Human Genetics - Chromosome Anomalies Lecture Notes PDF

CHROMOSOME ANOMALIES  Lecture Objectives: By the end of this lecture, the students should be able to: 1. Describe and explain the events in mitosis & meiosis. 2. Define non-disjunction and describe its consequences on meiosis. 3. Classify chromosomal abnormalities: Numerical & st...

CHROMOSOME ANOMALIES  Lecture Objectives: By the end of this lecture, the students should be able to: 1. Describe and explain the events in mitosis & meiosis. 2. Define non-disjunction and describe its consequences on meiosis. 3. Classify chromosomal abnormalities: Numerical & structural 3a Understand the common numerical autosomal disorders: trisomies 21, 13, 18. 3b Understand the common numerical sex chromosome disorders: Turner`s & Klinefelter`s syndromes 3c Recognize the main structural anomalies in chromosomes 1) Mitosis & Meiosis  Typical mitotic cell cycle During G1 = one diploid S phase = duplication of each chromosome’s DNA à Two sister chromatids G2 Phase = chromosomes begin to condense and become visible G1, S, and G2 phases = constitute interphase Two daughter cells = equal genetic information  Events of mitosis Prophase. formation of mitotic Spindle & pair of centrosomes Prometaphase. - Nuclear membrane dissolves - Chromosomes to disperse & attach by kinetochores to mitotic spindle microtubules Metaphase. Chromosomes condensed & line up at the equatorial plane Anaphase. - Chromosomes separate at centromere & - Sister chromatids of each chromosome become independent daughter chromosomes Telophase. - Chromosomes de-condense from their highly contracted state, - Nuclear membrane re-form around each of the two daughter nuclei, - resume their interphase Events of meiosis I & II 2-) Non-disjunction and its impact on meiosis  Non-disjunction in Meiosis - The failure of chromosomes to disjoin normally during meiosis phase 1 or phase 2. - Two chromosome homologs migrate to the same daughter cell instead of disjoining normally and migrating to different daughter cells. - The result of this error is a cell with an imbalance of chromosomes (Aneuploidy)  Meiotic non-disjunction § Can affect each pair of chromosomes § is not a rare event § Non disjunction in first meiotic division produces 4 unbalanced gametes. § Non disjunction in second division produces 2 normal gametes & 2 unbalanced gametes: – Gamete with an extra autosome – Nullosomic gamete (missing one chromosome)  In meiotic nondisjunction - This product of fertilization with normal gamete would be monosomic and trisomic offspring (Aneuploidy)  3- Classifications of chromosomal abnormalities CHROMOSOME ANOMALIES TYPES: - Numerical affect the number of complete haploid set (n) of chromosomes - Structural Affect the structure and organization of genomic content of the chromosome  3a. NUMERICAL CHROMOSOMAL ANOMALIES Numerical anomalies in autosomes  Down syndrome, trisomy 21 Karyotype: 47, XY, +21 - Most cases arise from non disjunction in the first meiotic division - The incidence of trisomy 21 rises sharply with increasing maternal age - The father contributing the extra chromosome in 15% of cases - The symptoms include characteristic facial dysmorphologies, and an IQ of less than 50.  Edward's syndrome, Trisomy 18 Karyotype: 47, XY, +18 - the second most common autosomal trisomy, after Down syndrome - It occurs in around one in 6,000 live births - Most babies die in the first year and many within the first month & has a very low rate of survival - Common anomalies are heart abnormalities, kidney malformations, and other internal organ disorders  Patau Syndrome, Trisomy 13 Karyotype: 47, XY, +13 - 50 % of these babies die within the first month and very few survive beyond the first year. - There are multiple dysmorphic features. Most cases, as in Patau syndrome, involve maternal non-disjunction.  3b. NUMERICAL CHROMOSOMAL ANOMALIES Numerical anomalies in Sex chromosomes  Monosomy X (Turner’s syndrome, 45,XO) - Occurring in 1 in 4000 phenotypic females - As a result of paternal meiotic nondisjunction - The only viable monosomy in humans - Characteristics: Webbed neck, Individuals are genetically female, not mature sexually, Sterile, Short stature, Boad chest, Low hairline, Streak ovaries, Normal intelligence, Normal life span  Klinefelter Syndrome: 47,XXY males - 1/600 males - Due to nondisjunction of X chromosomes during meiosis I in females - Male sex organs; unusually small testes which fail to produce normal levels of testosteroneà breast enlargement (gynaecomastia) and other feminine body characteristic - Patients are taller and thinner than average and may have a slight reduction in IQ but generally they have normal intelligence - No spermatogenesis à sterile  MOSAICISM The presence of more than one genetically distinct cell line in the body A mosaic individual is made of 2 (or more) cell populations, coming from only 1 zygote  MOSAICISM v A mosaic individual is made of 2 (or more) cell populations, coming from only 1 zygote v Is denoted by a slash between the various clones observed e.g.46, XY / 47, XY, +21). v Numerical mosaic anomaly is usually due to a mitotic non-disjunction v A mosaic must not be confused with a chimeras. v Chimerism is the presence in an individual of two or more genetically distinct cell lines derive from more than one zygote (e.g. 2 sperms fertilize 2 ova à 2 zygotes that fuse to form 1 embryo  3c. STRUCTURAL CHROMOSOMAL ANOMALIES  Reciprocal translocation - Reciprocal translocation between chromosome 22 and the long arm of chromosome 9 (the Philadelphia chromosome). - The occurrence of this translocation in hematopoietic cells can produce chronic myelogenous leukemia (CML)  Robertsonian translocation - Short arms of two non homologous chromosomes are lost and the long arms fuse at the centromere to form a single chromosome - Confined to the acrocentric chromosomes(13, 14, 15, 21, and 22) - Although carriers have only 45 chromosomes in each cell, they are phenotypically unaffected  Deletion v- Loss of a segment from a chromosome, either terminal or interstitial vInvariably, but not always, results in the loss of important genetic material vDeletion is therefore an unbalanced rearrangement. vIndicated in nomenclature del Terminal deletion ê 46,XX,del(18)(q21.3)  Interstitial deletion Sample karyogram karyotype description is as follows: - 46: the total number of chromosomes. - XY: the sex chromosomes (male). - del(7): deletion in chromosome 7. - (q11.23q21.2): breakpoints of the deleted segment. 46,XY,del(7)(q11.23q21.2)  Inversion - Occurs when a segment of chromosome breaks, and rejoining within the Pericentric chromosome effectively. - Written in nomenclature as inv. - Only large inversions are normally detected. They are balance Paracentric rearrangements that rarely cause problems in carriers  Isochromosome The most probable explanation for isochromosome is that the centromere has divided transversely rather than longitudinally Normal Isochromosome Normal Isochromosome  Ring formation (Ring chromosome) - A break on each arm of a chromosome - Two sticky ends - Reunion of the ends as a ring loss of the 2 distal chromosomal fragments - Ring chromosomes are often unstable in mitosis  Take home message Chromosome abnormalities can be numerical or structural. Normal meiotic division result in four haploid gametes In trisomy, a single extra chromosome is present, usually as a result of non-disjunction in the 1st or 2nd meiotic division. Mosaicism arize from one zygote while Chimera from the fusion of two fertilized eggs Structural abnormalities include translocations (balanced or unbalanced), inversions, deletions, isochromosome & rings.