Human Genetics Biology 311 Fall 2004Lecture 3: Chromosome DefectsReading: Chap. 2 pp. 47-53Outline:1. Variation in number2. Structural abnormalities3. Meiosis of carriersLecture: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 meiosisChromosome abnormalities can affect- Germ cell (constitutional)- Somatic cell1. Variation in chromosome numberpolyploidy: extra sets of chromosomes- 1-3% of human pregnancies- very few survive to birth- lethal; usually caused by 2 sperm fertilizing one egganeuploidy: one extra or one missing chromosometrisomy: three copies of one chromosomei.e. Down syndrome47, XX + 21 or 47, XY + 21have extra chromosome 21monosomy: lack of a chromosomei.e. Turner syndrome45, Xmonosomy for the X chromosomemixoploidy: different numbers of chromosomes in different cells mosaicism: An individual with a somatic chromosome defect will have a chimerawith different chromosome make-up in different cells.1chimera: (more rare) Genetically different cell lineages in one individual originating from different zygotes.Examples/nomenclature of chromosome abnormalities: Box 2.4Numerical AbnormalitiesTriploidy 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 longer2. Structural chromosome abnormalitiesChromosome breaks caused by- Radiation damage- Chemical damage- RecombinationBreaks usually repaired by cellular enzymesStructural 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 effecton phenotype- Unbalanced: net gain or loss of chromosomal material; often get effect on phenotypeExamples of structural abnormalitiesChromosome defect Karyotype nomenclatureDeletion* 46, XY del (4) (p16.3) terminal deletionInversion 46, XY inv (11) (p11p15)Duplication 46, XX dup (1) (q22q25) insertion into Chr.2 a segment of Chr. 22Insertion 46, XX ins (2) (p13q21q31)Ring 46, XYr (7) (p22q36)Marker extra unidentified chromosome 47, XX + marTranslocation, reciprocal 46, XX t (2;6) (q35;p21.3) balancedTranslocation, Robertsonian (non-reciprocal)45, XX der (14;21) (q10;q10)translocation Down syndrome*Nomenclature example:# chromosomesSex chromosomesAbnormality Chromosome affectedRegion affected46 XY del (4) (p16.3)3. Meiosis of carriersCarriers 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. 2.22Zygotes 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 viableExample 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