Genetics

1. Genetics To understand population genetics and evolution, we’ll begin with a brief review of Mendelian genetics (Chapter 9) The basis of modern trait genetics is Mendel’s studies. Mendel studied the garden pea - why? Cheap, quick, basic traits well-known More importantly, only two phenotypes for each trait - flowers either purple or white, seeds either yellow or green,…

2. He was also ‘lucky’ - each is a single gene trait each of the 7 traits he studied show simple dominance - a dominant gene, when present is always expressed in the phenotype each shows complete penetrance - there are no washed-out colors or incomplete expression when he studied multi-trait phenotypes, the pairs of traits he chose didn’t show effects of crossing over

3. What did he find? In a cross for seed colour - yellow is dominant over green -

4. As long as you consider single factor crosses with simple dominance, there are only a few possibilities: both parents homozygous YY Y Y y Yy Yy yy y Yy Yy all offspring will be identical

5. one parent homozygous, one heterozygous YY 1/2Y 1/2Y 1/2Y 1/4YY 1/4YY Yy 1/2y 1/4Yy 1/4Yy offspring are half homozygous (like the homozygous parent) and half heterozygous What’s important is to remember that half the gametes carry one of the parental chromosomes, and the other half carry the other parental chromosome.

6. both parents heterozygous Yy ½Y ½y ½Y ¼YY ¼Yy Yy ½y ¼Yy ¼yy 1/4 of offspring homozygous dominant 1/2 of offspring heterozygous 1/4 of offspring homozygous recessive

7. Mendel found that a trait (e.g. green pea colour) could disappear for a generation (hidden as a recessive gene in heterozygotes), then reappear in the next generation. He invented the terms dominant and recessive. He proved it using a test cross (a cross with a homozygous recessive individual. There are only two possible results: all offspring identical - unknown parent homozygous 1/2 and 1/2 - unknown parent heterozygous

8. The results of single factor crosses led to Mendel’s First Law - The Law of Segregation: Each sexually reproducing organism has two alleles for each trait. These alleles separate (segregate) during meiosis. Only one appears in each gamete.

9. Now consider two factor (trait) crosses - pea colour (yellow or green) and… pea shape (round or wrinkled) together

10. Results of a two factor cross of heterozygotes: 9/16 dominant phenotype for both traits 3/16 dominant for one trait, recessive for the other 3/16 dominant for other trait, recessive for first one 1/16 recessive for both traits

11. From results of two factor crosses, Mendel formulated the Law of Independent Assortment - If traits are not located on the same chromosome, then they are distributed independently in the formation of gametes.

12. Now let’s consider some human traits that are inherited simply, like Mendel’s traits in peas: Mid-digital hair - presence (or absence) of any hair on any finger between the middle and distal joints I think this is a recessive. Tongue -rolling - ability to curl your tongue into a U shape. An autosomal dominant. Clockwise rotation of the whorl of hair at the top back of your head. Also autosomal dominant. Brachydactyly - short fingers. An autosomal dominant.

13. Autosomal recessive genes? Blue eyes - presence of pigment in the iris is dominant. There are many others. We may be able to determine whether a trait is dominant or recessive from a pedigree. e.g.

14. Your assignment (not one that will be graded): For the following single gene traits in humans, determine the phenotypes of your parents, siblings, and, if possible, your grandparents: tongue-rolling hair whorl mid-digital hair Hitchhiker’s thumb We could try to determine your genotype for these traits from those of your relatives.

15. We use pedigrees to try to determine your genotype or to determine whether a trait is dominant or recessive. Here’s a pedigree for an autosomal dominant trait:

16. And here’s a pedigree for a recessive trait:

17. Not all traits are autosomal, some are carried on the unmatched X and Y chromosomes. These traits are called sex-linked. Most are carried on the X. They are inherited differently in males and females. The male chromosome complement is XY. A male cannot be heterozygous for an X-linked trait. There is no way to ‘hide’ recessive traits. Therefore, sex- linked recessive traits are much more frequently seen in males (their phenotypes) than females.

18. Examples of X-linked recessives: red-green color confusion hemophilia

19. Chromosome abnormalities: fragile-X syndrome - most common genetically caused mental retardation. A part of an X chromo- some “hangs by a thread”. More common in males than females. Effects partly determined by the parent providing the fragile X chromosome. arrow marks the fragile region

20. Retardation is more common if the fragile X came from the mother, and is more common in males. Is it sex-linked? The reason for fragility is a much multiplied triplet CGG repeat sequence (usually ~30x, in fragile X 100-1000s of times. Up to ~200 repeats there may be no retardation. But the number of repeats seems to increase when a woman passes the repeat segment to her children. So, it is sex-linked, but not in a simple Mendelian way.

21. In addition to mutations that can cause cancer, retardation, or various diseases, there can also be abnormalities in chromosome number. This is usually due to an error in meiosis producing either sperm or eggs. Because a female’s eggs only complete meiosis year’s after it began, scientists believe that chromo- some abnormalities are far more likely in older females than in males.

22. The most common error in humans is trisomy 21 - presence of (in whole or part) a 3rd copy of chromosome 21. Caused by non-disjunction during meiosis. Severity of resulting Down’s syndrome depends in degree of trisomy.

23. Other relatively common chromosome number errors occur in sex chromosomes. Why? Non-disjunction in X: fertilized by Y-bearing sperm - XXY Kleinfelter’s syndrome - externally male, but sterile, and may have some breast development fertilized by X-bearing sperm - XXX trisomy X - mostly normal, fully fertile, but may have abnormal menses

24. What about an egg which gets no X chromosome? fertilized by Y-bearing sperm - -Y aborted in early development, genes on the X are required for survival and development fertilized by X-bearing sperm - -X Turner’s syndrome - thickened skin fold alongside the neck, otherwise normal in appearance, but female sex organs and secondary sexual characters do not develop at puberty, sterile. Only about 2% develop to birth, most are auto-aborted.

25. What about non-disjunction in Y chromosome? if it fertilizes a normal egg - XYY “supermale” - taller than average, possibly (??) slightly lower IQ, some controversial evidence of a tendency to aggressiveness and a higher than expected presence in prison populations Sex chromosome compliments were also used in Olympic sex testing. How?

26. Females are like calico cats. In each cell (normally randomly) one of the X chromosomes is inactivated. It remains condensed and is bound to the nuclear membrane. The condensed X chromosome is called a Barr body. Males, with only one X, need it active. Testing involves taking a scraping from the inside of the cheek, putting the cells on a slide, and staining the DNA. If there is a condensed chromosome (a Barr body), the individual is a female. None and he is excused from competition.

27. This is what a Barr body looks like:

28. There can be problems with this determination. A few rare females (XX) carry, by translocation, the male determining gene from the Y on at least one of the X chromosomes. They would appear to be males, have approximately male muscle develop- ment, and apparently even have an enlarged, penis-like clitoris.

29. And some males (XY) may, by missing a burst of testosterone normally produced by the embryo in utero, develop as females externally, and even to the point of having a (non-functional) uterus. How should society deal with these individuals? These last questions remain unresolved, but modern molecular testing at least tells us how the tested individuals function.

30. Translocations - Pieces of chromosomes may end up attached to different places than normal. One example: a section of chromosome 22 attaches to chromosome 9. Result: chronic myelocytic leukemia, a form of cancer.

31. Finally, let’s look at one of the more important point mutations important in the human genome - the sickle cell trait.

32. Sickle cell anemia is caused by a single base change in the DNA for a protein chain in the hemoglobin molecule. The result is replacement of one amino acid (a glutamic acid replaced with a valine). There is only a slight effect if an individual is heterozygous. Some sickling occurs if the individual is exposed to low oxygen. About 9% of African- Americans/Canadians are heterozygous. The situation and effects are much more serious in those who are homozygous for the altered gene.

33. The sickling of red blood cells when oxygen is not bound to the hemoglobin. It causes these cells to stick in capillaries. That causes damage in various organs (e.g. liver, kidneys, and brain); joint problems … The disease used to be fatal by early adulthood. Now people survive into middle age. Why does a gene that causes such severe problems persist?

34. There are at least two reasons: 1) Being heterozygous confers a greater resistance to malaria. Where the gene is found at high frequency, malaria was a severe problem, and remains widespread.

35. 2. Women who are heterozygous for the sickle cell gene are more fertile (are more likely to have children, have more children) than those who lack the gene. Of course, those who are homozygous for the gene will have great difficulty with pregnancy and birth. Therefore, even where malaria is not a problem, e.g. North America, the gene persists. This is one of the reasons for the importance of genetic counselling for those who may be carriers of any of a large number of genetic diseases.

36. There are tests available during pregnancy that can spot literally hundreds of chromosome or biochemical abnormalities. Amniocentesis - amniotic fluid from within placenta extracted, cells in it cultured, tested for chromosome abnormalities and/or suspected biochemical problems Performed at 15-16 weeks into pregnancy. Chorionic villus sampling - cells from the fetal part of placenta extracted and tested. This test can be performed earlier in pregnancy (6-12 weeks)

37. Now back to the inheritance and expression of human traits - Mendelian genetics is relatively simple. The situation for most human traits is not quite that simple. There are complications. Expressivity - the same gene may be expressed differently in two individuals. Reasons may include environment, genetic background (the other genes), … Penetrance - the likelihood that an individual carrying a dominant gene will express it. Some traits with incomplete penetrance will be expressed in only a fraction of individuals.

38. Pleiotropy - one gene may affect many traits. Remember all those effects of sickle cell trait. The same sort of thing occurs with a 3 base deletion in the gene for a transmembrane protein that pumps Cl- out of cells. The defective protein leads to cystic fibrosis, affecting lungs, sweat, digestive glands (particularly the pancreas), and sex organs. Most (virtually all) traits are polygenic. What we see in the phenotype is the joint result of the actions of 2 or more genes. Eye color results from 2 genes - one determines whether pigment will be produced; the other determines how much.

39. Multiple alleles - the Mendelian traits we looked at had only two alternative alleles. Many traits have more than 2 possible versions. The classic example is blood types. There are 3 alleles involved in ABO blood group determination: IA , IB , and i. These alleles determine the presence of antigenic proteins on the surfaces of red blood cells. IA causes the presence of A-type glycoprotein on cell surfaces. IB causes B-type glycoprotein. i does not cause an effective antigen to be present.