Chromosomes and human inheritance

1. Chromosomes and human inheritance Genes are distributed in chromosomes. Each gene has a specific position (locus) on a chromosome. Each pair of homologous chromosomes has the same arrangement of genes. Genes on the same chromosome are linked. The genes may be identical or different. Variant forms of genes are called alleles.

2. The parts of a chromosome

3. Alleles form through mutation (changes in the DNA sequence) There may be many different alleles within the human population, but each individual will have only two. Combinations of alleles can be beneficial, have no particular effect, or contribute to disease

4. Humans have tens of thousands of genes arranged on 46 chromosomes: 22 pairs of autosomes (homologous pairs) 1 pair of sex chromosomes X and Y are NOT homologous Genes located on “sex” (X or Y) chromosomes are called sex- (or X or Y)-linked genes

5. The sex of an individual is determined by the sperm: Female gametes- X or X Male gametes- X or Y X X XX XX X XY XY Y

6. The Y chromosome is much smaller than the X chromosome. For many years it was thought that there were no genes on the Y chromosome. It is now known that there are several genes on the Y chromosome, that contribute to male sexual development. There are thousands of genes on the X chromosome. Do females get a “double dose” of these genes?

7. No- because of X inactivation In each cell in a female, one of the X chromosomes is condensed into a Barr body. nucleus Barr body

8. What happens if a zygote is formed with the • wrong number of chromosomes? • Aneuploidy- too many or too few chromosomes • Polyploidy- three or more sets of chromosomes • Triploidy- three sets of chromosomes • fairly common- 15-18% of miscarriages • A few are born alive- most die within • a month • Usually occurs when one egg is fertilized • by two sperm (75% of triploids) • In contrast, polyploid plants are common

9. Triploid infant Approximately 1% of conceptions are triploid

10. How does aneuploidy happen? addition or deletion of an individual chromosome This usually happens through nondisjunction (a chromosome pair fails to separate during meiosis) Trisomy 16 is the most common Can be “mosaic” (some but not all cells are affected)

11. n+1 Nondisjunction n-1 n n

12. When an aneuploid gamete fuses with a normal gamete, the offspring will be aneuploid. When this happens with an autosome the condition is usually lethal. About 50% of all abnormalities in fetal death involve trisomies. A few survive.

13. Trisomy 13: Patau syndrome most survive fewer than 6 months defects in face, eyes, feet, nervous system and heart More common if maternal age is higher (over 32). Also contributes to Trisomy 18: Edwards syndrome babies are very small, grow slowly, usually female, and die within 2-4 months due to heart or respiratory failure Diagnosis by karyotyping

14. Trisomy 13 (Patau syndrome) Cleft palate, eye and neurological problems Average survival: 6 months

15. Edwards syndrome Malformed hands and feet, heart defects Life expectancy: 4 months Maternal age is a factor

16. Trisomy 21 (Down syndrome) occurs in about 1:900 live births characteristic physical features growth and mental development are usually retarded approximately 40% of all people with this syndrome have heart defects later in life, have very high incidence of leukemia and/or Alzheimer’s disease few live past age 50

17. Down syndrome (trisomy 21)

18. Maternal age is a risk factor for trisomy 1:2000 births at age 20 1:100 at age 35 1:30 at age 45 Amniocentesis or CVS (chorionic villus sampling) recommended for this reason

19. Aneuploidy of sex chromosomes • more common (1:400 in males, 1:650 • in females • Turner syndrome (XO) • About 1:10,000 live births • females lack an X chromosome • short, broad-chested, do not undergo • secondary sexual development • infertile • not associated with mental retardation

21. II. Klinefelter syndrome (XXY) about 1:1000 live births not apparent until puberty immature sexual development- occasion- ally breast development infertile may have mild retardation advanced maternal age increases risk affected male may have several X chromosomes- the more chromosomes, the more severe the effect

23. III. XYY syndrome (Jacobs syndrome) about 1:1000 live births affected men tend to be unusually tall MAY have personality disorders or low intelligence (most don’t) Once thought to make men predisposed to criminal behavior (frequency of XYY men is unusually high in prisons and mental institution). No causal relationship has been proven, though

24. Conclusions At least one X chromosome is required for survival (OY is lethal) Extra X chromosomes seem to interfere with normal development (even though all but one is inactivated in cells) The more X chromosomes are present, the more severe the effect

25. Chromosomes can also be structurally altered common (1:400 frequency) Deletions- part of chromosome missing Translocation- part of one chromosome joined to another associated with a hereditary form of Down syndrome, some cancers Duplications- part of chromosome is duplicated effects vary Chromosomal mutations

26. Recombination: portions of chromosomes are rearranged (coy number variants) Genes are moved “out of position” inversions (ABCDACBD) duplications (ABCDABBCD) translocations (ABCDEFABCJKL (GHIJKLGHIDEF)   Effects can be drastic (and permanent)

27. Cri du chat syndrome Discovered by Jerome Lejeune http://learn.genetics.utah.edu/content/disorders/whataregd/cdc/

28. Rare chromosomal disorders Robertsonian translocation and others

29. Uniparental disomy herkules.oulu.fiherkules.oulu.fi

30. What kind of cell is affected and what Are the consequences? Germ-line cell (gamete) these mutations are inherited these give rise to alleles Somatic cell these affect the particular tissue but cannot be inherited example: tumors Implications for gene therapy

31. Mutations- changes in gene sequence damage errors in copying gene sequence Cells have mechanisms to repair this damage but they are not always completely successful These changes lead to alleles Sometimes they are harmless, sometimes they lead to disease

32. How do mutations happen? Spontaneous errors of replication Chemicals (“mutagens”) Radiation Viruses If damage to DNA is not repaired, the mutation becomes incorporated into the genome.

33. Genetic disorders Most are recessive (can be passed from two healthy, “carrier” parents to a child) Some alleles are more common than others; some are more common in certain ethnic groups than others Sickle cell allele- African descent Cystic fibrosis- European descent Many of these alleles can now be identified through testing

34. Genetic counseling What contributes to a high-risk pregnancy? Disease-causing alleles dominant or recessive alleles- relative risk of each? Maternal age (Paternal age not clear)

35. Summary • Human chromosomes are analyzed by karyotyping • Study of variations in chromosomes structure can provide insight into health and disease • Major sources of variation are changes in chromosome number and arrangement • Polyploidy is much rarer in animals than plants • Aneuploidy is usually fatal • Structural changes can have drastic effects- or not