1. Chapter 11 Chromosomes

2. Cytogenetics Sub-discipline within genetics that links chromosome variations to specific traits, including illnesses.

3. Portrait of a Chromosome A chromosome consists of: – DNA – Associated RNA – Histone proteins – DNA replication enzymes – Transcription factors During metaphase key physical features can be seen.

5. Heterochromatin versus Euchromatin Heterochromatin will form regions of the centromere and telomeres Euchromatin will form the protein encoding regions on the chromosome

6. Five human chromosomes: 13,14,15,21, & 22 Contain satellites that extend from a thinner, stalklike bridge from the rest of the chromosome. The stalk – codes ribosomal proteins

7. Visualizing Chromosomes Any cell other than mature red blood cells can be used to examine chromosomes. White Blood Cells – Generally used for family history or infertility tests Cancer Cells – may indicate which drugs are most likely to be effective. Blood-borne cancers – leukemias and lymphomas – Bone Marrow Cells Fetal Cells – reveal medical problems

8. Amniocentesis Sampling fetal cells shed into the amniotic fluid. Procedure – 10 days of culturing – 20 cells are karyotyped – Can detect 400 of more than 5,000 chromosomal abnormalities. – Done around the 15 th or 16 th week of gestation

9. Who gets them done? If the risk that the fetus has a detectable condition EXCEEDS the risk that the procedure will cause a miscarriage (1 in 350) Woman over 35 Several prior miscarriages Blood test reveals low levels of fetal liver protein called alpha fetoprotein and high levels of hCG (human chorionic gonadotropin)

10. Chorionic Villus Sampling Obtain cells from the chorionic villi, which develop into the placenta (fetal derived cells) Karyotype is performed Chromosomal Mosaicism – Cells of the villus differ from the embryo cells. – False negative or false positive results.

11. 1 in 1000 to 3000 procedures cause fatal limb defect. Couples need to choose: – Earlier results – Greater risk of spontaneous abortion Additional.8% compared to an addition.3%

12. Fetal Cell Sorting A new technique that separates fetal cells from the woman’s bloodstream. Fetal blood enters maternal circulation in up to 70 percent of pregnancies. Device: Fluorescence-activated cell sorter. – Looks for identifying cell surface markers. – Then the fetal cells can be karyotyped.

14. Preparing Cells for Chromosome Observation 1923 – chromosome sketches published = 48 chromosomes Obtained cells from three castrated prisoners in Texas. Since 1950, colchicine (chrysanthemum plant extract) is used to arrest cells during division.

15. Science happens on accident, sometimes… Problem: How to untangle spaghetti like mass of chromosomes. Mistakenly washed human cells with a hypotonic solution. Water rushed into the cells, which separated them.

16. Karyotyping Old School/North Penn Method Taking a picture Cutting out the pieces and aligning them based on size and shape. Placing them in order from largest to smallest. New School / Research Device scans a ruptured cell in a stain and selects one in which the chromosomes are the most visible and wide spread. Image software recognizes band patterns. If a strange band pattern is recognized, a database pulls out identical karyotypes from other patients.

17. Staining Earlier Stains – stained chromosomes all one color. 1959 – first chromosomal abnormalities – Down Syndrome – Turner Syndrome (Thought to once be genetic males) – lack of barr body – Klinefelter Syndrome (Though to once be genetic females) - barr body present

18. Staining 1970’s – stains that created banding patterns unique to each chromosome. – AT rich areas – GC rich areas – Heterochromatin

19. FISHing Fluorescence in situ hybridization Uses DNA probes that are complementary to DNA sequences found only on one chromosome. “Paint” chromosomes – 13, 18, & 21. FISH Process

20. Chromosomal Shorthand Total Number of Chromosomes followed by the sex chromosome constitution, then any abnormal chromosomes. Ex: – 46, XY – 46, XX – 47, XXY – 47, XX, +21 – 46XY t (7;9)

21. Ideogram Indicates p and q arms Delineated by banding patterns Loci of known genes

22. Abnormal Chromosome Number Polyploidy – Extra “sets” of chromosomes Aneuploidy – An extra or missing chromosome Deletion Duplication Inversion Translocation

23. Polyploid 2/3rds of cases from two sperm uniting with one egg. Other Cases: – Diploid gamete + haploid gamete 15% of spontaneous abortions caused by Triploids.

24. Aneuploidy “not good set” Normal Chromosome number = euploid – “good set” Most autosomal aneuploids cause spont. abortion. Those surviving generally suffer mental deficiencies. Most survivors are trisomy, not monosomy CAUSE: Nondisjunction – failure of chromosomes to separate during meiosis.

25. 49 types of aneuploids – Missing or extra copy of each autosome = 44 – Five abnormal sex chromosome combos Y, X, XXX, XXY, XYY – Only 9 types are known to appear in new borns. 50% of spontaneous abortions result from missing or having extra chromosomes – 45X, triploids, trisomy 16 – Trisomy 13, 18, 21 = common spont. Abortions, but also the most common aneuploids seen in new borns.

26. Polyploids and Aneuploids Mitotic Division Late onset – may not have an affect on the overall health Early onset – All future daughter cells will be affected, thus causing more of a chance of health risks. Meiotic Division Will affect every cell in the developing embryo.

28. Down Syndrome Most common live birth aneuploid Sir John Langdon Haydon Down Was it an abnormal chromosome number or not? Other Risks: – Leukemia – Alzheimer’s disease

29. Down Syndrome Causes – Nondisjunction 90% female 10% male – Translocation – Mosaic Mutation occurs after fertilization

30. Why is it affecting older woman How is meiosis different in woman compared to men? – Arrested development – Hypothesis: Mechanism that can identify aneuploid oocytes. Yellow starburst analogy

31. Trisomy 18 – Edward Syndrome Most do not survive birth Distinct Phenotypes – Overlapping fingers – Unusual or absent fingerprints Cause: – Nondisjunction in meiosis II of oocyte

32. Trisomy 13 – Patau Syndrome Rare Most striking characteristic: Fusion of developing eyes Cleft palate Highest development age is 6 months! (Yet on a very rare occasion someone has survived to adulthood)

33. Extra X syndromes 1 in 1,000 females are triplo-X. (47, XXX) Lack of symptoms – X-inactivation Klinefelter’s (47,XXY) – Underdeveloped sexual characteristics – Long limbs – testosterone injections at adolescents can control

34. XYY Syndrome 1965 – Patricia Jacobs published these results – 197 high security prisoners – 12 had abnormal chromosomes 7 had an extra Y Today – 96% of XYY are normal – Acne – Greater height – Speech and Reading problems

35. Abnormal Chromosome Structure Deletions Cri-du-chat syndrome “cat’s cry” – Missing the short arm (p) of chromosome 5 – High-pitched cry Y – chromosome infertility Duplications – Similar to deletions – the more likely to cause symptoms if they are extensive. – 15s chromosome

36. Translocation Robertsonian Trans- location – the short arms (p) of two different acrocentric chromo- somes break, leaving sticky ends that cause two long arms to adhere.

37. Translocation Reciprocal Translocation – two different chromosomes exchange parts. How can FISH be used to identify translocation? Examples: Alagille Syndrome

39. Inversion Pericentric – Includes the centromere in the inversion Paracentric – Does NOT include the centromere

40. Dicentric Inversion When a loop forms during crossing over, one chromatid will get two centromeres – a bridge forms. Acentric fragment – Due to lack of centromere, this piece is lost when the cell divides.

41. Isochromosome A chromosome that has lost one of its arms and has replaced it with an exact copy of the other arm. Can occur if the replicated chromosomes line up at the equator in the wrong plane.

42. Ring Chromosomes CAT EYE SYNDROME – Ring chromosome #22

43. Uniparental Disomy What would happen if nondisjunction occurred at the same chromsome within the egg AND the sperm… …Then the sperm that was missing the chromosome united with an egg that had double the chromosomes “Two bodies from one parent”

45. Inversions