03BIS1012012XLinkLect3

03BIS1012012XLinkLect3 - BIS101-001 Genes and Gene...

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Unformatted text preview: BIS101-001 Genes and Gene Expression X-Linkage, Pedigree Analysis and Non-disjunction (Lecture #3: Chapters 3, 4) March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 1 Last Lecture: The Study of Biological Information Mendel's 1st and 2nd Laws of Inheritance. Definitions Using crosses to infer the nature of inheritance. Test Crosses and recessive traits Mitosis and Meiosis. Mendelian inheritance and Chromosome Theory Cell cycle and chromosome replication Product and Sum Rules Application of Product and Sum Rules in genetic crosses. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 2 This Lecture: Mendel and Chromosomes Chromosomes are single strands of DNA packed with histone proteins into highly organized structures. Morgan and coworkers prove that genes are on chromosomes by showing that the eye color gene is linked to sex determining chromosomes. The "attached X" mutant provides cytological evidence in support of the Chromosome Theory. X-linked Inheritance provides insight into sex determination and well known genetics diseases. Basic pedigree analysis can reveal genotype. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 3 Definitions Bivalents: Homologous pairs of chromosomes seen in the pachytene stage of prophase I of meiosis. Chiasmata: The visible crossover structures commonly observed between nonsister chromatids during the diplotene stage of meiosis. Centromeres: A specialized region of the chromosome (usually constricted) where spindle fibers attach during mitosis and meiosis. Chromatids: Two daughter strands of the same duplicated chromosome joined together at the centromeree. Upon division of the centromeree in Anaphase II, the sister chromatids separate. Haplosufficient:In heterozygotes, if the single wild type allele is sufficient to produce the wild type phenotype (haplosufficient), then the mutation is recessive. If the single wild type allele is not sufficient for the wild type phenotype (haplo-insufficient), then the loss-of-function mutation is dominant Hemizygous: A single dose of a gene. One allele of the gene is missing either because it has been deleted from one member of the chromosome pair or because it is located on the X chromosome of a XY heterogametic organism. Kinetichore: A complex of DNA and protein at the centromeree to which spindle fibers attach. Meiocyte: A cell that is destined to become a gamete (sperm or egg). Also called germline cell. Monad: A haploid (1N) product of Telophase II of meiosis is destine to become a gamete. Pachytene Arrest: A temporary block between the pachytene and diplotene phase of prophase I. In human females this arrest occurs during fetal development and is not removed until the adult female ovulates. The purpose for this is to allow time to build up reserves in the egg. Somatic Cell: Any diploid cell that does not lead to a germline cell. Telomere: Highly repetitive DNA at the end of a chromosome, which functions as an aglet. Every time linear eukaryotic chromosomes are replicated, the DNA polymerase complex stops several hundred bases before the end. if it were not for telomeres, this would quickly result in the loss of useful genetic information. In prokaryotes, chromosomes are circular and thus do not have ends to suffer premature replication termination at. Only eukaryotes possess or require telomeres. Wild Type: The naturally occurring phenotype of an allele (eg., round peas, red-eyed fruit flies) compared to a variant, non-wild type or mutant allele that expresses a different phenotype. BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 4 March 19, 2012 A Review of General Chromosome Structure March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 5 Acrocentric Metaphase Chromosome Structure centromere "p" "q" telomere March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 6 Chromatin Structure March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 7 Chromatin Structure Movie March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 8 Sex Linkage The topic of sex-linkage (or the linkage of characters or genes to sex-determining chromosomes) illustrates three important concepts in genetics: Sex-linkage experiments performed by Morgan and associates in 1910, provide experimental evidence for the Chromosome Theory of Inheritance and the concept that genes are linked to chromosomes. Sex-linkage introduces the concept of distinct chromosomes associated with sex determination. Sex-linkage provides some of the best examples of genetically inherited diseases in man (e.g., hemophilia). March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 9 Morgan's Drosophila Experiments In 1910, Thomas H. Morgan, a zoologist at Columbia University, began re-examining Mendel's experiments using a new experimental system called Drosophila melanogaster (the fruit fly, a member of the order Diptera). March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 10 Biology of Drosophila Males and females are morphologically distinct 2N = 8 X and Y sex chromosomes Female the homogametic sex Males the heterogametic sex March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 11 Morgan's Red Eye - White Eye Crosses A spontaneous white-eyed mutant was found and bred to produce male and female mating stocks. Because white eyes are recessive to red, they were designated (w). WW ww March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 12 Morgan's Red Eye - White Eye Crosses Morgan performed the typical Mendelian monohybrid cross between a redeyed female (WW) and a white-eyed male (ww) and obtained the expected ratios in the F1 and F2 progeny (all red eyes in the F1 and 3:1 red to white in F2. WW female Parents ww male March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 13 Reciprocal Monohybrid Cross Mendel got the same F1 phenotypes whether the purple trait comes from pollen (male) or female (ovule) flower parts. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 14 Morgan's Exceptions to Mendel's 1st Law However, when Morgan performed a reciprocal cross, white-eyed female (ww) to red-eyed males (WW), he observed the first of two exceptions to Mendel's laws. First, eye-color in the F1 was divided by sex, females were red-eyed and the males were white-eyed. Second, instead of a 3:1 ratio of red to white eyes in the F2, a 1:1 ratio was observed. Parents ww female WW male March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 15 Morgan's X-linked-Hemizygous Hypothesis From these results, Morgan hypothesized: q The gene for eye-color in Drosophila is on the chromosome that determines femaleness (X). In the case of males, only one copy of the eye color gene is present. This is called "hemizygous." q Although Morgan was originally a critic of the chromosome theory, his experiments with eye-color in Drosophila provided some of the first evidence in support of the Chromosome Theory of Inheritance. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 16 Morgan's Interpretation of Reciprocal Cross March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 17 Attached X Experiments However, this was genetic evidence. Cytological evidence was needed to convince the scientific community that genes were on chromosomes. This evidence was provided by Morgan's wife, Mary and his graduate student, Calvin Bridges, who were working with a special mutant of Drosophila called "attached X." In the oocytes of these flies, the two X chromosomes could be seen to be connected at their ends. As a result, the X-linked traits of the mother (e.g., white eyes) were always passed on to the daughter (never to the son. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 18 Morgan/Bridges Attached X Experiment In reciprocal experiments using "attached X mutants, the eye color gene is always passed from the mother to the daughter but never to the son. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 19 Human Color Blindness -- X Linked A number of traits and diseases are linked to the X chromosome in humans. One example is red/green color blindness, a recessive trait. Approximately 8% of all males experience one of two forms of color blindness. With protanopia (25% of all color blind males) red and green are seen as green. With deuteranopia, (75% of all color blind males) red and green are seen as red. Color-blind Color-blind Color-blind Color-blind Color-blind Color-blind Colorblind Colorblind All sons, color-blind March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 20 Well-Known Single Gene Disorders Disease Thalassemia (Chr. 11 or 16, rec.) Sickle-Cell Anemia (Chr. 11, rec) Effect Defect in alpha or beta hemoglobin genes Abnormal hemoglobin shape, Malaria resistance Defective Cell membrane protein; excessive mucus, respiratory disease Missing enzyme resulting in build up of fatty deposits in the brain, MR Defective phenylalanine hydroxylase, blocks conversion of phenylalanine to tyrosine, MR Deficiency in galactose-1-phosphate uridyltransferase (GALT) leading to galactose build-up, MR Defective tyrosinase blocks conversion of tyrosine to DOPA in the pathway to melanin in eyes, hair and skin Missing protein that causes cholesterol buildup, early heart attacks Progress mental and neurological Damage and disorders by 40 Frequency 1/10 Italians 1/625 African Americans Cystic Fibrosis (Chr. 7, rec.) Tay Sachs (Chr. 15, rec.) 1/3000 White Americans 1/3300 E. Eur. Jews Phenylketonuria (PKU) (Chr. 12, rec.) 1/10,000 White Americans Galactosemia (Chr.9, rec.) 1/80,000 Albinism (Chr. 11, rec.) 1/10,000 in Northern Ireland Hypercholesterolemia (Chr. 19, dom.) 1/122 French Canadians Huntington disease (Chr. 4, dom.) 1/25,000 White Americans March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 21 The X-Chromosome X chromosome sequenced and reported in Nature on March 17, 2005. 1098 genes. Y chromosome sequenced and reported in Nature on June 19, 2003. 78 genes. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 22 X-Linked Inheritance Examples of X-Linked Disease in Humans Disease Anhidrotic ectodermal dysplasia (recessive) Duchenne muscular distrophy (recessive) Fragile-X Syndrome (recessive) Familial Hypophosatemia (dominant) Hemophilia A and B (recessive) Testicular Feminization (recessive) Frequency 7 in 10,000 1 in 3000 or 4000 1 in 1000 1 in 20,000 1 in 10,000 1 in 65,000 male births Symptom No sweat glands Muscular wastage in teenage years Mental retardation vitamin D resistant rickets Lack of blood clotting after trauma Lack of androgen receptors in males March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 23 Y-Linked Inheritance There seem to be few genes that have been linked to the human Y chromosome. Testis determining factor "TDF" and "Hairy ear" are two examples. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 24 Pedigree Analysis Because humans can not be bred like fruit flies, mice and flowers, geneticists must resort to analyzing the descendants of the affected individual to determine the genetic basis of certain traits and diseases. Over the years, geneticists and genetic counselors have developed symbols and a list of common characteristics of X-linked traits used for pedigree analysis. These symbols are shown on page 51 of your text and on handout accompanying this lecture. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 25 Pedigree Analysis (p.51) A pedigree is a diagram of family relationships that uses symbols to represent people and lines to represent genetic relationships. These diagrams make it easier to visualize relationships within families, particularly large extended families. Pedigrees are often used to determine the mode of inheritance (dominant, recessive, etc.) of genetic diseases. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 26 Pedigree Symbols (p.51) The "propositus" (also known as the "proband") is a male who first exhibits a medical condition (e.g, color blindness) in the family. The feminine of propositus is "proposita". Genetic counselors try to establish the proband as part of the pedigree analysis. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 27 General Characteristics of X-Linked Inheritance The simple rules provided in your text will help in evaluating these pedigrees. These rules are summarized below. Sex linked traits sometimes show a "cris-cross" pattern of inheritance because fathers pass the trait through the unaffected daughter, who in turn, passes it on to her affected sons. Reciprocal crosses resulting in different phenotypic ratios in the sexes often indicate X-linkage. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 28 Characteristics of X-linked Recessive Traits 1. Males are mostly affected because of the hemizygous condition. 2. Affected males result from mothers who are carriers (heterozygous) of the X-linked trait. 3. Approximately half of the sons of a carrier female should be affected. 4. The sons of affected females must be affected. 5. Affected females come from affected fathers and carrier mothers. 6. Males that are not affected carry the wild-type allele in their X chromosome. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 29 Characteristics of X-linked Dominant Traits The trait does not skip generations. Affected males must come from affected mothers. Approximately half of the children of an affected female are affected. Affected females come from affected mothers or fathers. An affected father passes the trait to all his daughters, but none of the sons. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 30 Examples of X-Linked Pedigrees X-Linked Recessive X-Linked Dominant (affected male) X-Linked Dominant (affected female) March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 31 Queen Victoria: a carrier for Hemophilia A March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 32 Hemophilia A Pedigree (Criss-Cross Inheritance March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 33 Hemophilia A (Recombinant Factor VIII) March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 34 Pedigree Analysis Pedigree of rare recessive trait (a). Propositus (or proband) is IV.2. Unrelated individuals are assumed to be non-carriers. Note the union of III.5 and III.6. The proband is the individual who first draws medical attention to a family . March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 35 Pedigree Analysis The absence of "crisscross" inheritance and the presence of an affected male and affected female in IV, suggest that this is not a X-linked recessive trait but rather a autosomal recessive trait (a). The propositus is IV.2. Unrelated individuals are assumed to be noncarriers. It is not possible to assign a complete genotypes to some normal looking individuals. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 36 This Lecture: Mendel and Chromosomes Chromosomes are single strands of DNA packed with histone proteins into highly organized structures. Morgan and coworkers prove that genes are on chromosomes by showing that the eye color gene is linked to sex determining chromosomes. The "attached X" mutant provides cytological evidence in support of the Chromosome Theory. X-linked Inheritance provides insight into sex determination and well known genetics diseases. Basic pedigree analysis can reveal genotype. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 37 ...
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