Genetics Lec.3

Chromosomal abnormalities Incidence is 1: 200 newborn, but it is much higher during pregnancy (50% in the first trimester abortions). Chromosomal features with position of the centromere is used for diagnosis of chromosomal abnormalities.

Karyotype (study of chromosome

The study of chromosomes-karyotyping is the basic tool of the cytogeneticits. The usual procedure is to arrest mitosis in dividing cells in metaphase,. The most commonly used stain is Giemsa, hence called G banding. Each chromosome has 2 arms p and q (short and long). Each arm is divided into 2 or more regions by prominent bands. The regions are numbered from the centromere outward. Each region is further subdivided into bands and sub-bands and these are ordered numerically as well.

p arm (short arm) q arm (long arm) Centromere Identification of chromosomes: Each human chromosome is numbered from 1-22, and sex chromosomes either X or Y Example - 1q2.4. The first chromosome, long arm, second region of the chromosome, the fourth band of that region

Cytogenetic disorders (chromosomal Disorders) may result from alterations in the number (genome mutation) or structure (chromosome mutation) of one or more of chromosomes & may affect autosomes or sex chromosomes.

Numeric abnormalities (Genome mutation ) Human chromosomes are arranged in 23 pairs of chromosomes (46); 22 autosomes (matched pairs) & one set of sex chromosomes (male = unmatched pair, XY & female=matched pair, XX).

Haploid=n=23 Diploid=2n=46 Euploid is any exact multiple of the haploid number (xn). Polyploid is 3n (triploid=69) & 4n (tetraploid=92) & generally results in a spontaneous abortion. Aneuploid is any number that is not an exact multiple of n. The causes of aneuploidy are: – Non-disjunction – Anaphase lag

Aneuploid The chief cause of aneuploidy is non- disjunction of the homologous pair of chromosomes at the first meiotic division or failure of sister chromatids to separate during the second meiotic division, leading to the production of two aneuploid cells. When nondisjunction occurs, the gametes formed have either an extra chromosome (n+1) or one less chromosome (n-1).

Fertilization of such gametes by normal gamete will result in two types of zygotes: trisomic with extra chromosome (2n+1) (e.g., Down s), or monosomic (2n-1) (e.g., Turner s). Monosomy involving an autosome is incompatible with life, whereas monosomy involving sex chromosomes & trisomies of certain autosomes is compatible with life.

Aneuploid In anaphase lag, one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus. The result is one normal cell and one cell with monosomy

Mosaicism Is a term used to describe the presence of two or more cell populations in the same individual (normal cells and monosomy or trisomy cells) Mosaicism affecting sex chromosomes is common. While autosomal variety is much less frequent.

Structural Abnormalities Chromosome Mutation ; Structural changes in chromosomes result from chromosomal breakage then loss or rearrangement of the materials. The mechanisms that can generate changes in chromosomes is the mutation

Types of structural abnormalities 1.Translocation (t): which implies transfer of a part of one chromosome to another. Two types of translocation are identified: – Balanced reciprocal translocation is a term used when the entire broken fragments are exchanged (without loss). It is not harmful.

– Robertsonian translocation, occurs between acrocentric chromosomes in most of which the breaks occur close to the centromere, affecting the short arms of both chromosomes. Transfer of the segments leads to one very large chromosome & an extremely small one which will be lost & the carrier will have 45 chromosomes. Such loss is compatible with survival.

2. Isochromosomes In which the centromere divides horizontally rather than vertically. One of the two arms is then lost & the remaining arm is duplicated resulting in a chromosome with either 2 long or 2 short arms only. The most common isochromosome in live births involve the long arm of X-chromosome & is designated as i(Xq), when fertilized with normal gamete the result will be monosomy for genes on Xp & trisomy for those on Xq.

3. Deletion: Involves loss of a portion of a chromosome. A single break may delete a terminal segment or two interstitial breaks which may result in loss of chromosome material between the breaks and reunion of the proximal & distal segments. Terminal (rare), result from single break in a chromosome arm producing a fragment with no centromere which is lost in next division.

Ring chromosome is a variant of a deletion, after loss of segments from each end of the chromosome, the arms unite to form a ring. Ring chromosomes do not behave normally in meiosis or mitosis and usually results in serious consequences.

4. Inversion occur when there are two interstitial breaks in a chromosome, & the segment reunite after a complete turnaround. There are 2 types, pericentric and para-centric. It is often compatible with normal development

Inversions PericentricParacentric

Features of chromosomal disorders Chromosomal disorders may be associated with Absence (deletion or monosomy) Excess (trisomy) or Abnormal rearrangement (translocation, inversion) – Loss of chromosomal material produces more severe defects than gain. – Excess chromosomal material may result from complete chromosome (as in trisomy) or part of a chromosome (as in robertsonian translocation).

 Imbalances of sex chromosome (excess or loss) are tolerated much better than similar changes of autosomes.  Sex chromosomal disorders often produce subtle abnormalities that are sometimes not detected at birth. Infertility which is a common manifestation cannot be diagnosed until adolescence.  Most of chromosomal disorders result from de novo changes (i.e. parents are normal & the risk of recurrence in siblings is low). An important exception is the translocation form of Down syndrome.