The Chromosomal Basis of Inheritance 2

1. The Chromosomal Basis of Inheritance 2 /

2. Review • Sex Linked traits: Inheritance of traits on the sex chromosomes. • X- Linkage (common) • Y- Linkage (very rare) • Males • Hemizygous - 1 copy of X chromosome. • Show ALL X traits (dominant or recessive). • More likely to show X recessive gene problems than females.

3. Samples of X Linked Patterns • Trait is usually passed from a carrier mother to 1/2 of sons. • Affected father has no affected children, but passes the trait on to all daughters who will be carriers for the trait.

4. Important Hint !!!! • Watch how questions with sex linkage are phrased: • Chance of children? • Chance of males? • Number of carriers?

5. Sex Linked Traits • Duchennes Muscular Dystrophy • Color Blindness • Hemophelia • Hairy ear pinnae. • Comment - new techniques have found a number of Y-linked markers that can be shown to run in the males of a family. X-Linkage Y-Linkage

6. Gender Differences • Traits that are only expressed in one sex. • Ex – prostate gland • Traits whose expression differs because of the hormones of the sex. • These are NOT on the sex chromosomes. • Ex. – beards, mammary gland development, baldness Sex Limited Traits Sex Influenced Traits

7. Baldness • Example of Epistasis • The gene for baldness acts • Dominant ion the presence of testosterone • Recessive without testosterone • This is why men are more likely to go bald &/or have thin hair • Male + Baldness gene = bald • Female heterozyogotes for baldness gene = normal • Female homozygous recessive for baldness gene = thin hair

8. X Inactivation in Female Mammals • Female mammals have 2 X chromosomes • One of them, though, becomes almost completely inactivated during embryonic development • As a result the cells of males and females have the same effective dose of genes • The inactive X of each female condenses into a compact object called a Barr Body, which lies along the inside of the nuclear envelope

9. Barr Body • The inactive X of each female condenses into a compact object called a Barr Body, which lies along the inside of the nuclear envelope • Most genes on a Barr Body are not expressed • Barr Body chromosomes are reactivated in the cells that give rise to the Ova so every female gamete has an active X • In early fetal development the presence of a barr body can be used to identify gender of the baby without a karyotype

10. Example • X inactivation is responsible for the tortoiseshell colored cat • The tortoiseshell gene is on the X chromosomes • The tortoiseshell phenotype requires 2 different alleles, one on each X chromosome (so the animal must be heterozygous) one for orange and one for black fur

11. If a female is heterozygous for the tortoishell gene she is tortioshell • Orange patches are formed in areas of the cat that have active X chromosomes with the orange gene • Black patches are formed in areas of the cat that have active X chromosomes with the black gene • HHMI animation

12. Can you have a Tortoiseshell Male Cat? If so, what would their genotype be? • Yes • They must be XB XOY and are sterile. • If you find one they’re worth big $

13. Barr Body • Geneticist Mary Lyon demonstrated that selection of the X chromosome that will form the Barr Body is random and independent of other cells during embryonic development at the time of X inactivation • As a result females consist of a mosaic of two types of cells • Those with maternally derived active X & paternally derived barr bodies • And those with paternally derived active X & maternally derived barr bodies

14. After an X chromosome is inactivated • All mitotic descendants of that cell will have the same X chromosome inactivated • If a female is heterozygous for a sex linked trait about half of her cells will express one allele and the other half will express the other allele • Example: X-link mutation that prevents the development of sweat glands • A heterozygous woman has patches of normal skin and patches of skin that cant sweat

15. How is an x chromosome inactivated • Inactivation of an x chromosome involves modification of the DNA • Methylation (remember a methyl group is CH3) to nitrogenous bases of nucleotides that make up the DNA strand • XIST gene • Active only on the Barr Body • RNA transcript from this gene coats the X chromosome • Initiation of RNA transcript from this gene seems to initiate X inactivation

16. How is an X Chromosome Inactivated • 1 Xist gene on one of the X chromosomes • 2 Xist is transcribed into RNA • 3The RNA binds to the X chromosome it was transcribed from causing • 4 methylation and histonedeacetylation leading to X inactivation

17. Figure 1: Xist and X inactivation • Xist RNA encompasses the X from which it is transcribed. RNA-fluorescence in situ hybridization detecting Xist RNA (red) localized on the inactive X in a preparation of condensed chromosomes from differentiated mouse cells. DNA is counterstained (blue). • X-Iinactivation Animation

18. Alterations Of Chromosome Number or structure cause some genetic disorders • Large scale chromosomal alterations often lead to spontaneous abortion (miscarriage) • If born, individuals commonly exhibit various developmental disorders • Plants have a higher tolerance for these defects than animals do

19. Abnormal Chromosome Numbers • Ideally the meiotic/mitotic spindle distributes chromosomes evenly between daughter cells • Sometimes mistakes are made, though • Nondisjunction: members of a pair of homologous chromosomes do not move apart properly during meiosis I, or sister chromatids fail to separate during meiosis II

20. Nondisjunction • Results in 2 types of gametes • One gamete will receive 2 of the same type of chromosome • This is called trisomy • Trisomy of the 21st chromosome produces Down Syndrome • One gamete receives no copy of that one type of chromosome • This is called monosomy • Other chromosomes are usually distributed normally

22. aneuploidy • Zygotes formed through the fertilization of one or more aberrant gametes containing abnormal numbers of chromosomes are called aneuploids • Aneuploidy may involve more than 1 chromosome • Monosomy: an individual lacking 1 chromosome • 2n-1 • Trisomy: an individual with an extra chromosome • 2n+1

23. Effects of aneuploidy on the Organism • Although organisms with extra chromosomes can survive, (usually only if the chromosome is smaller with fewer genes on it) organisms lacking chromosomes usually do not • If an organism does survive, it usually has an obvious set of traits caused by the abnormal does of genes

24. Polyploidy • Some organisms have more then 2 complete chromosomal sets in all somatic cells • This is called polyploidy • Use a prefix to indicate how many sets of chromosomes total • Example • Tripolidy = 3 sets • Tetraploidy = 4 sets • Fairly common in plants • Bananas = triploid (3n) • Wheat = hexaploid (6n)

25. What causes polyploidy • TriploidyFertilization of an abnormal diploid egg (or sperm) produced by nondisjunction of all its chromosomes • Tetraploidy failure of a 2n zygote to divide after replicating its chromosomes • Some drugs cause polyploidy by interfering with the ability to form the mitotic spindle • Colcemid: It depolymerises microtubules and limits microtubule formation (inactivates spindle fiber formation) • arrests cells in metaphase • allows cell harvest and karyotyping to be performed

26. Alterations of Chromosome structure • 4 main types of alterations in chromosome structure • Deletions • Duplications • Inversions • Translocations

27. Chromosome Mutations • Chromosome will be missing genes • If centromere is deleted entire chromosome can be lost • Occurs when a gene sequence is repeated Deletions Duplications

28. Translocation • moves a segment from one chromosome to a nonhomologous chromosome

29. Inversions • reverses a segment within a chromosome

30. Chromosome Mutation Animation

32. Human Disorders due to chromosomal alterations • Individuals with certain aneuploid conditions can survive to birth and beyond • Often there are a set of symptoms known as a syndrome characteristic of the type of aneuploidy • Downs syndrome • Turner syndrome • Certain cancers

33. Down Syndrome • Caused by trisomy of the 21st chromosome • Each body cell has 47 instead of 46 chromosomes • Affects about 1 out of 700 children born in the US • Characteristic facial features • Short stature • Heart defects • Susceptibility to respiratory infection • Mental retardation • Prone to leukemia and alzheimers • Usually sterile Characteristics

34. Down Syndrome & Maternal Age • Disorder occurs in just under 0.04% of children born to mothers under the age of 30 • Moms in their early 30s have a 1.25% incidence of children with the disease • Risk increase even more as women age

35. Aneuploidy of Sex Chromosomes • Aneuploidy of sex chromosomes is less detrimental than aneuploidy of autosomes • Y chromosomes carry very few genes • Extra X chromosomes become inactivated Barr Bodies • Kleinfelter Syndrome • 1 in every 2000 births • XXY • Abnormally small testes • Sterile • Some breast development • Trisomy X • 1 in every 1000 births • XXX • Turner Syndrome • 1 in every 5000 births • X ( monosomy) • sterile Examples

36. Disorders Caused by Structurally Altered Chromosomes • Deletions cause severe problems • Example: Cri Du Chat “cry of the cat” • Translocations • Example: chronic myelogenous leukemia (CML)

37. Cri Du Chat • Specific deletion in chromosome 5 • Mental retardation • Abnormally small head with unusual facial features • When they cry sounds like the mewing of a distrressed cat • Individuals usually die in infancy or early childhood

38. CML • Leukemia is a general term referring to cancers that give rise to white blood cells

39. Some inheritance patterns are exceptions to the standard chromosome theory • There are some exceptions to Mendelian inheritance that are normal (not disease causing) • Two examples described here • Involving genes in the nucleus • Involving genes outside of the nucleus

40. Genomic Imprinting • There are several traits in mammals that will be expressed differently depending if they were inherited maternally or paternally • Genomic imprinting: when variation in a phenotype is dependant on whether the gene was inherited from the male parent or the female parent • Not due to sex linkage • Most imprinted genes are found on autosomes

41. Genomic Imprinting • Occurs during the formation of gametes • Results in the silencing of one alleleof certain genes • Because these genes are imprinted differently in the ova and sperm, a zygote expresses only one allele of an imprinted gene • The imprints are transmitted to all body cells through mitosis of a developing organism

42. Genomic Imprinting • During gamete formation old imprints are erased, and genes are newly imprinted based on the sex of the organism making the gametes • Imprinted genes are few, but often critical for embryo development

43. insulin-like growth factor 2 • Example of imprinted gene • Igf2 • Only paternal gene expressed • Evidence came from crossing normal mice and dwarf mice homozygous for a recessive mutation • Phenotypes of heterozygous offspring differed depending on whether the mutant allele came from the mother or the father

44. Figure It out • Which parent would have to be a mutant for the Igf2 to produce mutant heterozygote's? • Which could be an affected parent that produces normal heterozygote's?

45. What exactly is a genomic imprint • In most cases it seems to consist of heavy methylation (addition of CH3 groups) to cytosine residues within genes • In the case of Igf2 methylation of the paternal allele activates gene expression • Note: In most cases of gene methylation, though, methylation seems to directly silence a gene • Evidence: heavily methylated genes are usually inactive

46. Inheritance of organelle genes • Extranuclear genes: genes not found on chromosomes in the nucleus • Small circular DNA molecules • Found in • Mitochondria • Chlorpolasts • Some plant plastids • These organelles reproduce themselves, and transmit their DNA to their daughter organelles • Don’t display mendelian inheritance

48. Mitochondrial genes • Mitochondria are inherited maternally, so all mitochondrial genes are inherited maternally • When an egg & sperm fuse, only the nucleus of the sperm enters the egg, not the sperms organelles • All organelles come from the egg, and so, the mother • Products of most mitochondrial genes help make up the protein complexes necessary for electron transport and production of ATP

50. Mitochondrial DNA Mutations • Mitochondrial myopathy • suffers from weakness • Intolerance of exercise • Muscle deterioration • Other Mitochondrial DNA Mutations • May be responsible for at least some cases of diabetes, Alzheimer's, and heart disease • Researches think accumulation of mutations in mitochondrial DNA may play a role in normal aging process