Ch. 5.2, 5.3 & Ch. 6

1. Ch. 5.2, 5.3 & Ch. 6 Extranuclear DNA, Gene Linkage, & Sex-Linked Traits

2. Mitochondrion Organelle providing cellular energy Contains small circular DNA called mtDNA - 37 genes withoutnoncoding “junk” sequences Many copies per mitochondrion and per cell No crossing over and little DNA repair Mutation rate is greater than nuclear DNA Inherited from the mother only High exposure to oxygen free radicals No histones (DNA- associated proteins)

3. Mitochondrion Mitochondrial genes are transmitted from mother to all of her offspring

4. A cell typically has thousands of mitochondria, and each has numerous copies of its “mini-chromosome”

5. Mitochondrial Disorders Mitochondrial genes encode proteins that participate in protein synthesis and energy production Several diseases result from mutations in mtDNA Examples: - Mitochondrial myopathies – Weak and flaccid muscles - Leber optical atrophy – Impaired vision Ooplasmic transfer technique can enable woman to avoid transmitting a mitochondrial disorder

6. Heteroplasmy The condition where the mtDNA sequence is not the same in all copies of the genome - Thus, a mitochondrion will have different alleles for the same gene At each cell division, the mitochondria are distributed at random into daughter cells If an oocyte is heteroplasmic, differing number of copies of a mutant mtDNA may be transmitted - The phenotype reflects the proportion of mitochondria bearing the mutation

7. Heteroplasmy • Most mitochondrial illnesses are heteroplastic, because homoplasmy (all mitochondrial bear the mutant allele) too severely impairs protein synthesis or energy production for embryonic development to be complete.

8. Mitochondrial DNA Reveals Past mtDNA provides a powerful forensic tool used to: - Link suspects to crimes - Identify war dead - Support or challenge historical records - Example: Identification of the son of Marie Antoinette and Louis XVI mtDNA is more likely to survive extensive damage and cells have many copies of it

9. Gene Linkage

10. Gene Linkage Most of Mendel’s traits had genes on different chromosomes or opposite ends of the same chromosome. Genes that are close on the same chromosome are said to be linked Linked genes do not assort independently in meiosis Rather, they are usually inherited together when the chromosome is packaged into a gamete Therefore, they do not produce typical Mendelian ratios

11. Linkage • William Bateson and R.C. Punnett were the first to observe linkage in the early 1900’s. • P1 generation = homozygous plants with purple flowers and long pollen grains (genotype PPLL) & homozygous plants with red flowers and round pollen rains (genotype ppll). • F1 = all PpLl • F1 X F1 = PpLl X PpLl • The ratio should be 9:3:3:1 • This ratio was not observed

12. The Actual Ratio Did Not Match The Expected Ratio. • The parental types were more commom P_L_ and p_l_, while the other two types ppL_ and P_ll – were less common. • They decided that the more prevalent parental genes were transmitted on the same chromosome. • The two less common offspring classes were explained by crossing over. • Crossing over - exchange between homologs that exchanges maternal and paternal gene combinations.

13. Recombination Chromosomes recombine during crossing-over in prophase I of meiosis New combinations of alleles are created Parental chromosomes have the original configuration Recombinant chromosomes have new combinations of alleles

14. Frequency of Recombination The correlation between crossover frequency and gene distance is used to construct linkage maps

15. Frequency of Recombination Frequency of recombination is based on percentage of meiotic divisions that result in breakage of linkage between parental alleles The frequency of recombination between two genes is proportional to the distance between them

16. Linkage Maps • Thomas Hunt Morgan was studying Drosophila melanogaster (fruit flies). He found that the number of linkage groups was the same as the number of chromosome pairs (4). He wondered if size of the recombinant groups was related to the physical position on the chromosomes. • Sturtvant (1911) proposed that the farther apart two genes are on a chromosome, the more likely they are to engage in a crossover, because there is more distance between the genes.

17. Linkage Maps A linkage map is a diagram indicating the relative distance between genes Maps are usually constructed by calculating percent recombination (crossovers) between two genes located on a particular chromosome. 1% recombination = 1 map unit

18. Mapping Linked Genes 1. Determine the % of recombinant offspring & the % of parental offspring. • % Recombinant Type (different mix of genes than the parents) • = Total Recombinant offspring/total number of offspring X 100 • % Parental Type (same mix of genes as the parents) • = Total parental offspring/total number of offspring X 100 2. % of Recombinants = # of map units = How far the genes are from each other.

19. Example Example: Gray –Normal X Black-Vestigial Gray –Normal Black- vestigial Gray-vestigial Black-normal 956 944 206 185 391 recombinants X 100 = 17 %Recombination 2300 total offspring The eye color gene is 17 map units away from the wing type gene.

20. Making Maps • 3. When you have several genes to order, put them on a number line beginning with the genes that are the farthest apart. • X-Y = 10 map unit • X-Z = 4 map units • Z-Y= 6 map units • X----4-------Z---------6-------------Y • [---------------10----------------------]

21. Linkage Disequilibrium (LD) Is the non-random association between DNA sequences Inherited together more often than would be predicted from their frequency The human genome consists of many “LD” blocks where alleles stick together These are interspersed with areas where crossing over is prevalent

22. Genetic Markers Are DNA sequences that serve as landmarks near genes of interest These were used starting in 1980 in linkage mapping Currently, they are used in genome-wide association studies

23. LOD Score Indicates the “tightness” of linkage between a marker and a gene of interest It is the likelihood that particular crossover frequency data suggests linkage rather than inheritance by chance LOD scores of 3 or higher signifies linkage Observed data are 1,000 times more likely to be due to linkage than chance

24. Haplotype Is the set of DNA sequences inherited on one chromosome due to linkage disequilibrium. The specific order of alleles on the chromosome Make it possible to track specific chromosome segments in pedigrees Disruptions of a marker sequence indicate crossover sites

25. Haplotype

26. Sex Determination

27. Our Sexual Selves • Maleness or femaleness is determined at conception • Another level of sexual identity comes from the control that hormones exert on development • Finally, both psychological and sociological components influence sexual feelings

28. Sexual Development During the fifth week of prenatal development, all embryos develop two sets of: Unspecialized (indifferent) gonads Reproductive ducts – Müllerian (female-specific) and Wolffian (male-specific) An embryo develops as a male or female based on the absence or presence of the Y chromosome Specifically the SRY gene (sex-determining region of the Y chromosome)

29. Sex Chromosomes Determine Gender Human males are the heterogametic sexwith different sex chromosomes, (XY) Human females are the homogametic sex(XX) In other species sex can be determined in many ways For example, in birds and snakes, males are homogametic (ZZ), while females are heterogametic (ZW)

30. X and Y Chromosomes X chromosome Contains > 1,500 genes Larger than the Y chromosome Acts as a homolog to Y in males Y chromosome Contains 231 genes Many DNA segments are palindromes and may destabilize DNA Figure 6.1

31. Anatomy of the Y Chromosome Pseudoautosomal regions (PAR1 and PAR2) - 5% of the chromosome - Contains genes shared with X chromosome Male specific region (MSY) - 95% of the chromosome - Contains majority of genes including SRY and AZF (needed for sperm production) Figure 6.2

32. SRY Gene – Sex Determining Gene Encodes a transcription factor protein Controls the expression of other genes Stimulates male development Developing testes secrete anti-Mullerian hormone and destroy female structures Testosterone and dihydrotesterone (DHT) are secreted and stimulate male structures

33. Abnormalities in Sexual Development Pseudohermaphroditism= Presence of male and female structures but at different stages of life Androgen insensitivity syndrome = Lack of androgen receptors 5-alpha reductase deficiency = Absence of DHT Congenital adrenal hyperplasia = High levels of androgens

34. Homosexuality Homosexuality has been seen in all cultures for thousands of years Documented in 500 animal species Evidence suggests a complex input from both genes and the environment Research in this area is controversial Studies of identical and fraternal twins Identifying possible markers

35. Sex Determination in Humans Figure 6.4 Figure 6.6

36. Sex-Linked Traits

37. What is a sex-linked trait? • Sex-linked traits are due to genes located on sex chromosomes.

38. Y-linked Traits Genes on the Y chromosome are said to be Y-linked Y-linked traits are very rare Transmitted from male to male No affected females Currently, identified Y-linked traits involve infertility and are not transmitted

39. X-linked Traits Possible genotypes X+X+ Homozyogous wild-type female X+XmHeterozygous female carrier XmXmHomozygous mutant female X+Y  Hemizygouswild-type male XmY Hemizygousmutant male

40. X-Linked Recessive Traits • Always expressed in the male. • Expressed in a female homozygote by rarely in a heterozygote. • Passed from heterozygote or homozyotemother to affected son. • Affected female has an affected father and a mother who is affected or a heterozygote.

41. Carriers • Because females have two copies of the X chromosome, it is possible to have certain traits “hidden” by a dominant copy. • However, because males only have one X chromosome, the observable phenotype is obvious and identifies the genotype.

42. Examples of X-linked genes • Other than determining sex, genes on the X chromosome are responsible for traits. Some examples are: • Hemophilia= Disorder of blood-clotting • Red-green color blindness • High blood pressure • Muscular dystrophy • Ichthyosis=Deficiency of an enzyme that removes cholesterol from skin • Some forms of Manic Depressive psychosis • Lesch-Nyhan

43. Sex-Linked Punnett Squares • If a man and a woman, both with normal vision, marry and have a colorblind son, draw the Punnett square that illustrates this. • If the man dies and the woman remarries to a colorblind man, draw a Punnett square showing the type(s) of children could be expected from her second marriage. How many/what percentage of each could be expected?

44. X-Linked Dominant Disorder • Expressed in female in one copy. • Much more severe effects in males. • High rates of miscarriage due to early lethality in males. • Passed from male to all daughters but no sons. • Examples = Incontinentiapigmenti & Hypertrichosis- lots of hair

45. Sex-Limited Traits Traits that affect a structure or function occurring only in one sex The gene may be autosomal or X-linked Examples: - Beard growth - Milk production - Pregnancy phenotypes - Sperm production

46. Sex-Influenced Traits • Traits in which the phenotype expressed by a heterozygote is influenced by sex • Allele is dominant in one sex but recessive in the other • Example: • - Pattern baldness in humans • - A heterozygous male is bald, but a heterozygous female is not

47. X-Inactivation

48. Females have two alleles for every gene on the X chromosome, whereas males have only one. • X inactivation balances this inequality. • Early in the embryonic development of a female, most of the genes on one X chromosome in each cell are inactivated. • Which X chromosome is turned off in each cell-the one inherited from the mother or the one from the father- is random. • The inactivated X chromosome is called a Barr body. • The XIST gene encodes an RNA that binds to and inactivates the X chromosome

49. A female expresses the X chromosome genes inherited from her father in some cells and those from her mother in others. • Once an X chromosome is inactivated in one cell (early in development), all its daughter cells have the same inactivated X chromosome.