1. Chapter 2 Genetics Genetics is the study of genes. Genes are composed of sequences of DNA. Genes are packaged together as chromosomes and are passed from parent to offspring. It is our genes that determine who we are and how we function. Sometimes mistakes (mutations) cause significant disability or death.

2. Chromosomes Chromosomes are made up of molecules of DNA, complexed with proteins called histones. Chromosomes carry the genetic blueprint of an individual. All human somatic (body) cells contain 23 pairs of chromosomes, one pair from each parent, for a total of 46 chromosomes. Each human sex cell, an egg or a sperm, contains 23 unpaired chromosomes.

3. Cellular Reproduction -All cells reproduce during embryonic development, which allows for making up tissues and organs. -After birth and throughout adulthood, many cells continue to reproduce. - Cells that reproduce throughout a lifetime include cells of the bone marrow, skin, and digestive tract. -Liver and kidney cells reproduce when replacement of lost or destroyed cells is required. -Other cells, including nerve, skeletal muscle, and cardiac muscle cells, do not reproduce significantly after the first few months following birth. Damage to these tissues generally cannot be repaired by growth of new cells.

4. The Cell Cycle The cell cycle refers to a sequence of stages a cell goes through during its lifetime. The cell cycle is divided into two parts: interphase and mitosis. Interphase When not actively dividing, a cell is said to be in interphase. Mitosis Mitosis is the stage of cell division. Mitosis is a shorter than interphase;it lasts about 1 hour.

5. Meiosis Meiosis is the process during which germ cells of the ovary (primary oocytes) or testicle (primary spermatocytes) give rise to mature eggs or sperm. Meiosis involves two cell divisions rather than one, which results in four daughter cells, each with 23 (unpaired) chromosomes.

6. -In males, all four daughter cells differentiate into mature sperm. -In females, only one viable daughter cell (egg) is formed; the other three cells become nonfunctional polar bodies. - During fertilization, genetic information contained in the 23 chromosomes of the egg joins with genetic information contained in the 23 chromosomes of the sperm. This results in an embryo with 46 total chromosomes.

7. An interesting phenomenon occurs during DNA replication in the first meiotic stage. At this time, pieces of DNA may shift between the matched chromosome pairs, in a process called crossing-over. Crossing-over increases the genetic variability of offspring, and is one reason why siblings within a family may vary considerably in genotype and phenotype.

8. Genotype and Phenotype - Genotype is the precise genetic information carried in the chromosomes of the offspring. – phenotype is the physical representation of genetic information (tall or short, dark or light).

9. Genetic Testing (cytogenetics) Genetic testing, called cytogenetics, involves looking at the overall structure and number of the chromosomes. - testing in children and adults is usually done by withdrawing white blood cells in a venous blood sample. - For prenatal testing, fetal cells may be gathered by amniocentesis, or by chorionic villi sampling.

10. Amniocentesis Amniocentesis is performed by inserting a needle through the abdominal wall of a pregnant woman into the amniotic sac that surrounds the fetus. Amniotic fluid, into which fetal cells have been shed, is withdrawn and the cells are cultured. This test is usually done at approximately 16 weeks' gestation and results are available in approximately 2 weeks.

11. Chorionic Villi Sampling It involves gathering cells of the chorion (the outer border of the fetal membranes). The cells are gathered by placing a needle through the woman's lower abdomen or cervix between 8 and 12 weeks of pregnancy. The cells do not need to be cultured, so the chromosomal analysis is available in approximately 1 to 2 days..

12. Pathophysiologic Concepts 1-Mutation Is an error in the DNA sequence. Mutations can occur spontaneously, or after the exposure of a cell to radiation, certain chemicals, or various viral agents. Most mutations will be identified and repaired by enzymes working in the cell. If a mutation is not identified or repaired, or if the cell does not undergo programmed death, that mutation will pass in all subsequent cell divisions. Mutations may result in a cell becoming cancerous. Mutations in the gametes (the egg or sperm) may lead to congenital defects in an offspring.

13. 2-Errors in Chromosome Number Any change from the normal human chromosome number of 46 chromosomes is called aneuploidy. - An aneuploidy in which there are only 45 chromosomes is called a monosomy. - An aneuploidy in which there are 47 chromosomes is called a trisomy. - Having more than 47 chromosomes is possible but rare.

14. A-Monosomy -If any chromosome other than the X or Y is lost, the embryo will spontaneously abort. – The loss of one of the sex chromosomes (usually the Y chromosome ), resulting in 44 somatic chromosomes and one sex chromosome (often expressed 45, X/O, to indicate no Y chromosome). The resulting disorder is called Turner's syndrome. Monosomy of any chromosome is a major cause of spontaneous abortion in the first trimester.

15. B-Trisomy A trisomy occurs when somatic or sex chromosomes do not separate properly during meiosis. This is called non- disjunction. Most trisomies cause spontaneous abortion, but rarely live births may result. Trisomies that may result in live births include trisomies of the sex chromosomes and trisomies of chromosomes 8, 13, 18, and 21. Trisomy 21 is called Down syndrome.

16. 3- Congenital Defects Also called birth defects, include genotypic and phenotypic errors occurring during embryogenesis and fetal development. Some congenital defects, such as cleft palate and limb abnormalities, may be apparent at birth, whereas other congenital defects, such as an abnormal or absent kidney and certain types of heart disease, may not be recognized immediately. Congenital defects may result from: 1- genetic mistakes made during meiosis of the sperm or egg, 2-or from environmental insults experienced by the fetus during gestation.

17. Teratogenesis Teratogenesis is an error in fetal development that results in a structural or functional deficit (e.g., a deficit in brain function). Environmental stimuli that cause congenital defects are called teratogenic agents. Common manifestations of teratogenic exposure include :congenital heart disease, abnormal limb development, mental retardation, blindness, hearing loss, and abnormalities in growth.

18. Teratogenic Agents 1 - Alcohol The most common teratogenic drug used in the United States is alcohol. Alcohol at any dose is capable of causing neurologic deficits and facial deformities ranging from mild to severe. Each year, approximately 4,000 children are born in the United States with fetal alcohol syndrome. Fetal alcohol syndrome is 100% preventable.

19. 2 - The TORCH Group of Teratogens Several different microorganisms are known to be teratogenic in humans. Many of these are described under the acronym TORCH, in which each letter stands for a particular microorganism that may infect the embryo or fetus. T stands for toxoplasmosis, R for rubella, C for cytomegalovirus, and H for the herpes simplex virus. The letter O stands for all other infections, especially syphilis, hepatitis B, mumps, gonorrhea, and chickenpox.

20. -A newborn infected during gestation with any of the TORCH group of microorganisms may show microcephaly, hydrocephaly, mental retardation, or loss of hearing or sight. -Congenital heart defects are common, especially with rubella.

21. 3 – Radiation Radiation exposure may increase the risk of developing cancer. *Whether an embryo or fetus will be affected by any teratogenic agent depends on 1-timing of exposure 2- dose of exposure, 3- maternal health and nutritional status.

22. Timing of Exposure to a Teratogen - Because most organs and tissues are formed during the first trimester, teratogenic agents are most likely to cause structural defects at this time. - However, the nervous system is always susceptible to a teratogen because it continues to develop even after birth. - Infants exposed to an infectious agent in the third trimester or during the birth process are at increased risk of developing the disease. This is true for neonatal infection by hepatitis B virus or HIV.

23. Dose of a Teratogen - The dose of exposure is important in determining the likelihood that a teratogenic agent will cause a congenital defect. - Levels of radiation used in most diagnostic techniques or low concentrations of a drug may not produce any effect on the fetus. - Higher doses of radiation or a drug may adversely affect the fetus.

24. Maternal Health and Nutritional Status Infants born to women with diabetes or seizure disorders are at higher risk of fetal anomalies, the latter perhaps due to the effects of both the seizures themselves and the medications used to treat the disorder. Maternal diets low in folic acid have been associated with development of neural tube defects such as spina bifida..

25. Down Syndrome Down syndrome is a genetic disorder caused by a trisomy of chromosome 21. Down syndrome is seen in 1 in 800 live births, making it the most common chromosomal disorder seen in live births. In 95% of cases, Down syndrome is caused by non-disjunction of maternal chromosome number 21 during meiosis. The incidence of Down syndrome related to non- disjunction increases with maternal age.

27. Clinical Manifestations - Variable levels of mental retardation. - Upward slanting of the eyes. - Short hands that have only one crease on the palm (a simian crease) - low-set ears. - Short stature. - Protruding tongue. Complications - - Congenital heart or other organ defects are frequent. - Risk of childhood leukemia is increased in children with Down syndrome. - Spontaneously abortion of about 20% between 10 and 16 weeks' gestation.

28. Turner syndrome Is a monosomy of the sex chromosomes. Infants born with Turner syndrome have 45 chromosomes: 22 pairs of somatic chromosomes and 1 sex chromosome, usually the X (45, X/O). Klinefelter Syndrome Is a polysomic disorder characterized by one or more extra X chromosomes in a genotypic male (47, X/X/Y; 47, X/X/X/Y). Klinefelter syndrome may result from non-disjunction of the male or female X chromosome during the first meiotic division, at approximately equal rates in males and females..