Presentation on theme: "Pedigree Analysis For researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritance Pedigrees are symbolic representations."— Presentation transcript:
1 Pedigree AnalysisFor researchers, families are tools; the bigger the family, the easier it is to discern modes of inheritancePedigrees are symbolic representations of family relationships and the transmission of inherited traits1
6 An Inconclusive Pedigree This pedigree can account for either an autosomal dominant or an autosomal recessive traitFigure 4.186
7 Multifactorial traits Victor McKusick: father of human geneticsThe 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 Genes, Environment and Traits Few, if any, genes act aloneEnvironmental factors and other genes may modify expressionTraits can be described as- Mendelian = Caused by a single gene- Polygenic = Caused by multiple genesBoth can be multifactorial or complex due to an interaction between genes and the environment8
9 Genes, Environment and Traits Single-gene traits are discrete or qualitative- Often produce an “all-or-none” effectPolygenic traits produce a continuously varying phenotype- Also called quantitative traits- DNA sequences involved are termed quantitative trait loci (QTLs)9
11 Polygenic multifactorial Traits Are influenced by interaction of genes and by the environmentExamples:- Height- Skin color- Body weight- Fingerprint patterns- Behavioral traits11
12 multifactorial traits Lung cancer caused by smoking illustrates the compexity of multifactorial traits.Migraines are also multifactorial:chromosome 1 contributes to sensitivity to soundchromosome 5 produces the pulsating headache and sensitivity to lightchromosome 8 is asssociated with nausea and vomiting
13 Polygenic TraitsIndividual genes follow Mendel’s laws, but their expression is hard to predictEffect of genes is additive or synergistic- However, input of genes is not necessarily identicalThe frequency of distribution of phenotypes forms a bell-shaped curve!13
14 Fingerprint Patterns Dermatoglyphics is the study of fingerprints The number of ridges is largely determined by genes and prenatal contactThe average total ridge count is 145 in a male and 126 in a female14
17 HeightThe difference in height between the two sets of students is attributed to improved diet and better overall healthGenome-wide association studies have identified dozens of genes that affect height- Also, certain SNPs patterns are seen in individuals with periods of rapid height increase17
18 Skin ColorMelanin protects against DNA damage from UV radiation, and exposure to the sun increases melanin synthesisWe all have same number of melanocytes per unit area of skin- However, we differ in melanosome number, size and density distribution18
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 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.
22 Skin ColorThe definition of race based largely on skin color is a social construct more than a biological conceptSkin 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 other22
23 Investigating Multifactorial Traits Cleft lip is more likely in a person who has a relative with the conditionFigure 7.523
27 Heritability (H)Researchers use several statistical methods to estimate heritabilityOne way is to compare the proportion of people sharing a trait to the proportion predicted to share the traitThe expected proportion is derived by knowing the blood relationships of the individuals27
28 Coefficients of Relatedness The proportion of genes shared between two people related in a certain way28
30 Adopted IndividualsSimilarities between adopted people and adopted parents reflect mostly environmental influencesSimilarities between adoptees and their biological parents reflect mostly genetic influencesTherefore, information on both sets of parents can reveal how heredity and the environment both contribute to a trait30
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 itFor a trait largely determined by genes, concordance is higher for MZ than DZ twins31
33 Separating Genetic and Environmental Influences Dizygotic twins = Shared environment and 50% of genesMonozygotic twins = Identical genotype and shared environmentTwins raised apart = Shared genotype but not environmentAdopted individuals = Shared environment but not genes33
35 Genome-Wide Association Studies Older techniques search for known gene variants, typically in only a few peopleSequencing of the human genome and the HapMap project (which identifies SNPs) have led to a new toolGenome-wide association studies seek correlations between SNP patterns and phenotypes in large groups of individuals35
36 Genome-wide association studies seek SNPs that are shared with much greater frequency among individuals with the same trait than among othersFigure 7.936
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 SNPsSNPs (single nucleotide polymorphisms) are sites in a genome where the DNA base varies in at least 1% of the populationIn these studies, SNPs span the genome, rather than define a single gene- A SNP can be anywhere among our roughly 3.2 billion base pairs38
40 A Step-wise Approach to Gene Discovery Figure 7.1140
41 Study DesignsIn a cohort study, researchers follow a large group of individuals over time and measure many aspects of their healthIn 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 disorder41
42 Study DesignsThe “affected sibling pair” strategy scans genomes of siblings for SNPs shared by those with the condition, but not by those who don’t have itHomozygosity mapping is performed on families that are consaguineous ( inbreed)- The children in this case are more likely to inherit two copies of the mutation42
44 Limitations of Genome-Wide Association Studies 1) They include so many data points and so are prone to error2) They reveal associations between two types of information, not causes3) Bias can be introduced in the way the patient population is selected4) Their accuracy is affected by complicating factors, such as phenocopy and epistasis5) They may miss extremely rare SNPs44
46 Body WeightBody weight is a multifactorial trait that reflects energy balanceAbout 30% of all adults in the US are obese, and another 35% are overweightScientific studies use a measurement called body mass index (BMI)= weight (kg)/height2 (m2)46
48 BMI AnimationPlease 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 atFigure 2.3
49 Body WeightStudies on adopted individuals and twins indicate a heritability of 75% for obesityLifestyle, including diet and exercise, are environmental components impacting weightGenes influence hunger and metabolism49
50 Multiple AllelesAn individual carries two alleles for each autosomal geneHowever, a gene can have multiple alleles because its sequence can deviate in many waysDifferent allele combinations can produce variations in the phenotype- PKU gene has hundreds of alleles resulting in four basic phenotypes- CF gene has over 1500 alleles50
51 Incomplete DominanceThe heterozygous phenotype is between those of the two homozygotesExample: 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 high51
53 Blood problems1900 Karl Landsteiner’s Observations lead to the ABO blood typing due to antigen-antibody reactions
54 Agglutinins Aggutinogens (antibodies) (anti-antibodies)A may be A/A or A/O B AB may be B/B or B/O A BAB is A/B none AB (universal donar)O is O/O A, B none( universal donar)
55 CodominanceThe heterozygous phenotype results from the expression of both allelesThe ABO gene encodes a cell surface protein- IA allele produces A antigen- IB allele produces B antigen- i (IO) allele does not produce antigensAlleles IA and IB are codominant, and both are completely dominant to i55
57 Offspring from Parents with Blood Type A and Blood Type B Figure 5.4Figure 5.4
58 Bombay phenotype.In 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 OPeople with this condition are thus to distinguished as having Bombay phenotype.
59 EpistasisThe phenomenon where one gene affects the expression of a second geneExample: 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)59
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.Heterozygous individuals produce both proteins and have blood group MN.
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 Rh AntigensAnother 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 Blood typesConsequently, 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 Rh85% population is Rh positive15% population is Rh negative
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.
65 Rabbit coat colorIn rabbits the ordinary ( wild type) color is called agouti ( banded hairs with gray at base then yellow then black tip)Albino lack pigmentThen there is chinchilla ( black gray color) and himalayan ( white with black extremities)
67 S antigens and Sectetors Closely related to MN antigensS = SS or SsS = ssEx MS/Ns x NS/NSF1 ½ MS/NS ½ Ns/NSSecretors release antigens in body secretions ex eyes, noses ect.78% population are secretorsSecretor: HH or HhNon secretor: hhSecretors
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