in <5% of DNA

     Telomeric DNA caps chromosomes (IG1 11.1 Research Briefing)

        may limit lifespan of cells in vitro and in vivo (aging) [Nobel Prize, 2009]

     Repetitive DNA accounts for >>50% of human genome, within and between coding gene loci
                Repeats may be dispersed or tandem
        Tandem repeats - multiple copies arranged end-to-end
            satellite DNA - variable [G+C] content
            NORs (nucleolus-organizer regions) comprise multiple rDNA genes
                    5S, 18S & 28S rRNA gene clusters
                     multiple rDNAs allow more efficient production of rRNA
            VNTRs (variable number of tandem repeats)
                        micro- & minisatellites - 2 or 4~10bp repeats

        Dispersed repeats -  scattered throughout chromosome set
            SINEs (short interspersed elements) may occur within introns
                    Alu family200 ~ 300 bp x 105s copies
                    Alphoid family - centromeric heterochromatin, 170bp x ~103 copies
            LINEs (long interspersed elements) occur between genes
                    LI family - 6,400bp x 10,000 copies

All text material ©2012 by Steven M. Carr