1. INHERITED TRAITS THAT HAVE MAJOR EFFECTS ON HEALTH Nutrition and Gene Expression Jan 23, 2014

2. These lectures are about the possibility that a child may get ONE good copy of a gene, or and another copy that does not function. The defective copy may also (rarely) cause problems. A RECESSIVE trait is when the one good copy basically does the job with no problems. The first example is sickle cell disorder.

3. Each hemoglobin molecule requires 2 alpha chains, and two beta chains. The gene for the beta chain is on Chromosome 11, near location: “11p15.5” Gene for the beta chain. M-11P-11 Topic: Normal Hb, Sickle trait, and Sickle Cell Disorder M is the chromosome from the mother, and P is the chromosome from the father.

4. Paternal and maternal: same DNA sequence, two functional globin proteins are made, with common amino acid sequence Paternal and maternal: the variation in the paternal gene leads to beta-globin S production, but beta-globin from the maternal gene is standard. This USUALLY does not cause problems, since the cell has a lot of normal beta-globin Paternal and maternal: the beta-globin made from BOTH chromosomes is B-globin S. This can result in sickle cell disease. P M Recessive mutation Homozygous mutation FROM EACH PARENT, YOU CAN GET THE COMMON OR THE VARIANT GENE FOR BETA-CHAIN OF Hb.

5. What is the mutation that accompanies sickle trait and sickle disease? At position 6 of the BETA-CHAIN, there is a substitution of VALINE for GLUTAMIC ACID. The new protein is called Beta-Globin-S. A cell can make Beta-globin-normal from one chromosome, and Beta-Globin-S from the other chromosome. Hemoglobin molecules will be assembled from random mixtures of the two kinds of chains. Change in the DNA from GAG to GTG: The result is the VALINE in the peptide chain.

6. 2d-alpha-chain 2d beta-chain Each Hb molecule gets 2 beta chains. If all the Hb molecules in the cell contain beta-globin-S, the Hb in that cell can sickle under low oxygen conditions.

7. The boy only gets ONE copy of the X chromosome! WHAT ABOUT THE EFFECT IN BOYS OF MUTATIONS ON THE X-CHROMOSOME? They don’t have “spare copy” to provide a good backup gene, and those mutations can be serious. These are called “X-linked traits”, and can lead to major disorders.

8. THE GENES ON THE X-CHROMOSOME CAN BE RANKED BY THE SEVERITY OF MUTATIONS: Essential for embryonic development: mutation causes loss of the fetus Needed for survival to adulthood: child will be born, but may be critically ill Important for health: child may survive, but may have lifelong illness and disability Mutation causes secondary loss of function, but can usually be tolerated Harmless mutation (for example, the code still generates the same amino acid).

9. TYPE OF MUTATION: Gene is essential for embryonic development: mutation causes loss of the fetus. Several genes on the X-chromosome have been identified that are essential for development, and effect the skin, CNS and skeleton. THERE WILL BE SUBSTANTIAL NATURAL SELECTION AGAINST THESE MUTATIONS. Why?

10. TYPE OF MUTATION: Gene is needed for survival to adulthood: child will be born, but may be critically ill, with limited survival. Dystrophin gene, at Xp21. X-linked (Duchenne’s) muscular dystrophy is caused by a mutation in the Dystrophin gene (at Xp21) which codes for a very large protein (3500 amino acids). This protein is needed for the cytoskeleton in striated muscle cells, including heart muscle. Boy children become handicapped by age 5, and then death from heart failure occurs by age 30. Functioning contractile cells in the heart (myocytes) are gradually replaced by fibroblasts (a form of scar tissue). Milder defects in Dystrophin protein are compatible with survival, accompanied by muscle weakness.

11. TYPE OF MUTATION: Gene needed for health: child will survive, but may have lifelong illness The gene for Factor VIII is at Xq28. There are several mutations possible. The male offspring can inherit a mutant version of the gene. With no (or very little) Factor VIII made, blood coagulation is defective, and hemorrhage can occur. WHY ARE FEMALE CARRIERS PROTECTED FROM THE DISORDER? Xq28

12. TYPE OF MUTATION: Mutation in the gene causes secondary loss of function, but can the mutation be tolerated The genes for the pigments in the red and green photoreceptors are ALSO near Xq28! There are about 1000 genes on the X-chromosome, so addresses are just approximate. A GOOD TEST FOR COLOR VISION IS AVAILABLE AT: http://colorvisiontesting.com/ishihara.h tm#plate%20with%2010%20answer

13. Since only 5% of our genes are on the X-chromosome (and <1% on the Y-chromosome), most of the interest in mutations focuses on chromosomes 1-22, which are called AUTOSOMES. Disorders on these chromosomes are called AUTOSOMAL DISORDERS, and are of two types: - Autosomal recessive - Autosomal dominant

14. -Autosomal recessive: The working copy of the gene maintains normal functions (commonly happens). The defective copy has minimal impact. -Autosomal dominant: The mutant gene makes a protein, that interferes with the protein from the working gene.

15. CARRIERSAFFECTED

16. Paternal and maternal: same DNA sequence, two functional globin proteins are made, with common amino acid sequence Paternal and maternal: the variation in the paternal gene leads to beta-globin S production, but beta-globin from the maternal gene is standard. This USUALLY does not cause problems, since the cell has a lot of normal beta-globin Paternal and maternal: the beta-globin made from BOTH chromosomes is B-globin S. This can result in sickle cell disease. P M Recessive mutation Homozygous mutation Sickle-cell disease: AUTOSOMAL RECESSIVE If one gene is OK, it largely blocks the harmful effects of the other gene.

17. Some important autosomal recessive traits in nutrition. -Phenylketonuria (PKU): both genes are defective that make the enzyme phenylalanine hydroxylase. Phenylalanine accumulates and is converted to the harmful product phenylpyrvuvate -Hereditary galactosemia: galactose accumulates, along with galactose-1-phosphate. BOTH CAN BE MANAGED BY SPECIAL DIETS. HOMEWORK ASSIGNMENT: Look up the biochemistry of these disorders, and sketch the abnormal molecular pathway that results from the enzymatic defect.

18. AFFECTED

19. AUTOSOMAL DOMINANCE AND DISEASE: The protein made from the mutant gene actually BLOCKS the function of the protein from the normal gene. These mutations are much less common than RECESSIVE mutations. Autosomal dominant mutations lead to MARFAN syndrome. People with this syndrome make a large amount of defective FIBRILLIN, which leads to problems with connective tissue. In nutrition, autosomal dominant mutations have been more difficult to identify. Polycystic kidney disease (PKD) is caused by a defective protein (PDK1, on chromosome 16) that leads to the formation of CYSTS within the kidney. The mechanism of cyst formation is still not well-defined. Low-salt diets are of some benefit.

20. NEXT WEEK, WE WILL DISCUSS IN DETAIL THE KINDS OF MUTATIONS THAT CAN OCCUR, WHICH CAN LEAD TO DEFECTIVE GENE FUNCTION. The key principle is that: “DNA REPLICATION IS NOT ALWAYS PERFECT”. When DNA is replicated to provide chromosomes to ova and sperm, MISTAKES CAN BE MADE and THE WRONG BASE CAN BE INCORPORATED IN THE DNA. There are >100 enzymes that function to maintain proper DNA replication, but mistakes still happen (not very often!, and that can lead to harmful mutations.

21. RECESSIVE TRAITS AND HEALTH There are LOTS of recessive traits, covered in basic biology texts, that are completely OK (red hair, blue eyes, etc). This web document lists some of them (you will have to research the genetics of each trait): http://employees.csbsju.edu/ssaupe/biol115/genetics_single_gene.htm IN THIS CLASS, WE WILL FOCUS ON RECESSIVE TRAITS WITH HEALTH IMPACTS, ESPECIALLY GENES THAT ARE CRITICAL FOR HEALTHY NUTRITION.