Fundamentals of human genetics. Human hereditary diseases. Methods of research of human heredity

1. Fundamentals of human genetics. Human hereditary diseases. Methods of research of human heredity Ass. Nedoshytko Khrystyna

2. Genotype- the alleles a person has Phenotype- the observable trait a person has Dominant- Alleles affect masks the other allele it is paired with Recessive- Alleles affect is masked by the other allele it is paired with. Homozygous- Pair of alleles for a trait are identical Heterozygous- Pair of alleles for a trait are not identical Hybrid- Inherit non-identical alleles for a trait Genetic Terminology

3. VISUAL REPRESENTATION Pair of Chromosomes Gene Locus (loci) Alleles Heterozygous Homozygous A pair of homologous chromosomes, each in the unduplicated state (most often, one from a male parent and its partner from a female parent) Heterozygous Homozygous A gene locus (plural, loci), the location for a specific gene on a specific type of chromosome A pair of alleles (each being a certain molecular form of a gene) at corresponding loci on a pair of homologous chromosomes Three pairs of genes (at three loci on this pair of homologous chromosomes); same thing as three pairs of alleles

4. Homologous Chromosomes • Homologous autosomes are identical in length, size, shape, and gene sequence • Sex chromosomes are nonidentical but still homologous • Homologous chromosomes interact, then segregate from one another during meiosis DNA DNA and proteins arranged as cylindrical fiber Nucleosome Histone

5. Human Karyotype 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 XX (or XY)

6. Karyotype Preparation • Cultured cells for 3 to 4 days in thepresence ofphytohaemagglutinin(mitogen)and arrested at metaphase • This is when cells are most condensed and easiest to identify Arrested cells are broken open • Metaphase chromosomes are fixed and stained (how many copies of each chromosome in one cell?) • Chromosomes are photographed through microscope • Photograph of chromosomes is cut up and arranged to form a karyotype diagram

7. Karyotypes • The Alaskan king crab has 208 chromosomes. • The fruit fly has 4. • Number has nothing to do with complexity of the organism Cotton Rat (Sigmodon hipsidus) Pied Kingfisher (Ceryle rudis) Carrion Beetle (Phosphuga atrata)

8. Prenatal Diagnosis • Amniocentesis (1-2%) • Amniotic fluid removed • Chorionic villus sampling (0.3%) • Cells from the chorion (surrounds ammnion) • Fetoscopy (2-10%) • Direct visualization, removal of blood from umbilical vein

9. cordocentesis amniocentesis Chorion villi sampling Preimplantation genetic diagnosis Prenatal diagnosis www.visembryo.com/baby/hp.html

10. Amniocentesis Removal of about 20 ml of amniotic fluid containing suspended cells that were sloughed off from the fetus Performed during weeks 15-17 of pregnancy A few biochemical analyses with some of the amniotic fluid Centrifugation Quick determination of fetal sex and analysis of purified DNA Fetal cells Biochemical analysis for the presence of alleles that cause many different metabolic disorders Growth for weeks in culture medium Fig. 11.19, p. 186 Karyotype analysis

11. Sex Chromosomes • Discovered in late 1800s • Mammals, fruit flies • XX is female, XY is male • Human X and Y chromosomes function as homologues during meiosis (In some organisms XX is male, XY female but for this class XX is female and XY is male, no tricky stuff)

12. X X X Y Y X X X XX XX XY XY Sex Determination eggs sperm Female germ cell Male germ cell sex chromosome combinations possible in new individual

13. The Y Chromosome Fewer than two dozen genes identified One is the master gene for male sex determination SRY gene (Sex-determining region of Y) SRY present, testes form SRY absent, ovaries form The X Chromosome Carries more than 2,300 genes Most genes deal with nonsexual traits Genes on X chromosome can be expressed in both males and females The Sex Chromosomes

14. Pedigree • Chart that shows genetic connections among individuals • Standardized symbols • Knowledge of probability and Mendelian patterns used to suggest basis of a trait • Conclusions most accurate when drawn from large number of pedigrees

15. The individual who needs genetical medical consultation is called the probandO, • Proband tells to doctor medical history about his disorder and any other affected persons in the family. If this disorder (disease) is inheritance, we can draw family trees.

16. Pedigree symbols

17. Children marked under horizontal line from left to right, in order of birth. Members of the same generation are placed on the same horizontal level. Roman numbers are used for each generation and Arabic numerals are used to indicate each individual within a generation.

18. I II III IV V *Gene not expressed in this carrier. Pedigree for Polydactly female male * 1 2 3 4 5

19. Autosomal Recessive Inheritance Patterns • If parents are both heterozygous, child will have a 25% chance of being affected

20. Galactosemia • Caused by autosomal recessive allele • Gene specifies a mutant enzyme in the pathway that breaks down lactose enzyme 1 enzyme 2 enzyme 3 GALACTOSE-1- PHOSOPHATE GALACTOSE-1- PHOSOPHATE LACTOSE GALACTOSE +glucose intermediate in glycolysis

21. Autosomal Dominant Inheritance Trait typically appears in every generation

22. Huntington Disorder • Autosomal dominant allele • Causes involuntary movements, nervous system deterioration, death • Symptoms don’t usually show up until person is past age 30 • People often pass allele on before they know they have it

23. Genetics Problem • A woman (hh) with normal nerve physiology has a child with a man (Hh) who will develop Huntington Disease • What is the chance that the child will have Huntington Disease?

24. Sex-Linked Genes Is there a special pattern of inheritance for genes located on the X chromosome or the Y chromosome? Because these chromosomes determine sex, genes located on them are said to be sex-linked genes Many sex-linked genes are found on the X chromosome More than 100 sex-linked genetic disorders have now been mapped to the X chromosome The human Y chromosome is much smaller than the X chromosome and appears to contain only a few genes

26. X-Linked Recessive Inheritance • Males show disorder more than females • Son cannot inherit disorder from his father

27. A typical X-linked recessive pedigree

28. X Linked Recessive Inheritance • Trait is much more common in males than females • An affected man passes the gene to all of his daughters • A son of a carrier mother has a 50 % chance of inheriting the trait • Male-to-male transmission never occurs • Carrier females are usually asymptomatic, but some may express the condition with variable severity because of Lyonization, or X-inactivation.

29. X-Chromosome Inactivation • Females have two X chromosomes, but males have only one • If just one X chromosome is enough for cells in males, how does the cell “adjust” to the extra X chromosome in female cells? • The answer was discovered by the British geneticist Mary Lyon • In female cells, one X chromosome is randomly switched off • That turned-off chromosome forms a dense region in the nucleus known as a Barr body • Barr bodies are generally not found in males because their single X chromosome is still active

30. Barr body

31. X linked recessive, normal father, carrier mother carrier daughter 1 normal daughter 1 affected son 1 normal son

32. X linked recessive, affected father • 2 carrier daughters • 2 normal sons: Never any Male-to- • Male transmission!

33. Examples of X-Linked Traits • Color blindness • Inability to distinguish among some of all colors • Hemophilia • Blood-clotting disorder • 1/7,000 males has allele for hemophilia A • Was common in European royal families

35. Royal Hemophilia Pedigree

36. Duchenne Muscular Dystrophy  Duchenne muscular dystrophy is a sex-linked disorder that results in the progressive weakening and loss of skeletal muscle In the United States, one out of every 3000 males is born with this condition Duchenne muscular dystrophy is caused by a defective version of the gene that codes for a muscle protein Researchers in many laboratories are trying to find a way to treat or cure this disorder, possibly by inserting a normal allele into the muscle cells of Duchenne muscular dystrophy patients

38. Distribution of Mendelian disorders • 68 % Autosomal dominant • 26 % Autosomal recessive • 6 % X-linked recessive

39. In a sex-influenced trait, an allele is dominant in one sex but recessive in the other. • Hormonal differences can cause this difference in expression. For example, a gene for hair growth pattern has two alleles, one that produces hair all over the head and another that causes pattern baldness. The baldness allele is dominant (A) in males but recessive (a) in females, which is why more men than women are bald. A heterozygous male (Aa) is bald, but a heterozygous female is not. The genotype of a bald women is aa.

40. More Sex-Linked Recessive Inheritance Male-pattern baldness By age 50, nearly 60% of all men will experience some male pattern baldness. 35 million Americans experience some degree of hair loss, resulting in $900 million dollars a year being spent in efforts to grow it back. Rogaine: only 5% actually grow hair, 20-30% will have no effect,

41. X-Linked Dominant inheritance: 1) a trait affects mostly females; 2) if the affected female is heterozygous, she will pass the trait to a half of her offspring (male and female); 3) an affected male passes the trait to his daughters.

42. Enamel hypoplasia (hereditary defect that cause holes and cracks to appear around the crowns of the teeth) is sex-linked dominant trait.

43. Y-Linked inheritance: 1)a trait affects only males; 2) father passes a trait to all sons.

44. Hairy pinnae (hairy ears) – Y-linked trait

45. X y X X Y-linked Ear-Hair XX Xy XX Xy y = Ear Hair

46. Thank you for attention !