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1 Pedigree Analysis For researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritance Pedigrees are symbolic.

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Presentation on theme: "1 Pedigree Analysis For researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritance Pedigrees are symbolic."— Presentation transcript:

1 1 Pedigree Analysis For researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritance Pedigrees are symbolic representations of family relationships and the transmission of inherited traits

2 2 Pedigree Analysis Figure 4.15

3 3 An Unusual Pedigree A partial pedigree of Egypt’s Ptolemy Dynasty showing: - Genealogy not traits - Extensive inbreeding Figure 4.16a

4 4 Autosomal Dominant Trait Polydactyly = Extra fingers and/or toes Figure 4.16b

5 5 Autosomal Recessive Trait Albinism = Deficiency in melanin production Figure 4.17

6 6 An Inconclusive Pedigree This pedigree can account for either an autosomal dominant or an autosomal recessive trait Figure 4.18

7 7 Victor McKusick: father of human genetics The new emerging area of genetics is multifactorial in nature and includes common diseases such as: type 2 diabetes, macular degeneration, hypertension, heart disease, cancer, stroke, bipolar, ADHD, autism…all are genetic diseases. These complex genetic traits are multifactorial, common but complex

8 8 Genes, Environment and Traits Few, if any, genes act alone Environmental factors and other genes may modify expression Traits can be described as - Mendelian = Caused by a single gene - Polygenic = Caused by multiple genes Both can be multifactorial or complex due to an interaction between genes and the environment

9 9 Genes, Environment and Traits Single-gene traits are discrete or qualitative - Often produce an “all-or-none” effect Polygenic traits produce a continuously varying phenotype - Also called quantitative traits - DNA sequences involved are termed quantitative trait loci (QTLs)

10 10 Genes, Environment and Traits Figure 7.1

11 11 Polygenic multifactorial Traits Are influenced by interaction of genes and by the environment Examples: - Height - Skin color - Body weight - Fingerprint patterns - Behavioral traits

12 12 multifactorial traits Lung cancer caused by smoking illustrates the compexity of multifactorial traits. Migraines are also multifactorial: chromosome 1 contributes to sensitivity to sound chromosome 5 produces the pulsating headache and sensitivity to light chromosome 8 is asssociated with nausea and vomiting

13 13 Polygenic Traits Individual genes follow Mendel’s laws, but their expression is hard to predict Effect of genes is additive or synergistic - However, input of genes is not necessarily identical The frequency of distribution of phenotypes forms a bell-shaped curve!

14 14 Fingerprint Patterns Dermatoglyphics is the study of fingerprints The number of ridges is largely determined by genes and prenatal contact The average total ridge count is 145 in a male and 126 in a female

15 15 Fingerprint Patterns Figure 7.2

16 16 Height Figure 7.3

17 17 Height The difference in height between the two sets of students is attributed to improved diet and better overall health Genome-wide association studies have identified dozens of genes that affect height - Also, certain SNPs patterns are seen in individuals with periods of rapid height increase

18 18 Skin Color Melanin protects against DNA damage from UV radiation, and exposure to the sun increases melanin synthesis We all have same number of melanocytes per unit area of skin - However, we differ in melanosome number, size and density distribution

19 19 Testing DNA indicates that biologically speaking, it makes more sense to classify people by ancestry rather than by the color of their skin. Offering medical treatments based on skin color may make sense on a population level, but on the individual level it may lead to errors.

20 20 A white person might be denied a drug that would work, or a black person given one that doesn’t if treatment is based on a superficial trait not related to how the body responds t a particular drug.

21 21 Skin Color Figure 7.4

22 22 Skin Color The definition of race based largely on skin color is a social construct more than a biological concept Skin color is NOT a reliable indicator of ancestry - Overall, 93% of varying inherited traits are no more common in people of one skin color than any other

23 23 Investigating Multifactorial Traits Cleft lip is more likely in a person who has a relative with the condition Figure 7.5

24 24 Investigating Multifactorial Traits

25 25 Heritability (H) Estimates the proportion of the phenotypic variation in a population due to genetic differences Figure 7.6

26 26 Heritability (H)

27 27 Heritability (H) Researchers use several statistical methods to estimate heritability One way is to compare the proportion of people sharing a trait to the proportion predicted to share the trait The expected proportion is derived by knowing the blood relationships of the individuals

28 28 Coefficients of Relatedness The proportion of genes shared between two people related in a certain way

29 29 Tracing Relatives Figure 7.7

30 30 Adopted Individuals Similarities between adopted people and adopted parents reflect mostly environmental influences Similarities between adoptees and their biological parents reflect mostly genetic influences Therefore, information on both sets of parents can reveal how heredity and the environment both contribute to a trait

31 31 Twins Twin studies have largely replaced adoption methods Concordance measures the frequency of expression of a trait in both members of monozygotic (MZ) or dizygotic (DZ) twins - Twins who differ in a trait are said to be discordant for it For a trait largely determined by genes, concordance is higher for MZ than DZ twins

32 32 Twins

33 33 Separating Genetic and Environmental Influences Dizygotic twins = Shared environment and 50% of genes Monozygotic twins = Identical genotype and shared environment Twins raised apart = Shared genotype but not environment Adopted individuals = Shared environment but not genes

34 34 Twins Figure 7.8

35 35 Genome-Wide Association Studies Older techniques search for known gene variants, typically in only a few people Sequencing of the human genome and the HapMap project (which identifies SNPs) have led to a new tool Genome-wide association studies seek correlations between SNP patterns and phenotypes in large groups of individuals

36 36 Genome-wide association studies seek SNPs that are shared with much greater frequency among individuals with the same trait than among others Figure 7.9

37 37 If SNP always occurs in individuals who share a specific trait, then it may do so because it lies in or near a gene that does cause the trait.

38 38 SNPs SNPs (single nucleotide polymorphisms) are sites in a genome where the DNA base varies in at least 1% of the population In these studies, SNPs span the genome, rather than define a single gene - A SNP can be anywhere among our roughly 3.2 billion base pairs

39 39 SNPs Figure 7.10

40 40 A Step-wise Approach to Gene Discovery Figure 7.11

41 41 Study Designs In a cohort study, researchers follow a large group of individuals over time and measure many aspects of their health In a case-control study, pairs of individuals are matched so that they share as many characteristics as possible - SNP differences are then associated with the presence or absence of the disorder

42 42 Study Designs The “affected sibling pair” strategy scans genomes of siblings for SNPs shared by those with the condition, but not by those who don’t have it Homozygosity mapping is performed on families that are consaguineous ( inbreed) - The children in this case are more likely to inherit two copies of the mutation

43 43

44 44 Limitations of Genome-Wide Association Studies 1)They include so many data points and so are prone to error 2)They reveal associations between two types of information, not causes 3)Bias can be introduced in the way the patient population is selected 4)Their accuracy is affected by complicating factors, such as phenocopy and epistasis 5) They may miss extremely rare SNPs

45 45

46 46 Body Weight Body weight is a multifactorial trait that reflects energy balance About 30% of all adults in the US are obese, and another 35% are overweight Scientific studies use a measurement called body mass index (BMI) = weight (kg)/height 2 (m 2 )

47 47 Body Mass Index (BMI) Figure 7.12

48 48 Figure 2.3 BMI Animation Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at

49 49 Body Weight Studies on adopted individuals and twins indicate a heritability of 75% for obesity Lifestyle, including diet and exercise, are environmental components impacting weight Genes influence hunger and metabolism

50 50 Multiple Alleles An individual carries two alleles for each autosomal gene However, a gene can have multiple alleles because its sequence can deviate in many ways Different allele combinations can produce variations in the phenotype - PKU gene has hundreds of alleles resulting in four basic phenotypes - CF gene has over 1500 alleles

51 51 Incomplete Dominance The heterozygous phenotype is between those of the two homozygotes Example: Familial hypercholesterolemia (FH) - A heterozygote has approximately half the normal number of receptors in the liver for LDL cholesterol - A homozygous for the mutant allele totally lacks the receptor, and so their serum cholesterol level is very high

52 52 Incomplete Dominance Figure 5.2

53 53 Blood problems 1900 Karl Landsteiner’s Observations lead to the ABO blood typing due to antigen-antibody reactions

54 54 Agglutinins Aggutinogens (antibodies) (anti-antibodies) A may be A/A or A/O B A B may be B/B or B/O A B AB is A/B none AB (universal donar) O is O/O A, B none ( universal donar)

55 55 Codominance The heterozygous phenotype results from the expression of both alleles The ABO gene encodes a cell surface protein - I A allele produces A antigen - I B allele produces B antigen - i (I O ) allele does not produce antigens Alleles I A and I B are codominant, and both are completely dominant to i

56 56 Figure 5.3

57 57 Figure 5.4 Offspring from Parents with Blood Type A and Blood Type B Figure 5.4

58 58 Bombay phenotype. In 1952 a very unusual situation provided information concerning the genetic basis of H substance. A woman in Bombay displayed a unique genetic history that was inconsistent with her blood type. In need of a transfusion, she was found to lack both the A and B antigens and was thus typed as O. However, it was shown that one of her parents was type AB, and she had donated a B allele to two of offsprings…thus, she was genetically type B, but functionally type O. The Bombay woman was shown to be homozygous for a rare recessive mutation, h which prevented her from synthesizing the complete H substance…thus was functionally type O People with this condition are thus to distinguished as having Bombay phenotype.

59 59 Epistasis The phenomenon where one gene affects the expression of a second gene Example: Bombay phenotype - The H gene is epistatic to the I gene - H protein places a molecule at the cell surface to which the A or B antigens are attached - hh genotype = no H protein - Without H protein the A or B antigens can not be attached to the surface of the RBC - All hh genotypes have the phenotype of type O, although the ABO blood group can be anything (A, B, AB, or O)

60 60 MN blood groups Genotype to Phenotype Individuals who inherit two N alleles have blood group N. Individuals who are homozygous for the M allele have blood group M.homozygous HeterozygousHeterozygous individuals produce both proteins and have blood group MN.

61 61 Rh Antigen: In 1939 Levine and Stetson, and in 1940 Landsteiner and Weiner made observations which laid the foundations of our knowledge about the remaining major blood group - the Rhesus system. Once reliable tests for Rhesus grouping had been established, transfusion reactions became rare

62 62 Rh Antigens Another set of antigens that was discovered by about 1940 Can cause the disorder erythroblastosis fetalis also referred to as hemolytic disease of newborns, it is a form of anemia. This condition occurs if an Rh- positive fetus whose mother is Rh-negative and whose father is Rh-positive, contributing that allele to the fetus.

63 63 Blood types Consequently, we each belong to one of 8 different blood groups Within the ABO system people can be one of four types - 0, A, B or AB, whilst in the Rh system they can be either Rh positive or Rh 85% population is Rh positive 15% population is Rh negative

64 64 PROBLEM: A man is suing his wife for divorce on the grounds of infidelity. Their first child and second child, whom they both claim, are blood groups O and AB, respectively. The third child, whom the man disclaims, is blood type B. Can this information be used to support the man’s case? Another test was made in the M-N blood group system. The third child was group M, the man was group N. Can this information be used to support the man’s case?

65 65 Rabbit coat color  In rabbits the ordinary ( wild type) color is called agouti ( banded hairs with gray at base then yellow then black tip)  Albino lack pigment  Then there is chinchilla ( black gray color) and himalayan ( white with black extremities)

66 66 Rabbit coat color Phenotype: Genotype Agouti c + c +, c + c ch, c + c h, c + c Chinchilla c ch c ch,c ch c h, c ch c Himalayan c h c h, c h c Albino cc DO SOME BOARD PROBLEMS ch

67 67 S antigens and Sectetors Closely related to MN antigens S = SS or Ss S = ss Ex MS/Ns x NS/NS F1 ½ MS/NS ½ Ns/NS Secretors release antigens in body secretions ex eyes, noses ect. 78% population are secretors Secretor: HH or Hh Non secretor: hh Secretors


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