# Lecture 6: Chromosomal Abnormalities and Human Disease
## Genetics
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Classify chromosomal abnormalities as numerical (aneuploidy, polyploidy) or structural
2. Explain the mechanisms of nondisjunction in meiosis I and meiosis II
3. Describe the clinical features and genetic basis of common aneuploidies (Down, Turner, Klinefelter syndromes)
4. Identify types of structural chromosomal abnormalities (deletions, duplications, inversions, translocations)
5. Explain the clinical significance of Robertsonian and reciprocal translocations
6. Describe the process and role of X-inactivation in dosage compensation
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## Lecture Content
### I. Numerical Abnormalities: Aneuploidy
**Aneuploidy** refers to an abnormal chromosome number that is not a complete multiple of the haploid set. Several types exist: **monosomy** is the loss of one chromosome (2n - 1), as in Turner syndrome (45,X); **trisomy** is the gain of one extra chromosome (2n + 1), as in Down syndrome (47,XX,+21); **tetrasomy** involves the gain of two copies of one chromosome (2n + 2), which is rare and usually lethal; and **nullisomy** is the loss of both copies of one chromosome (2n - 2), which is lethal in humans.
The primary cause of aneuploidy is **nondisjunction**, the failure of chromosomes or chromatids to separate properly during cell division. When nondisjunction occurs in meiosis I, homologous chromosomes fail to separate, and both homologs travel to the same daughter cell. In this scenario, all four resulting gametes are abnormal: two carry an extra chromosome and two are missing one. When nondisjunction occurs in meiosis II, sister chromatids fail to separate, producing two normal gametes, one gamete with an extra chromosome, and one missing a chromosome. Mitotic nondisjunction occurs after fertilization and leads to mosaicism, where some cells in the organism have a normal chromosome complement while others are aneuploid. The strongest risk factor for autosomal trisomies is advanced maternal age, because oocytes remain arrested in meiosis I for decades and the cohesin proteins that hold homologs together degrade over time.
Panel A: Side-by-side diagram comparing normal meiosis, nondisjunction at meiosis I, and nondisjunction at meiosis II, showing the chromosome content of each resulting gamete and the resulting zygotes after fertilization (trisomic, monosomic, or normal). Panel B: Graph showing the relationship between maternal age (x-axis, 20-45 years) and incidence of Down syndrome (y-axis), demonstrating the exponential increase after age 35. Panel C: Diagram explaining mosaicism arising from mitotic nondisjunction in early embryonic development, showing how one normal and one aneuploid cell line coexist.
### II. Common Autosomal Aneuploidies
**Trisomy 21 (Down syndrome)** is the most common viable autosomal trisomy, with an incidence of approximately 1 in 700 live births. The karyotype is 47,XX,+21 or 47,XY,+21. Clinical features include intellectual disability, characteristic facial features (flat nasal bridge, epicanthal folds, protruding tongue), hypotonia, congenital heart defects in 40-50% of cases, increased risk of leukemia, and early-onset Alzheimer disease. Approximately 95% of cases result from maternal meiotic nondisjunction, about 4% from a Robertsonian translocation, and roughly 1% are mosaic.
**Trisomy 18 (Edwards syndrome)** occurs in approximately 1 in 5,000 live births and presents with severe intellectual disability, clenched fists with overlapping fingers, rocker-bottom feet, congenital heart defects, and kidney malformations. The median survival is approximately 5-15 days, with only about 10% surviving to one year. **Trisomy 13 (Patau syndrome)** occurs in approximately 1 in 16,000 live births and features holoprosencephaly, cleft lip and palate, polydactyly, microcephaly, congenital heart defects, and eye defects, with a median survival of approximately 7-10 days. Most other autosomal trisomies are lethal in utero; trisomy 16 is the most common trisomy found in spontaneous abortions.
### III. Sex Chromosome Aneuploidies
Sex chromosome aneuploidies are generally better tolerated than autosomal aneuploidies, thanks to X-inactivation and the limited gene content of the Y chromosome. **Turner syndrome (45,X)** is the only viable monosomy in humans, occurring in approximately 1 in 2,500 female births. Features include short stature, webbed neck, shield-shaped chest, lymphedema at birth, gonadal dysgenesis (streak ovaries), infertility, coarctation of the aorta, and normal intelligence. About 50% have a pure 45,X karyotype, while others are mosaic (45,X/46,XX) or carry structural X abnormalities.
**Klinefelter syndrome (47,XXY)** occurs in approximately 1 in 650 male births and presents with tall stature, small testes, infertility due to azoospermia, gynecomastia, mild learning difficulties, and reduced body hair. Additional X chromosomes (48,XXXY or 49,XXXXY) produce progressively more severe phenotypes. **Triple X syndrome (47,XXX)** generally produces a mild phenotype with tall stature, normal fertility, and possible learning difficulties. **47,XYY syndrome** features tall stature, normal fertility, usually normal intelligence, and a mildly increased risk of learning difficulties.
### IV. Polyploidy
**Polyploidy** is the presence of more than two complete sets of chromosomes. **Triploidy** (3n = 69) involves three complete haploid sets and can result from dispermy (fertilization by two sperm), failure of a meiotic division in the egg or sperm, or fertilization by a diploid gamete. Triploidy is always lethal in humans, resulting in spontaneous abortion, and produces partial hydatidiform moles if the extra set is paternal. **Tetraploidy** (4n = 92), usually caused by failure of an early mitotic division, is also lethal. While polyploidy is common and well tolerated in plants, it is invariably fatal in mammals.
### V. Structural Chromosomal Abnormalities
Structural chromosomal abnormalities arise from chromosome breakage followed by abnormal repair or rejoining. **Deletions** involve the loss of a chromosomal segment and may be terminal (one break causing loss of an end segment) or interstitial (two breaks causing loss of an internal segment). Clinical examples include cri-du-chat syndrome (deletion of 5p15, producing a cat-like cry, microcephaly, and intellectual disability), Williams syndrome (deletion of 7q11.23 affecting the elastin gene, causing supravalvular aortic stenosis, a characteristically friendly personality, and intellectual disability), and 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome, with cardiac defects, palatal abnormalities, thymic hypoplasia, and hypocalcemia).
**Duplications** involve the gain of an extra copy of a chromosomal segment, which may be in tandem (same orientation) or inverted. Duplications are generally less harmful than deletions of equivalent size. Charcot-Marie-Tooth type 1A, for example, results from duplication of 17p12 containing the PMP22 gene. **Inversions** involve reversal of a chromosomal segment and may be paracentric (not including the centromere) or pericentric (including the centromere). Inversion carriers are usually phenotypically normal, but problems arise during meiosis when the inverted segment forms an inversion loop. Crossing over within this loop can produce recombinant chromosomes with deletions or duplications, leading to unbalanced gametes.
**Translocations** involve the transfer of chromosomal material between non-homologous chromosomes. In a **reciprocal translocation**, segments are exchanged mutually between two non-homologous chromosomes. Carriers are usually phenotypically normal because the translocation is balanced, but during meiosis the involved chromosomes form a quadrivalent structure that can undergo alternate, adjacent-1, or adjacent-2 segregation, creating a risk of unbalanced offspring with partial trisomy or monosomy. A **Robertsonian translocation** involves the fusion of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, or 22) at their centromeres. Carriers have 45 chromosomes but are usually phenotypically normal. The most common Robertsonian translocations are rob(13;14) and rob(14;21). Carriers of rob(14;21) have an increased risk of producing offspring with Down syndrome.
Panel A: Diagrams of the four types of structural chromosomal abnormalities — deletion (terminal and interstitial), duplication (tandem and inverted), inversion (paracentric and pericentric), and translocation (reciprocal and Robertsonian) — each shown with before and after chromosome diagrams with breakpoints indicated. Panel B: Meiotic segregation diagram for a Robertsonian translocation carrier rob(14;21), showing the six possible gamete types and their resulting offspring (normal, balanced carrier, Down syndrome, monosomy 21, trisomy 14, monosomy 14), with viable outcomes highlighted. Panel C: Karyogram of an individual with trisomy 21 (Down syndrome) showing three copies of chromosome 21.
### VI. X-Inactivation and Dosage Compensation
The **Lyon hypothesis**, proposed by Mary Lyon in 1961, states that in female mammals, one X chromosome in each cell is randomly inactivated early in development. The purpose of this process is dosage compensation, which equalizes X-linked gene expression between XX females and XY males. Inactivation occurs during early embryonic development, around day 16 in humans at the roughly 1,000-cell stage. The choice of which X to inactivate is random with respect to maternal versus paternal origin, but once inactivated, the same X remains inactive in all daughter cells through clonal inheritance. The inactivated X forms a dense structure of condensed heterochromatin called the **Barr body**, visible at the nuclear periphery.
The molecular mechanism centers on the **XIST gene** (X-Inactive Specific Transcript), located at the X-inactivation center (Xic). XIST encodes a long non-coding RNA that coats the X chromosome from which it is transcribed. This RNA recruits Polycomb repressive complexes, leading to histone H3K27 trimethylation and subsequent DNA methylation, ultimately silencing the chromosome.
Importantly, approximately 15-25% of X-linked genes escape inactivation, particularly those in the pseudoautosomal regions. These genes typically have Y-chromosome homologs, which explains why Turner syndrome (45,X) still produces a phenotype despite X-inactivation: the genes that normally escape inactivation are present in only one copy instead of two. The number of Barr bodies in a cell equals the number of X chromosomes minus one: 46,XX individuals have 1 Barr body, 47,XXX individuals have 2, and 47,XXY individuals have 1.
Panel A: Diagram of X-inactivation in a female embryo showing random inactivation of the maternal or paternal X chromosome at the ~1000-cell stage, leading to a mosaic of two cell populations, illustrated as a calico cat pattern where different colored patches represent clonal populations expressing different X-linked alleles. Panel B: Molecular mechanism of X-inactivation showing XIST RNA coating the chromosome, recruitment of PRC2, histone methylation (H3K27me3), and DNA methylation leading to heterochromatin formation and gene silencing. Panel C: Table showing the number of Barr bodies for various sex chromosome constitutions (XX, XY, XXX, XXY, XO, XXXY) with corresponding syndromes.
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