Pedigree Analysis in Human Genetics

1. Pedigree Analysis in Human Genetics Chapter 4

2. Aborted or stillborn offspring Male Female Deceased offspring Mating Mating between relatives (consanguineous) or Unaffected individual Parents and children. Roman numerals symbolize generations. Arabic numbers symbolize birth order within generation (boy, girl, boy) or Affected individual I II Proband; first case in family that was identified or 1 2 3 P P Monozygotic twins Known heterozygotes or Carrier of X-linked recessive trait Dizygotic twins Offspring of unknown sex Infertility Fig. 3-16, p. 60

3. Human Pedigrees Ancestry.com—beware this can be addictive!

4. Patterns of Inheritance • Patterns in the pedigree are used to determine how a trait is inherited • Autosomal dominant • Autosomal recessive • X-linked dominant • X-linked recessive • Y-linked • Mitochondrial inheritance

5. 4.2 Autosomal Recessive Traits • Characteristics of autosomal recessive traits • For rare traits, most affected individuals have unaffected parents • All children of affected parents are affected • The risk of an affected child with heterozygous parents is 25% • The trait is expressed in both males and females

6. 4.2 Autosomal Recessive Pedigree

7. Example of an Autosomal Recessive Trait : Cystic Fibrosis • Cystic fibrosis: A fatal recessive genetic disorder associated with abnormal secretions of the exocrine glands • 1 in 25 Americans of European descent • 1 in 46 Americans of Hispanic descent • 1 in 65 African Americans • 1 in 250 Asian Americans

8. Cystic Fibrosis Gene Product (CTRF) • The CFTR gene was identified in 1989 • CFTR protein controls the movement of chloride ions across the plasma membrane • Water moves from the outside of the cell to the inside • In lung cells, this makes the mucus very thick

9. Exploring Genetics:: • Noah’s “flesh was white as snow” • From the Book of Enoch the Prophet • Phenotype: Lack of pigmentation • Albinism is inherited as an autosomal recessive trait • From chapter 1—old paintings and historical texts described birth defects that were inherited

10. 4.3 Autosomal Dominant Traits • Characteristics of autosomal dominant traits • Heterozygotesexhibit the phenotype • Every affected individual has at least one affected parent (except in traits with high mutation rates) • Two affected individuals can have an unaffected child • Usually an affected family member in each generation

11. 4.3 Autosomal Dominant Pedigree

12. Example of an Autosomal Dominant Trait: Marfan Syndrome • Marfan syndrome • An autosomal dominant genetic disorder that affects the skeletal system, cardiovascular system, and eyes • Individuals are tall, thin, long arms and legs. Thin fingers • Heart defects • Abraham Lincoln?????

13. 4.4 Sex Linked Inheritance • Genes on sex chromosomes have a distinct pattern of inheritance • X-linked • When a gene for a particular trait is located on the X chromosome • Y-linked • Pattern of inheritance that results from genes located only on the Y chromosome

14. For sex-linked traits males are Hemizygous • Hemizygous • Refers to males when the gene for a trait is on the X-or Y- chromosome. • Since males have just one X-chromosome, and one Y-chromosome, they will express whatever allele is present—the recessive or dominant

15. Fig. 4-10, p. 79

16. X-Linked Dominant Traits • Quite rare inheritance pattern (only 3 known) • Affected males produce all affected daughters and no affected sons • A heterozygous affected female will transmit the trait to half of her children • Sons and daughters are equally affected (e.g., vitamin D resistant rickets)

17. X-Linked Recessive Traits • X-linked recessive traits affect males more than females because males are hemizygous for genes on the X chromosome • Color blindness • Defective color vision caused by reduction or absence of visual pigments • Three forms: red, green, and blue blindness • About 8% of the male population in the US affected

18. Testing For Color Blindness • People with normal color vision see the number 29 in the chart; those who are color-blind cannot see the number Fig. 4-14, p. 81

19. X-linked recessive trait Punnett square Pause the presentation and try to answer these questions. A woman who is heterozygous for color-blindness is expecting a child. The father had normal vision. What is the probability that, if female, the child will be color-blind? What about the probability for a male child?

20. X-linked recessive trait Punnett square XC Y XCY XC XCXC XcY XCXc Xc Zero probability the baby, if female will be color-blind, but there is a 50% chance she will be a carrier. And there is a 50% chance that, if male, he will be color-blind.

21. Example of an X-linked Recessive Trait: Muscular Dystrophy • Muscular dystrophy • A group of genetic diseases associated with progressive degeneration of muscle tissue • Duchenne and Becker muscular dystrophy are inherited as X-linked recessive traits • Duchenne muscular dystrophy (DMD) affects 1 in 3,500 males in the US

22. 4.5 Paternal Inheritance: Y Chromosome • Only males have Y chromosomes • Genes on the Y chromosome are passed directly from father to son • All Y-linked genes are expressed • Males are hemizygous for genes on the Y chromosome • To date only 36 Y-linked traits have been identified

23. 4.6 Non-Mendelian Maternal Inheritance: Mitochondrial Genes • Mitochondria • Cytoplasmic organelles that convert energy from food into ATP (ATP powers cellular functions) • Have their own DNA that codes 37 mitochondrial genes • Genetic disorders in mitochondrial DNA are associated with defects in energy conversion

24. Mitochondrial Inheritance • Mitochondria (and genetic disorders caused by mutations in mitochondrial genes) are maternally inherited • Mitochondria are transmitted from mothers to all their offspring through the cytoplasm of the egg

25. 4.7 An Online Catalog of Human Genetic Traits • OMIM • Genetic traits are described, cataloged, and numbered in a database called Online Mendelian Inheritance in Man • OMIM is updated daily and contains information about all known human genetic traits • Each trait is assigned an OMIM number • There are more that 10,000 entries • **Chapter 4 Web Assignment on OMIM (See the course site for week 2 assignments.)

26. Fig. 4-20, p. 86

27. 4.8 Many Factors can Affect the Pattern of Inheritance • Variations in gene expression affect pedigree analysis and assignment of genotypes to members of the pedigree • Several factors can affect gene expression • Interactions with other genes • Interactions between genes and the environment

28. 4.8 Many Factors can Affect the Pattern of Inheritance • Phenotypes are often age related (onset of symptoms occurs in adulthood) • Example: Huntington disease • Penetrance and expressivity cause variations in phenotype • Penetrance: the probability the the phenotype will appear • Expressivity: The range of phenotypes from a given genotype

29. Penetrance and Expressivity Baby Born In Bay Area With 12 Functioning Fingers, 12 Toes Posted: 6:07 pm PST January 30, 2009Updated: 2:25 pm PST November 13, 2009 DALY CITY, Calif. -- A Daly City couple is beaming after becoming the proud parents of a healthy but incredibly rare baby boy this month. Baby Kamani Hubbard has six-fully formed and functional fingers and toes on his hands and feet. It's called "polydactyly" -- extra digits -- not an uncommon genetic trait, but Bay Area doctors say they've never seen a case so remarkable. Born at San Francisco's Saint Luke's Hospital three weeks ago, Hubbarb seemed so perfect at birth no one noticed. (Polydactyly is an autosomal dominant trait that was in the father’s family.)