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Chromosomes Genetics 2005 Chromosomal Anomalies Cytogenetics The subdivision of genetics that focuses on chromosomes and cell division Abnormal cell divisions can lead to abnormal chromosomal numbers or other anomalies Chromosome anomalies may cause phenotype abnormalities. Wendy Weisz has Down syndrome. A chromosome karyotype revealed she carries three copies of chromosome 21, a condition called trisomy 21. Karyotype A chart arranging chromosome pictures according to their size, Chromosomes were grouped by named in order of their pairs of size and centromere position. homologs. Anatomy of a chromosome Centromeres are the largest constriction of the chromosome •Site of attachment of spindle fibers •100,000s of 171 base pair repeat, called alpha satellite sequences •Centromere associated proteins are bound Anatomy of a chromosome Telomeres are: •At the tips of chromosomes •Many repeats of the sequence TTAGGG •Subtelomeres have more varied short re Subtelomeres The chromosome region next to the telomere consists of 8,000 - 300,000 bases including: Repeats similar to the telomere sequence Shorter repeats Multigene families of genes (e.g. olfactory receptor genes) Anatomy of a chromosome Chromosomes are categorized by the relative location of their centromere. •At tip - telocentric •Close to tip - acrocentric •At midpoint - metacentric •Displaced from center submetacentric Largest, Metacentric Smallest acrocentric Sex chromosomes XX (shown) Metaphase chromosomes are squashed on a slide and stained with DNA binding dyes. Banding patterns help define different chromosomes. Chromosome Spreads Ideograms Chromosome Map P arm Chromosome #1 Centrome re Q arm An Chromosomal shorthand ideogram represents a chromosome schematically. The major banding regions are indicated with numbers. Sucrose intolerance is located at 3q.26 Chromosomes carry different genes Chromosomes differ in size Chromos ome Size in million bases % of genome 5 194 6 16 98 3 19 60 2 21 33.55 1 22 33.46 1 in situ hybridization DNA probes labelled with fluorescing dye bind complementary DNA telomeres centromeres Metaphase Chromosomes Karyotyping Visualizing chromosomes Obtain tissue from person Fetal tissue: amniocentesis chorionic villi sampling fetal cell sorting Adult tissue: blood (white blood cells) cheek swab (buccal cells) skin cells tissue biopsy Prepare cells on slide to remove rest of cell matter Stain DNA with dyes or DNA probes karyotype: 23 diploid chromosome Human somatic cells contain 46 s chromosomes: paired homologs of chromosomes 1 to 22 and sex chromosomes (XX or XY) • Diploid refers to the presence of two copies of each different chromosome. Gametes have one set of each chromosome and are called haploid. Chromosome Abnormalities Polyploidy Extra chromosome set Aneuploidy monosomy trisomy Extra or missing chromosome one chromosome absent one chromosome extra Deletion Part of a chromosome Duplication missing Inversion Part of a chromosome Translocation present twice Segment of chromosome Iso reversed chromosome Two chromosome arms Ring exchanged chromosome in part or entirely A chromosome with identical arms Chromosomal Abbreviatioshorthand What it means n 46, XY Normal male 46, XX Normal female 45, X Turner syndrome female 47, XXY Klinefelter syndrome male 47, XYY Jacobs syndrome male 46, XY del (7q) 47, XX+21 Male missing part of long arm of chromosome 7 Female with trisomy 21 46, XY t Male with translocation (7;9) between short arm of (p21.1;q34.1) chromosome 7 band 21.1 Polyploidy Individuals with three copies of each chromosome are triploid. Polyploidy accounts for 17% of all spontaneous abortions and 3% of stillbirths/newborn deaths. Result of: Two sperm fertilize one egg. Aneuploidy Cells with extra or missing chromosomes are aneuploid. •Nondisjunction is a common cause of aneuploidy resulting in a gamete with one extra chromosome and another gamete with one missing chromosome. •Nondisjunction during the first meiotic division results in a copy of each homolog in the gamete. •Nondisjunction during the second meiotic division results in a both sister chromatids in one gamete. Nondisjunction causes aneuploidy Nondisjunction in meiosis I Anaphase I Anaphase II Nondisjunc in meiosis I Gametes Abnormal gametes Abnormal gametes Normal gametes Nondisjunction in meiosis I Anaphase I Homologs of small chromosome fail to separate Anaphase II Sister chromatids separate normally Gametes trisomic monosomic Abnormal gametes Nondisjunction in meiosis II Anaphase I Homologs segregate normally Anaphase II Sister chromatids fail to separate Gametes (left) trisomic monosomic Abnormal gametesNormal gametes Sex Chromosome Aneuploidy Situation Oocy Spe Consequence te Normal Female Nondisjun ction rm X Y 46, XY normal male X X 46, XX normal female XX Y 47, XXY Klinefelter syndrome XX X 47, XXX triplo-X Y 45, Y nonviable X 45, X Turner syndrome Male Nondisjun ction (meiosis I) X 45, X Turner syndrome X XX 47, XXX triplo-X Male X YY 47, XYY Jacobs Turner syndrome 45, X 1 in 2,000 female births 99% of Turner die in utero Absence of Y leads to development as a female. Absence of two copies of Xlinked genes in Relative risk of disease among Turner syndrome adults Triplo-X aneuploidy 47, XXX 1 in 1,000 female births Extra copy of every X-linked gene Few modest effects on phenotype include tallness, menstrual irregularities and slight impact on intelligence X-inactivation of two X chromosomes occurs while Klinefelter syndrome 47, XXY 1 in 1,000 male births Extra copy of each X-linked gene Phenotypes include incomplete sexual development (rudimentary testes and prostate), long limbs, large hands and feet, some breast tissue development. Some cases are not diagnosed until fertility problems arise or remain undiagnosed. XYY syndrome 47, XYY 1 in 1,000 male births Extra Y chromosome 96% phenotypically normal Modest phenotypes may include great height, acne and minor speech and reading problems. Studies suggesting some increase in aggressive behaviors remain controversial. Trisomies Trisomies and Monosomies One extra or one missing chromosome results in extra or missing copies of all of the genes on that chromosome. Most trisomies and monosomies produce inviable embryos. Some fetuses with trisomy of smaller autosomes trisomy survive to birth % with syndromic (syndro conditions: conceptions me) Incidence at birth 13 (Patau) 1/12,500 to 1/21,700 18 1/6,000 to (Edward that survive >1 year <5% < 5% Down Syndrome – Trisomy, 21 EDWARDS SYNDROME Three Forms Full form (severe) - in this every cell in the body has three no.18 chromosomes instead of two. Mosaic form (less severe) - in this some cells have two no.18 chromosomes while others have three. The extent and severity of the condition will depend upon the ratio of normal to abnormal cells. Partial form - in some cases there may be an extra copy of part of chromosome 18. This is referred to as partial trisomy 18. The effects of this may be milder and would require further medical advice. Unusually large uterus during pregnancy Low birth weight infant Mental deficiency Low-set ears Small jaw Clenched hands Hypoplastic fingernails Umbilical hernia or inguinal hernia Diastasis recti Cryptorchidism Crossed legs (preferred position) Congenital heart disease VSD (ventricular septal defect) ASD (atrial septal defect) PDA (patent ductus arteriosus) Congenital kidney abnormalities Horseshoe kidney Hydronephrosis Polycystic kidney Coloboma of iris Microcephaly Motormental retardation Pectus carinatum Ventricular Septal Defect - A hole between the lower chambers of the heart which prevents the heart from pumping blood correctly; a heart murmur is generally heard with this congenital defect. Atrial Septal Defect - A hole between the two upper chambers of the heart which makes it difficult for the heart to pump sufficient oxygen-rich blood to the bodys tissues; a heart murmur can be heard. Patent Ductus Arteriosus - A congenital heart defect in which closure of a duct fails to occur, resulting in abnormal direction of blood flow. Diagnosis in utero Examination of the pregnant woman may show polyhydramnios. At the birth of the child, an unusually small placenta may be noted. Physical examination may show an excess of arched type finger print patterns. X-rays may reveal a short breast bone. Chromosome studies show trisomy 18, partial trisomy, or translocation. Patau’s Syndrome Living with Chromosome 13 Josiah is diagnosed as a Trisomy 13 with holoprosencephaly and a Dandy-Walker cyst. His left eye has a coloboma and he is now fitted with (the cutest little) glasses. He has hearing aids, a "flattened" windpipe, and one vocal cord is paralyzed. His cleft palate has not been repaired yet, but his lip has. A V.S.D. is in past, and has dextrocardia. He still uses a G-tube, and is just the stoutest little thing ever. Last but not least, he has the cutest sixth toe Risk of Patau’s Syndrome Trisomy 13 occurs in approximately 1 in 12,000 live births. In many cases, spontaneous abortion (miscarriage) occurs and the fetus does not survive. The risks of trisomy 13 seem to increase with the mother's age, particularly if she is older than her early 30s. Male and female children are equally affected, and the syndrome occurs in all races. Patau syndrome is caused by the presence of three copies of chromosome 13. The presence of these three copies---rather then the normal two--is a random error Segregation of a Robertsonian translocation Reciprocal Exchange of material from one translocation chromosome arm to another is called a reciprocal translocation. Rearrangement of the genetic material results in an individual who carries a translocation but is not missing any genetic material unless a translocation breakpoint interrupts a gene. Isochromosomes Chromosomes with identical arms form when centromeres divide along the incorrect plane during meiosis. Uniparent al disomy Inheritance of two chromosomes from one parent is called uniparental disomy. May occur when nondisjunction occurs in both parents (one disomic gamete and one without homolog) Loss or nondisjunction of one homolog in Chromosome structural abnormalities Chromosomal deletions or duplications result in extra or missing copies of genes in the involved segment. Causes of chromosomal abnormalities Polyploidy Error in cell division in which all chromatids fail to separate at anaphase. Multiple fertilizations. Aneuploidy Nondisjunction leading to extra or lost chromosomes Deletions Translocations. and Crossover between a pericentric duplications inversion and normal homologue Translocatio Recombination between n nonhomologous chromosomes Inversion Breakage and reunion with wrong orientation Dicentric or Crossover between paracentric acentric inversion and normal homologue. fragments Isochromoso Division of centromeres on wrong me plane Cri du Chat Cri Du Chat Syndrome results from the loss or deletion of a significant portion of the genetic material from the short arm of one of the pair of number five chromosomes. Cri Du Chat Syndrome is also known as 5P Minus syndrome, Le Jeune's It Cri du Chat Incidence is a relatively rare genetic condition with an estimated incidence of between around 1:25,000 to 1:50,000 births. There are more children being diagnosed now that genetic testing is carried out more frequently and is more accurate. In addition, since records of this nature are not kept in Features of the Disease The gene causing the cry has been located in band 15.3. This would explain why some babies with other features of the syndrome do not have the characteristic cry and some babies have the cry but not the other characteristics. In most cases the deletion is spontaneous and no specific cause can be identified. The parents did nothing wrong to Ring chromosomes Chromosomes shaped like a ring occur in 1 of 25,000 conceptions. May arise when telomeres are lost and sticky chromosome end fuse. Ring chromosomes have phenotypes associated with the loss or addition of genetic material. Ring chromosomes By two DNA breaks, one in each arm of the same chromosome, followed by fusion of the proximal broken ends. The causes of these DNA breaks are usually unknown and so is the mechanism behind ligation of the ends. It is possible that the non-homologous end-joining machinery plays a role in this process (Smith et al. 2001). A ring can also be formed by fusion at two breakpoints in the same chromosome arm. However, only few examples of such rings have been described. Most probably, this is because they are acentric and will lack attachment point for the cell division machinery. Unless there is a Ring Chromosome Formation of the Ring Translocation Different nonhomologous chromosome exchange portions of chromosomes. Two major types: Robertsonian translocation Two nonhomologous acrocentric chromosomes break at the centromere and long arms fuse. The short arms are often lost. 5% of Down syndrome results from a Robertsonian translocation between chr 21 and chr 14 . Reciprocal translocation Segregation of a pericentric inversion Segregation of a paracentric inversion Chromosome structure abnormalities Larger regions of deletion or duplication increase the likelihood that there will be an associated phenotype. Inversions Inverted chromosomes have a region flipped in orientation compared to wildtype chromosomes. 5-10% cause health problems probably due to disruption of genes at the breakpoints. Crossing over within the inverted segments leads to genetically imbalanced gametes. Two types of inversions occur: Paracentric inverted region does NOT include centomere