MED 1 L.O. 1-14

• Karyotype


  An individual's collection of chromosomes
• Karyotyping


  A laboratory technique that produces an image of an individual's chromosomes
• Giemsa banding (G-banding)


  1. Slides with chromosome preparation (In metaphase stage) are treated with trypsin to break chromosomal proteins

  2. Stained with Giemsa solution

  3. The chromosomes show dark and light bands, which can be viewed through microscope
• Numbering the Bands on Chromosomes

  • 16p32 refers to chromosome 16, p arm 3rd region, 2nd band
  • 7q12.2 refers to 2nd sub band of 2nd band in 1st region of long arm of chromosome 7
• 1. Chromosome Inactivation (Aka Lyonization)


  • Only one X chromosome is transcriptionally active in each somatic cell in females
  • The second X chromosome is almost completely transcriptionally inactive and exists in the form of heterochromatin
• Number of Barr bodies

  No. of Barr bodies = No. of X Chromosomes - 1
• Number of Barr bodies

  • In normal females (46, XX): 1
  • In 47, XXX (abnormal) female: 2
  • In 45, X (abnormal, only one X) female: 0
  • In males (46, XY) there is only one X chromosome, so no Barr body is formed: 0
  • In 47 XXY (abnormal) male: 1
• X chromosome inactivation


  • Inactivation occurs early in embryonic stage
  • Inactivation is random but fixed
  • Once an inactivation of a particular X chromosome in a cell happens it is binding to all its descendant daughter cells
  • The ratio of maternal & paternal inactive X chromosomes in somatic cells of females ranges from 75:25 to 25:75, with an average ratio of 50:50
• Mechanism of X chromosome inactivation

  Involves DNA methylation, histone modifications (e.g., deacetylation), and the presence of a specific histone variant – macro H2A in inactive X
• X inactivation center (XIC)


  • Contains an unusual gene XIST, which is supposed to play a key role in X inactivation
  • The XIST gene is transcriptionally silent in the active X chromosome but expressed (transcriptionally active) in inactive X chromosome
• Escape from X Inactivation

  • Even in inactive X Chromosome, a few genes are found to be transcriptionally active
  • These transcriptionally active genes are located mainly in pseudo-autosomal regions of the inactive X chromosome, near the terminal regions
• The human Y chromosome contains the least number of genes than any other chromosome, less than 100 genes
• Holandric genes


  Genes present on the Y chromosome, code for about 23 different proteins
• SRY gene


  Located at the p arm and codes for testis determining factor (TDF)
• AZF genes


  Mutation of which lead to azoospermia (absence of sperm), and oligospermia (low amount of sperm)
• Only few Y chromosome genes linked to diseases: Retinitis Pigmentosa (RPY gene)
• Numerical Abnormalities


  Aneuploidy, when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy), or Euploidy, having abnormal set of chromosomes, e.g., triploid or tetraploid
• Numerical Abnormalities


  • 46, XY, del(22)(q21): a male with 46 chromosomes and a deletion on chromosome 22, with the breakpoint at band q21
  • 47, XX, +21: a female with 47 chromosomes with an extra copy of chromosome 21, trisomy 21 or Down syndrome
  • 46, XX, t(1;6)(p23;q21): a female with 46 chromosomes and a translocation between chromosomes 1 and 6 with breakpoints at band p23 on the short arm of chromosome 1 and at band q21 on the long arm of chromosome 6
• Structural Abnormalities


  When the structure of the chromosome is altered so rearrangements involving one or more chromosomes
• Balanced structural abnormalities


  The genome has the normal complement of chromosomal material
• Unbalanced structural abnormalities


  If there is additional or missing material
• Cri-Du-Chat Syndrome


  Caused by a deletion on the short arm of chromosome 5
• Down Syndrome/Trisomy 21


  • Approximately 95% of affected individuals have trisomy 21
  • Maternal age has a strong influence on the incidence of trisomy 21
  • They have an increased risk of developing a number of medical problems: respiratory infections, gastrointestinal tract obstruction, leukemia, heart defects, hearing loss, hypothyroidism, and various eye abnormalities
  • Approximately 40% of the patients have congenital heart disease
  • Children with trisomy 21 have a 10-fold to 20-fold increased risk of developing acute leukemia
  • Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimer disease
  • Patients with Down syndrome have abnormal immune responses that predispose them to serious infections
• Meiotic Nondisjunction


  The most common cause of Down syndrome
• Trisomy 21 due to Translocation

  In about 4% of Down syndrome cases, the extra chromosomal material derives from the presence of a Robertsonian translocation of the long arm of chromosome 21 to another acrocentric chromosome (e.g., 22 or 14)
• Klinefelter Syndrome


  • Males who have an extra X chromosome
  • The classic pattern of Klinefelter syndrome is associated with a 47,XXY karyotype (90% of cases)
• Klinefelter Syndrome


  • Small testicles and penis
  • Breast enlargement
  • Infertility
  • Consistent with hypogonadism, the hormonal findings typically show elevated plasma gonadotropin concentrations, especially FSH, elevated plasma estradiol and reduced testosterone
• Metafemale (XXX)


  A woman who has an extra X chromosome
• Metafemale (XXX)


  • Generally normal
  • Tall stature
  • Behavioral problems
  • Clumsiness and poor coordination
  • Wide-set eyes
  • Reduced muscle tone
  • Ovarian failure
• Turner Syndrome (Monosomy)


  • Occurs in about 1 in 2,500 female births worldwide, but is much more common among pregnancies that do not survive to term (miscarriages and stillbirths)
  • Results from complete or partial monosomy of the X chromosome and is characterized primarily by hypogonadism in phenotypic females
• Turner Syndrome


  • Extra skin on the neck (webbed neck)
  • Puffiness or swelling (lymphedema) of the hands and feet
  • Skeletal abnormalities
  • Heart defects
  • Kidney problems
  • The mental status of these patients is usually normal, but subtle defects in nonverbal, visual-spatial information processing have been noted
• Aneuploidy


  The term refers to an addition or deletion of one or more chromosomes from the normal set of chromosomes
• Autosomal aneuploidy


  Autosomal monosomies are usually incompatible for survival. However, Trisomy are seen with appreciable frequencies, e.g., Down syndrome
• Sex Chromosome Aneuploidy


  • Among live infants, 1/400 males and 1/650 females have some form of Sex chromosome aneuploidy
  • The consequences are less severe than autosomal aneuploidy
  • Generally compatible for survival, the exception being the cases where there is complete absence of X chromosome
• Aneuploidy


  Results from nondisjunction, mostly during meiosis (at Anaphase stage)

  
• Aneuploidy


  An addition or deletion of one or more chromosomes from the normal set of chromosomes
• Common types of aneuploidy

  • Monosomy: One chromosome is missing in a diploid set
  • Trisomy: One chromosome is extra in a diploid set
• Monosomy


  • 45,X (seen in Turner syndrome)
• Trisomy


  • 47, XX (or 47, XY) + 21 (seen in Down syndrome)
• Autosomal aneuploidy


  Autosomal monosomies are usually incompatible for survival, but Trisomies are seen with appreciable frequencies