Human Genetics

1. Human Genetics Chapter 15: The Chromosomal Basis of Inheritance

2. Genes & Chromosomes • Mendel’s “hereditary factors” were genes, though this wasn’t known at the time • Today we can show that genes are located on • The location of a particular gene can be seen by tagging isolated chromosomes with a fluorescent dye that highlights the gene

3. Chromosomal Theory of Inheritance • Mitosis and meiosis were first described in the late 1800s • The chromosome theory of inheritance states: • Mendelian genes have specific on chromosomes • Chromosomes undergo segregation and • The behavior of chromosomes during meiosis was said to account for Mendel’s laws of segregation and independent assortment

5. Experimental Evidence • The first solid evidence associating a specific gene with a specific chromosome came from Thomas Hunt Morgan, an embryologist • Morgan’s experiments with fruit flies provided convincing evidence that chromosomes are the location of Mendel’s heritable factors

6. Experimental Evidence • In one experiment, Morgan mated male flies with white eyes (mutant) with female flies with red eyes (wild type or normal) • The F1 generation all had red eyes • The F2 generation showed the 3:1 red:white eye ratio, but only males had white eyes • Morgan determined that the • Morgan’s finding supported the chromosome theory of inheritance

7. Sex linkage • Sex chromosomes determine gender of individual • XX in females, XY in males • Each ovum contains an X chromosome, while a sperm may contain either an X or a Y chromosome • The on the Y chromosome codes for the development of testes • X chromosome has genes for many traits NOT associated with

9. A gene located on either sex chromosome is called a In humans, sex-linked usually refers to a gene on the larger X chromosome If gene is on Y chromosome Females don’t get Y-linked traits Y-linked genes not common Example: Hairy ears Sex-linked Inheritance

10. If gene is on X chromosome Can inherit from Sons always get X chromosome from mom and Y chromosome from dad X-linked Inheritance

11. X-linked traits • Color blindness • Hemophilia • Duchene muscular dystrophy • (SCID) Severe Combined Immunodeficiency Syndrome • AKA Bubble boy disease

12. X-linked recessive genes • Sex-linked genes follow specific patterns of inheritance • For a recessive sex-linked trait to be expressed • A female needs of the allele • A male needs only of the allele • Sex-linked recessive disorders are much more common in males than in females

13. Females & X-linked • In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development • The inactive X condenses into a • If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character

14. Carriers • Females can be carriers • Other X has normal dominant gene • Males cannot be carriers, they either have it or they do not • Males will give gene to all daughters, none to sons • If he has the gene all his daughters will be carriers of trait

15. Red-green color blindness • X-linked disorder • Can’t differentiate these two colors • Many people who have this are not aware of the fact • First described in a boy who could not be trained to harvest only the ripe, red apples from his father’s orchard. • Instead, he chose green apples as often as he chose red • What serious consequence could result from this?

17. Hemophilia • An X-linked disorder that causes a problem with • If your blood didn’t have the ability to clot and you bruised yourself or scraped your knee, you would be in danger of bleeding to death • Queen Victoria was a carrier and she passed the trait on to some of her children

18. Hemophilia • About 1 in every 10,000 males has hemophilia, but only about 1 in every 1 million females inherits the same disorder • Why???? • Males only have one X chromosome • A single recessive allele for hemophilia will cause the disorder • Females would need two recessive alleles to inherit hemophilia • Males inherit the allele for hemophilia on the X chromosome from their carrier or infected mothers

19. Hemophilia

20. Hemophilia • Hemophilia can be treated with and injections of Factor VIII, the blood-clotting enzyme that is absent in people affected by the condition • Both treatments are expensive • New methods of DNA technology are being used to develop a safer and cheaper source of the clotting factor

21. Sex-linked Questions • Both the mother and the father of a male hemophiliac appear normal. From whom did the son inherit the allele for hemophilia? What are the genotypes of the mother, the father and the son? • A woman is color blind. If she marries a man with normal vision, what are the chances that her daughter will be color blind? Will be carriers? What are her chances that her sons will be color blind? • Is it possible for two normal parents to have a color blind daughter?

22. What is on our chromosomes? • Each chromosome has hundreds or thousands of genes • Genes located on the same chromosome that tend to be inherited together are called • Thomas Morgan found that body color and wing size of fruit flies are usually inherited together in specific combinations • He noted that these genes do not assort independently, and reasoned that they were on the same chromosome • However, nonparental phenotypes were also produced • Understanding this result involves exploring genetic recombination

23. Genetic Recombination • Mendel observed that combinations of traits in some offspring differ from either parent • Offspring with a phenotype matching one of the parental phenotypes are called • Offspring with nonparental phenotypes (new combinations of traits) are called • Morgan discovered that genes can be linked, but the linkage was incomplete, as evident from recombinant phenotypes • Morgan proposed that some process must sometimes break the physical connection between genes on the same chromosome • Mechanism was the of homologous chromosomes

24. Genetic map • Alfred Sturtevant, one of Morgan’s students, constructed a , an ordered list of the genetic loci along a particular chromosome • Sturtevant predicted that the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency

25. Genetic map • A is a genetic map of a chromosome based on recombination frequencies • Distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency (max value = 50%) • Map units indicate relative distance and order, not precise locations of genes

26. Human Genome Project • The most ambitious mapping project to date has been the sequencing of the human genome • Officially begun as the Human Genome Project in 1990, the sequencing was largely completed by 2003 • The project had three stages: • Genetic (or linkage) mapping • Physical mapping • DNA sequencing

27. Human Genome Project • A expresses the distance between genetic markers, usually as the number of base pairs along the DNA • It is constructed by cutting a DNA molecule into many short fragments and arranging them in order by identifying overlaps • Sequencing was then done on the chromosomes

28. Gene Manipulation • DNA sequencing has depended on advances in technology, starting with making recombinant DNA • In recombinant DNA, nucleotide sequences from two different sources, , are combined in vitro into the same DNA molecule • Methods for making recombinant DNA are central to , the direct manipulation of genes for practical purposes

29. Biotechnology • DNA technology has revolutionized biotechnology, • One benefit of DNA technology is identification of human genes in which mutation plays a role in genetic diseases • Scientists can diagnose many human genetic disorders by using molecular biology techniques to look for the disease-causing mutation • Genetic disorders can also be tested for using genetic markers that are linked to the disease-causing allele

30. Transgenics • Advances in DNA technology and genetic research are important to the development of new drugs to treat diseases • Transgenic animals are made by introducing genes from • Transgenic animals are pharmaceutical “factories,” producers of large amounts of otherwise rare substances for medical use • “Pharm” plants are also being developed to make human proteins for medical use • This is useful for the production of insulin, human growth hormones, and vaccines

31. Gene Therapy • Gene therapy is the • Gene therapy holds great potential for treating disorders traceable to a single defective gene • Vectors are used for delivery of genes into specific types of cells (example = bone marrow) • Gene therapy raises ethical questions, such as whether human germ-line cells should be treated to correct the defect in future generations

32. Causes of Genetic Disorders • Meiosis usually functions accurately, but problems may arise at times • Large-scale chromosomal alterations often lead to or cause a variety of developmental disorders • In , pairs of homologous chromosomes do not separate normally during meiosis • May occur in Meiosis I or II • One gamete receives two of the same type of chromosome • Another gamete receives no copy of the chromosome

34. Fertilization after nondisjunction • Nondisjunction results in gametes with an • If the other gamete is normal, the zygote will have 2n + 1 (47 in humans) or 2n - 1 (45 in humans) • Most of the time an extra chromosome prevents development from occurring • results from the fertilization of gametes in which nondisjunction occurred • Offspring with this condition have an abnormal number of a particular chromosome

35. Fertilization after nondisjunction • occurs when thezygote has only one copy of a particular chromosome (2n -1) • occurs when thezygote has three copies of a particular chromosome (2n+1) • is a condition in which an organism has more than two complete sets of chromosomes • Triploidy (3n) is three sets of chromosomes • Tetraploidy (4n) is four sets of chromosomes • Polyploidy is common in plants, but not animals • Polyploids are more normal in appearance than aneuploids

36. Nondisjunction animation Animation #2

37. Human Disorders due to chromosome alterations • Alterations of chromosome number are associated with some serious disorders • Some types of aneuploidy appear to upset the genetic balance less than others, resulting in individuals surviving to birth and beyond • These surviving individuals have a set of symptoms, or syndrome, characteristic of the type of aneuploidy

38. Down Syndrome • Down syndrome is an aneuploid condition that results from three copies of chromosome 21 • Most common serious birth defect • 1 in 700 births • Varying degrees of mental retardation • Due to Gart gene on 21st chromosome • 1/2 eggs of female will carry extra 21 and 1/2 will be normal • Risk increases with

40. Incidence of Down Syndrome

41. Klinefelter Syndrome • Klinefelter syndromeis the result of an extra X chromosome in a male, producing XXY individuals • 1 in every 2,000 births • Could be from nondisjunction in either parent

42. Turner Syndrome • Turner syndrome produces XO females, who are sterile • 1 in every 5,000 births • It is the only known viable monosomy in humans • Girls with Turner Syndrome do not develop secondary sex characteristics such as breast tissue and underarm or pubic hair

43. Mutation types • Alterations of chromosome structure may also lead to genetic disorders • Breakage of a chromosome can lead to four types of changes in chromosome structure: • removes a chromosomal segment • repeats a chromosomal segment • reverses a segment within a chromosome • moves a segment from one chromosome to another

44. Mutation types

45. Cri du chat • The syndrome cri du chat (“cry of the cat”), results from a specific deletion in chromosome 5 • A child born with this syndrome is mentally retarded and has a catlike cry • Individuals usually die in infancy or early childhood

46. Chronic Myelogenous Leukemia • Certain cancers, including chronic myelogenous leukemia (CML), are caused by translocations of chromosomes • Occurs with the exchange of a large portion of chromosome 22 with a small fragment from the tip of chromosome 9 • Shortened, easily recognizable chromosome 22 is called the

47. Genomic imprinting • There are two normal exceptions to Mendelian genetics • One exception involves genes located in the nucleus, and the other exception involves genes located outside the nucleus • Genes marked in gametes as coming from mom or dad • Genes inherited from father expressed differently than genes inherited from mother • For a small fraction of mammalian traits, the phenotype depends on which parent passed along the alleles for those traits • Such variation in phenotype is called • Example = Insulin-like growth factor in mice

48. Organelle genes • Extranuclear genes (or cytoplasmic genes)are genes found in organelles in the cytoplasm • Mitochondria, chloroplasts, and other plant plastids carry small circular DNA molecules • Extranuclear genes are inherited because the zygote’s cytoplasm comes from the egg

49. Organelle genes • The first evidence of extranuclear genes came from studies on the inheritance of yellow or white patches on leaves of an otherwise green plant • Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems • For example, mitochondrial myopathy and Leber’s hereditary optic neuropathy

50. Review Questions State the 2 basic ideas behind the chromosomal theory of inheritance. Explain Morgan’s experiment and how it gave evidence that genes are located on chromosomes. Explain sex linkage and sex-linked inheritance. Name and describe characteristics of 4 genetic diseases that are known to be X-linked. Explain the idea of a “carrier” for an X-linked genetic disease. Carry out a monohybrid cross of an X-linked trait using a Punnett square. Explain the idea of linked genes. Explain the result of genetic recombination. Identify the significance of genetic maps and linkage maps Describe the Human Genome Project and differentiate between its 3 main stages. Discuss the advantages of gene manipulation and biotechnology. Describe various uses of transgenic animals. Explain the purpose and use of gene therapy. Explain how errors in meiosis can cause genetic syndromes.