Chromosomes: normal and aberrant structure and karyotypes n Chromosomes are comprised of a single, uninterrupted DNA molecule complexed with proteins (histones and others). n Landmarks of human chromosome structure include telomeres and the centromere demarcating the two “arms” (p and q). n A karyotype is a visual display of the chromosomes of an individual. –A human karyotype is generally prepared from cultured white blood cells treated with a mitogen and then colchicine to arrest cells in mitotic metaphase (chromosomes highly condensed and visible). Cells are then swollen hypotonically and chromosomes released onto a slide and then stained to reveal species-specific banding patterns of individual chromosomes. FISH can be performed for mapping.

Klug and Cummings, 6th Ed., 2000

Chromosome numerical variations n Polyploidy: extra complete sets of chromosomes, e.g., 3n (triploidy). This is found in some spontaneously aborted human fetuses. n Aneuploidy:”wrong number” of chromosomes, e.g., –2n + 1 = trisomy, the presence of an extra copy of one specific chromosome –2n - 1 = monosomy, the absence of one copy of a specific chromosome –Origins of aneuploidy most frequently lie in meiotic nondisjunction

Common human aneuploidies n There are no viable human monosomies except that of the X chromosome: XO, Turner syndrome. n Other sex-chromosome aneuploidies associated with viability are XXY (Klinefelter syndrome) and XYY. n Most human autosomal trisomies are embryonic lethals, but Ts 13, 18 and 21 survive in many cases. n The most viable human trisomy is Ts21, Down syndrome. Incidence of nondisjunction-related Ts21 increases with increasing maternal age. n Abnormalities and lethality associated with monosomy and trisomy suggest tight dosage control, with no dosage compensation.

Chromosomal structural aberrations n The most frequent structural aberrations include: deletions, duplications, inversions, and translocations. n These abnormalities of structure can give rise to abnormalities in meiotic segregation of chromosomes as well as further structural abnormalities after crossing over. n Translocations can be reciprocal or non- reciprocal, or Robertsonian centric fusions.

Chromosome structure and aberrations: Summary n Important landmarks of chromosome structure includes telomeres, a centromere and the arms. n Construction of karyotypes enables not only cytogenetic analysis of defects but also gene mapping (e.g., by FISH). n Aberrations of chromosome number include polyploidy and aneuploidy, but aneuploidy is much more common in humans. n Aberrations of structure include inversions, deletions, duplications and translocations, both reciprocal and non-reciprocal. These can be useful reagents for gene mapping.