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Chapter 6

Chapter 6. DNA Detective Complex Patterns of Inheritance, and DNA Fingerprinting. 0. Real life is a bit more complicated than Mendelian genetics Codominance and incomplete dominance Polygenic traits Sleuthing using genetics Blood typing: who can donate and who can receive???

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Chapter 6

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  1. Chapter 6 DNA DetectiveComplex Patterns of Inheritance, and DNA Fingerprinting 0 • Real life is a bit more complicated than Mendelian genetics • Codominance and incomplete dominance • Polygenic traits • Sleuthing using genetics • Blood typing: who can donate and who can receive??? • Determining disease inheritance and dominance from pedigrees • Using DNA fingerprints to determine genetic identity and relationships

  2. 1 Some notation To quickly describe genotypes we use capitalized or regular letters….. A gene name tyrosinase makes an enzyme that starts converting an amino acid called tyrosine into a brown pigment called eumelanin or red/yellow pigments called pheomelanin. In genetic contexts, we abbreviate the allele that makes the functional enzyme (dominant) as T and the allele that makes a dysfunctional enzyme (recessive) as t. Any notation can be used (eg., ‘Tyr / tyr or C and c, or T+ for wild-type and tm for a mutant) The wild-type homozygous dominant genotype would be written as TT. The heterozygote genotype would be written as Tt The homozygous recessive genotype would be written as tt.

  3. 1 Extensions of Mendelian Genetics Incomplete Dominance is when a heterozygote expresses a phenotype intermediate between both alleles because neither allele is “very strong”. This resembles a heterozygote of recessive alleles For example, RR produces red flowers, Rr produces pink flowers and rr produces white flowers Codominance is when two alleles are expressed at the same time, but either allele can be dominant on its own. ABO blood type is an example of this with both the dominant A and B “types” being expressed in a type AB person. Multiple allelism (or polymorphism) occurs when there are more than two alleles of a gene. One can establish a dominance series of the alleles. Both the red/pink/white flowers and ABO blood types exhibit this.

  4. 1 Extensions of Mendelian Genetics Incomplete Dominance occurs when the phenotype of the heterozygote is blended because neither allele alone is strong enough to control the phenotype Wavy hair Straight hair Curly hair Wavy hair In humans, hair curliness is controlled by the angle in which the hair follicle pushes out hair. Angled follicles have elliptical tubes, and the elliptical tubes produce curlier hair. Wavy hair Curly hair Wavy hair In snapdragons (and roses), red and colorless (white) dye genes combine to make pink flowers, not white flowers or red flowers straight hair Wavy hair The gene controls the follicular angle

  5. 1 Extensions of Mendelian Genetics Hair follicle trivia At least two genes control hair follicle features in humans Orientation of the follicle relative to the skin surface (Indo-Europeans, Africans) Thickness of the follicle (East Asians have thicker) A deeply-curved thinner follicle appears to be the ancestral allele.

  6. 1 Extensions of Mendelian Genetics Codominance is when two alleles that alone could be dominant are coexpressed in heterozygotes IAand IB are codominant to each other; i is recessive to both IAand IB. An individual will have two of these alleles. US Prevalence 17% 25% 4% 9% 1% 44%

  7. 1 Extensions of Mendelian Genetics Codominance is when two alleles that alone could be dominant are coexpressed in heterozygotes • Black and white feather color alleles in chickens are codominant to each other. • A heterozygote individual will express both alleles in a checkered pattern.

  8. 1 Extensions of Mendelian Genetics Multiple allelism (or polymorphism) occurs when there are more than two alleles of a gene. One can establish a dominance series of the alleles. Ex: IA and IB are co-dominant, both are dominant over i (O) Hair color in rodents is controlled by a polymorphic tyrosinase gene

  9. 1 Extensions of Mendelian Genetics Testing for Dominance in an allelic series

  10. 1 Extensions of Mendelian Genetics Intensity of brown hair in humans is an allelic series Darker brown alleles are dominant over lighter brown alleles

  11. 1 Polygenic traits Many easily observable traits are the result of many steps of a long pathway. Three famous examples are skin, hair, and eye color in humans. They are all related very closely! Colored skin (hair, and eyes) is the result of many steps, including. Import of tyrosine into melanocytes Inclusion of tyrosine into melanosomes Synthesis of pheomelanin (reddish) Switch to eumelanin (brown/black) synthesis by melanocyte-stimulating hormone Switch-back to pheomelanin synthesis by agouti-signaling peptide Transport of melanosomes to dendrites Export of melanosomes into tissues Uptake of melanosomes by epithelial cells in skin, hair, or eyes Different genes control each step; mutations in any of these genes can contribute to lighter skin, hair, and eyes

  12. 1 Polygenic traits Different genes control each step of melanin incorporation into skin, hair, or iris epithelial cells! Variations in any of these genes can contribute to lighter skin, hair, or eyes, or even albinism

  13. 1 Becoming a sleuth – blood typing Blood between a donor and a recipient must be matched to prevent rejection of the blood by the immune system, that comes with dangerous consequences (acute hemolytic reaction) Blood type can be used to test familial relationships In addition to ABO compatibility, the next major compatibility must be with another blood group called the Rh factor. The Rh factor is expressed by the functional, dominant allele (Rh+). Those who are Rh(+) have a genotype of either Rh+Rh+ or Rh+Rh-. To be Rh(-), both Rh gene copies must be the nonfunctional, recessive alleles (Rh-). The genotype must be Rh-Rh-. Blood typing can be used to exclude potential parents. E.g., an AB parent can “never” have an O child and two Rh- parents can never have a Rh+ child. (Why? Discover on your own!) See Table 8.2 for compatibilities of blood types.

  14. 1 Becoming a sleuth – blood typing Blood type matching is done by ensuring that the antibodies raised against missing ABO, and Rh antigens in the recipient do not bind to any ABO or Rh antigens in the donor • Example: Who can donate blood to someone who is A-? • (1) A recipient with A- blood will have antibodies against the B and Rh antigens. • (2) The donor must not have the A or Rh antigens • (3) possible donors are A or O blood that is Rh- Whose blood can be donated to anyone (the universal donor)? Whose body can take blood from anyone? (the universal recipient)?

  15. 1 Extensions of Mendelian Genetics Pleiotropy is the ability of a single gene to cause multiple effects on the individual’s phenotype. Albinism is an example of pleiotropy. The inability to convert tyrosine to melanin Eyes lose all color and appear red from blood vessels Hair and skin lose color, and appear white Vision is usually greatly hindered because extra light absorbed by melanin interferes with vision Preponderance to develop melanoma from excess sun exposure due to lost protection from UV damage by melanin

  16. 2 Sex Determination and Sex Linkage Humans have 22 pairs of autosomes and one pair of sex chromosomes Women: two X chromosomes Men: one X and one Y chromosome

  17. 2 Sex Determination and Sex Linkage Sex-linked genes: genes located on the sex chromosomes X-linked: located on the X chromosome Y-linked: located on the Y chromosome SRY gene which leads to the development of the testes Males always inherit their X from their mother Males are more likely to express recessive X-linked traits than females due to carrying only 1 X. Females are less likely to express X-linked traits since they have to have 2 copies of the bad X’s.

  18. 2 Sex Determination and Sex Linkage • Only females can be unafflicted carriers of X-linked recessive traits. • Carriers express the normal trait but are heterozygous, so they carry the allele for the recessive trait. • Hemophilia A and B, red-green color blindness, and Duchenne Muscular dystrophy are examples of X-linked traits. • Because men only need one defective X-linked genes to suffer an X-linked genetic disease, X-linked diseases are far more common in men than in women

  19. Solving the Gene Dosage Problem Let’s solve one quirk of X-linked inheritance… • Dozens of millions of years ago, the X and Y chromosomes were regular autosomes, until the right genes came together, and the Y chromosome became the gender identifier. Thus began the process to eliminate any genes not necessary for male developmental function, limited by the need to still pair with the X chromosome during meiosis. • The now-unpaired genes on the X chromosome in males needed to double their expression to re-balance the original gene dosage level. However, in females, doubling the X-based gene dosage (due to their having two double-strength X chromosomes) will be lethal! • How can this lethality be eliminated? By preventing genes on the second X chromosome from being expressed! This prevention process is called X Chromosome Inactivation (XCI). The inactivation is caused by a noncoding RNA called Xist and chromosome-silencing histone modifications. The inactivated chromosome is “pushed aside” to the periphery of the nucleus and forms what is called a Barr body. Because Barr bodies are large parts of a chromosome, they are easily visible structures at the edge of the nucleus. What keeps Xist off of the active X Chromosome? A transcribed complementary non-coding RNA called Tsix that destroys Xist as a dsRNA

  20. Solving the Gene Dosage Problem Let’s observe three phenomena of random x-inactivation: A female carrier of X-linked hypohidrotic ectodermic dysplasia (HED) has a mosaic pattern of defective or absent sweat glands, hair follicles, fingernails (integumentary system), and teeth • XCI occurs in humans when the embryo reaches the 20-cell stage. All females are therefore mosaics, in which, in all organs, some cells express only the paternal X chromosome (XP), and other cells express only the maternal X chromosome (XM). • This pattern is seen in calico cats: both in female cats and rare (1:3000) male cats with Klinefelter syndrome (XXY). • XCI of two X chromosomes in triple X females (XXX) explains why most of these females are nearly normal. (Be careful with Google searches on this topic) An HED-afflicted boy Littermates. XCI-induced mosaic patterns are not hereditary and occurs randomly in each individual, like a fingerprint A male calico cat. All male calico cats are sterile. Note the differently-colored eyes (remember that eye and hair color are related?)

  21. 2 Sex Determination and Sex Linkage X inactivation guarantees that all females receive only 1 dose of the proteins by the X chromosomes. Inactivation is irreversible and propagated during cell division. It is caused by RNA wrapping around the X chromosome.

  22. When you cannot analyze dozens of children from the same parents Sometimes we need to determine whether a trait or a genetic disease is dominant or recessive when only a few progeny exist, or if progeny are no longer possible. In this case, pedigree analysis and lots of logic are essential. Pedigree: a family tree, showing the inheritance of traits through several generations Commonly used symbols unaffected female, male (could be carrier!) affected female, male known carrier female, male deceased female, male mating between female and a male resulting in n conceptions (here, 2) in order from left to right fraternal, identical twins propositus/proband (first investigated person)

  23. Determining inheritance pattern from a pedigree By analyzing a pedigree, answering certain questions, and understanding the genetics underlying these patterns, one can deduce the pattern of inheritance of most genetic diseases. • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • (Does at least one parent, grandparent, great-grandparent have the disease also?) • Is the disease seen only when carriers in two families come together?

  24. Determining inheritance pattern from a pedigree By analyzing a pedigree, answering certain questions, and understanding the genetics underlying these patterns, one can deduce the pattern of inheritance of most genetic diseases. • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • Is the disease seen only when carriers in two families come together? Y Y Y NN N Y Because there is no gender bias, it is not seen in every generation, and appears when carriers of two families come together, it is autosomal recessive

  25. 3 Pedigrees Pedigree for an autosomal recessive trait:

  26. Let’s determine genotype from a pedigree The mode of inheritance MUST be known (here, autosomal recessive) • Let’s start with: • filled-in shapes must be have a genotype of ‘aa’ (Why?) • unfilled shapes must have a partial genotype of ‘A’ (Why?) • one allele must come from mother and one from the father (Why?) • not every genotype may be able to be determined by logic alone!

  27. Let’s determine genotype from a pedigree The mode of inheritance MUST be known (here, autosomal recessive) • Let’s start with: • filled-in shapes must be have a genotype of ‘aa’ • unfilled shapes must have a partial genotype of ‘A’ • one allele must come from mother and one from the father • not every genotype will be fully determined What is the most likely unknown allele? aa Aa aa A? aa aa Aa aa Aa Aa Aa Aa Aa Aa Aa Aa Aa Aa Aa Aa aa Aa aa Aa aa A? A? aa A?

  28. 3 Pedigrees Pedigrees reveal modes of inheritance Pedigree for an autosomal dominant trait Note that most afflicted individuals are heterozygous. This is not guaranteed to be true though

  29. Determining inheritance pattern from a pedigree • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • Is the disease seen only when carriers in two families come together?

  30. Determining inheritance pattern from a pedigree • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • Is the disease seen only when carriers in two families come together? ?? Y Y N Y N Because there is no gender bias, and it is passed through every generation, it is autosomal dominant (a lot of carriers would need to marry in for this to be autosomal recessive; that possibility is unlucky and thus unlikely)

  31. Let’s determine genotype from a pedigree The mode of inheritance MUST be known (here, autosomal dominant) • Let’s start with: • unfilled shapes must be have a genotype of ‘aa’ (why?) • Filled-in shapes must have a partial genotype of ‘A’ (why?) • one allele must come from mother and one from the father • not every genotype may be able to be determined

  32. Determining inheritance pattern from a pedigree • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • Is the disease seen only when carriers in two families come together?

  33. Determining inheritance pattern from a pedigree • Gender passage: • Can men pass the trait to women? • Can men pass the trait to men? • Can women pass the trait to men? • Are only men affected? Only women? • Is the disease seen in every generation • Is the disease seen only when carriers in two families come together? Y N Y YN N N Because only males are afflicted, and men do not pass it to men, it is X-linked recessive What are the genotypes of the people in the pedigree?

  34. 3 Pedigrees Pedigree for an X-linked trait:

  35. The X-linked recessive disease Hemophilia B propagated within European royal families The mutation probably occurred in her germline. Why not his??? Disease appears to originate here Note the consanguineous marriage and offspring (i.e., inbreeding) that has been common among European royalty for centuries; Fourth generation shows only 3.1% homozygous alleles Prince George Princess Charolette The lineage of George VI is drawn wrong (on purpose) in two areas… do you know where they are?

  36. 3 Pedigrees

  37. Royal Inbreeding • In the British Royal Family, Queen Elizabeth and Prince Philip share two great-great-grandparents (they are third cousins) • In the Russian Rurik dynasty, Dmitri Donskoi and Eudoxia of Nizhniy Novgorod share his father’s parents and her mother’s mother’s parents (Ivan I and Helena): a grandchild and a great-grandchild married each other • The ancestry of Charles II of Spain is…complicated

  38. 4 DNA Fingerprinting No two individuals are genetically identical except for identical twins. Small differences in nucleotide sequences of their DNA This is the basis for DNA fingerprinting Unambiguous identification of people When sample size is small it is necessary to copy the genetic material to increase the quantity available for testing.

  39. 4 DNA Fingerprinting Small amounts of DNA can be amplified using PCR (polymerase chain reaction) DNA is mixed with nucleotides, specific primers, Taq polymerase, and then is heated Heating splits the DNA molecules into two complementary strands Taq polymerase builds a new complementary strand DNA is heated again, splitting the DNA and starting a new cycle.

  40. 4 DNA Fingerprinting Each cycle, the amount of DNA doubles.

  41. 4 DNA Fingerprinting DNA is analyzed two different ways: DNA is cut into fragments using restriction enzymes, which cut at various sites around the genome PCR is performed around regions of the genome that vary highly among members of the population Many areas of the genome vary considerably among individuals around DNA sequences called VNTRs (variable number tandem repeats), a special type of simple sequence repeat (SSR) Combinations of these SSRs/VNTRs around the genome can be used to distinguish among up to 10 trillion potential genomic combinations Restriction enzyme cut sites

  42. 4 DNA Fingerprinting Gel electrophoresisseparates DNA fragments on basis of their sizes Electric current is applied to an agarose gel (resembles a sponge) Smaller fragments run faster through the gel DNA analyzed two different ways: Older way: Fragments are transferred to a sheet of filter paper Labeled probe reveals locations of fragments containing VNTRs Newer way: Differently colored fluorescent primers are used to amplify diferent parts of the genome Sizes of bands are matched up with specific fluorescent color combinations

  43. 4 DNA Fingerprinting Each person’s set of fragments is unique. All of a child’s bands must be present in one or both of the parents.

  44. I can beat Mark Fuhrman/Law and Order Who is the perp? Match up the banding pattern of the crime scene with the banding pattern of the DNA samples You must be sure! Someone’s reputation may be at stake! …a harder one …an easy one

  45. How is DNA now “fingerprinted”? Old technologies are still being used and are fairly inexpensive; however, increased need for rigorous and exacting data require the used of more modern, whole-genome analyses • SSR profiling is the current standard used by the FBI and most police laboratories nationwide, especially after 9/11. • Recall that SSRs change very rapidly from generation to generation • Most humans within a given nationality are separated by at least 20 generations. Some separations between human beings among the planet can be 1000s of generation separated • On average, 10% of people in the population share a given SSR (generational mutations in SSRs cap this number) • PCR-based analysis of a panel of 13 SSRs mixed throughout the 23 chromosomes will allow one to determine an individual almost uniquely, as there will be only a 1:1013 chance that two unrelated individuals will match all 13 SSR patterns (there are only 6x109 humans on the planet!). It is the equivalent of our bar code or our own biological social security number! (or IRSC student number)

  46. Which forensic technique was used to determine the identity of the Romanovs? examining fingerprints ballistic (firearm) evidence DNA fingerprinting toxicology

  47. Which forensic technique was used to determine the identity of the Romanovs? examining fingerprints ballistic (firearm) evidence DNA fingerprinting toxicology

  48. Snapdragon color is an example of incomplete dominance. If you cross a red snapdragon with a white snapdragon, what will the offspring look like? All of the offspring will be red. All of the offspring will be white. All of the offspring will be pink. Half the offspring will be red and half will be white.

  49. Snapdragon color is an example of incomplete dominance. If you cross a red snapdragon with a white snapdragon, what will the offspring look like? All of the offspring will be red. All of the offspring will be white. All of the offspring will be pink. Half the offspring will be red and half will be white.

  50. Coat color of cattle displays codominance. A red coated cattle is bred with a white coated cattle. What color coat will their offspring have? Red coat C. Pink coat White coat D. Red and white coat

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