Human Genetics Biology 311

Human Genetics Biology 311 Fall 2006

Lecture 3: Chromosome Defects

Reading: Chap. 2 pp. 47-53

Outline:

1. Variation in number

2. Structural abnormalities

3. Meiosis of carriers

Lecture:

Chromosome abnormalities=changes that usually visibly alter the chromosomes.

·  caused by misrepair of broken chromosomes, improper recombination, or improper segregation of chromosomes during mitosis or meiosis

Chromosome abnormalities can affect

·  Germ cell (constitutional)

·  Somatic cell

1. Variation in chromosome number

polyploidy: extra sets of chromosomes

·  1-3% of human pregnancies

·  very few survive to birth

·  lethal; usually caused by 2 sperm fertilizing one egg

aneuploidy: one extra or one missing chromosome

trisomy: three copies of one chromosome

i.e. Down syndrome

47, XX + 21 or 47, XY + 21

have extra chromosome 21

monosomy: lack of a chromosome

i.e. Turner syndrome

45, X

monosomy for the X chromosome

mixoploidy: different numbers of chromosomes in different cells

mosaicism: An individual with a somatic chromosome defect will have a chimera with different chromosome make-up in different cells.

chimera: (more rare) Genetically different cell lineages in one individual originating from different zygotes.

Examples/nomenclature of chromosome abnormalities: Box 2.4

Numerical Abnormalities

Triploidy 69, XXX; 69 XXY; 69 XYY (all lethal)

Trisomy 47, XX +21 (Down syndrome)

Monosomy 45, X (Turner syndrome)

Mosaicism 47, XXX/46, XX

Clinical consequences of numerical abnormalities:

·  Serious, usually lethal

·  Usually pleiotrophic effects=Multiple abnormalities in phenotype

·  Imbalance in levels of gene products produced

·  Wrong number of sex chromosomes has fewer deleterious effects than wrong number of autosomes

·  Autosomal monosomy invariably lethal in early embryo

·  Trisomies less harmful than autosomal monosomies

·  Trisomies 13, 18 and 21 can survive until birth

·  Trisomy 21 may survive to age 40 or longer

2. Structural chromosome abnormalities

Chromosome breaks caused by

·  Radiation damage

·  Chemical damage

·  Recombination

Breaks usually repaired by cellular enzymes

Structural abnormalities

·  Breaks repaired incorrectly

·  Give rise to other abnormalities when cells divide in mitosis or meiosis

·  Balanced, no net gain or loss of chromosomal material; generally no effect on phenotype

·  Unbalanced: net gain or loss of chromosomal material; often get effect on phenotype

Examples of structural abnormalities

Chromosome defect / Karyotype nomenclature
Deletion* / 46, XY del (4) (p16.3) terminal deletion
Inversion / 46, XY inv (11) (p11p15)
Duplication / 46, XX dup (1) (q22q25) insertion into Chr. 2 a segment of Chr. 2
Insertion / 46, XX ins (2) (p13q21q31)
Ring / 46, XYr (7) (p22q36)
Marker extra unidentified chromosome / 47, XX + mar
Translocation, reciprocal / 46, XX t (2;6) (q35;p21.3) balanced
Translocation, Robertsonian (non-reciprocal) / 45, XX der (14;21) (q10;q10)
translocation Down syndrome

*Nomenclature example:

# chromosomes / Sex chromosomes / Abnormality / Chromosome affected / Region affected
46 / XY / del / (4) / (p16.3)

3. Meiosis of carriers

Carriers of structural abnormalities have a high risk of passing on these or other abnormalities to the gametes due to abnormal segregation of the chromosomes in meiosis or due to the nature of the products of crossing over events.

Example 1: Meiosis in a carrier of a balanced reciprocal translocation, Fig. 2.22

Zygotes produced from fertilization of the four types of gametes produced from the carrier include

·  Normal

·  Balanced carrier

·  Partial trisomy and partial monosomy (usually lethal)

·  Partial monosomy and partial trisomy (usually lethal)

·  Thus at least half the zygotes produced would not be viable

Example 2: Crossover events occurring in meiosis in heterozygotes for paracentric inversions can result in production of dicentric and acentric chromosomes which segregate in an unstable manner.

Example 3: Heterozygotes for pericentric inversions can have recombination events that lead to formation of duplications and deletions.

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