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Chapter 24 Lecture PowerPoint Genetics and genomics Anatomy and Physiology D- 1 Chapter 24 Genetics and Genomics 3 24.1: Introduction • Packaged into our cells are instruction manuals • The manual is the human genome • It is written in the language of the DNA molecules • DNA consists of a sequence of nucleotide building blocks A, g, C, and T • Sequences of DNA that encode particular proteins are called genes • A gene has different forms and can vary from individual to individual • Genetics is the study of the inheritance of characteristics • A genome is a complete set of genetic instructions • Genomics is the field in which the body is studied in terms of multiple, interacting genes 4 Base pair DNA Gene Cell Nucleus Chromosome 5 Chromosome 7 Organs affected in cystic fibrosis Airways Mucus-clogged bronchi and bronchioles. Respiratory infections. (Common) DNA Transcription Liver Blocked small bile ducts impair digestion. (Rare) mRNA Pancreas Blocked ducts prevent release of digestive enzymes, impairing fat digestion. Diabetes is possible. (Common) Translation Intestines Hard stools may block intestines. (Rare) Reproductive tract Cell membrane Absence of ductus deferens. (Common) Cystic fibrosis transmembrane conductance regulator (CFTR) protein Skin Salty sweat. (Common) 6 (a) (b) 24.2: Modes of Inheritance • Genetics has the power of prediction • Knowing how genes are distributed in meiosis and the combinations in which they join at fertilization makes it possible to calculate the probability that a certain trait will appear in the offspring of two particular individuals • These patterns in which genes are transmitted in families are termed modes of inheritance 7 Chromosomes and Genes Come in Pairs • This normal karyotype shows 23 pairs of chromosomes: • Pairs 1-22 are autosomes (they do not determine sex) • Pair 23 are the sex chromosomes Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 2 3 6 7 8 13 14 15 19 4 9 5 11 10 16 20 17 21 Sex chromosomes (female) © SPL/Photo Researchers, Inc. 12 18 22 8 Chromosomes and Genes Come in Pairs • A gene consists of hundreds of nucleotide building blocks and exists in variant forms called alleles that differ in DNA sequence • An individual who has two identical alleles of a particular gene is homozygous for that gene • A person with two different alleles for a gene is heterozygous • The particular combination of gene variants (alleles) in a person’s genome constitutes the genotype • The appearance or health condition of the individual that develops as a result of the ways the genes are expressed is termed the phenotype • Wild type alleles produce mutations 9 Dominant and Recessive Inheritance • For many genes, in heterozygotes, one allele determines the phenotype • Dominant allele masks the phenotype of the recessive allele • Recessive allele is expressed only if in a double dose (homozygous) • Autosomal conditions are carried on a non-sex chromosome • Sex-linked conditions are carried on a sex chromosome • X-linked conditions are carried on the X chromosome • Y-linked conditions are carried on the Y chromosome 10 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. + = wild type allele cf = cystic fibrosis allele • Recessive Inheritance • 3:1 Phenotype • 1:2:1 Genotype + cf + cf Carrier parents For each child conceived: + + + 25% chance unaffected noncarrier cf + cf cf cf 50% chance unaffected carrier 25% chance (cf allele inherited from either affected parent) (a) cf I cf cf cf Joe Mary cf cf 11 II (b) Punnett Square (c) Bill Sue Tina Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Dominant Inheritance • 1:1 Phenotype • 1:1 Genotype + = wild type allele HD = Huntington disease allele + HD Affected parent ++ Unaffected parent For each Individual conceived: 50% chance unaffected 50% chance affected ++ + HD (a) I Dan HD HD Ann HD 12 II (b) Punnett Square (c) Pam Eric Different Dominance Relationships • Most genes exhibit complete dominance or recessiveness • Exceptions are incomplete dominance and codominance Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Plasma cholesterol (milligrams/deciliter) 1000 Homozygotes for FH 900 800 • Heterozygote has a phenotype intermediate between homozygous dominant and homozygous recessive • Familial hypercholesterolemia is an example here 700 600 500 Heterozygotes for FH 400 300 200 General population 100 0 From Genest, Jacques, Jr., Lavoie, Marc-Andre. August 12, 1999. "Images in Clinical Medicine." New England Journal of Medicine, pp 490. ©1999, Massachusetts Medical Society. All Rights Reserved. 13 Different Dominance Relationships: Codominance • Different alleles expressed in a heterozygote are codominant • ABO blood type is an example: • Three alleles of ABO blood typing are IA, IB, I • A person with type A may have the genotype IA i or IA IA • A person with type B may have the genotype IB i or IB IB • A person with type AB must have the genotype IA IB • A person with type O blood must have the genotype ii • There is an exception – see example later with polygenic traits 14 24.1 Clinical Application Genetic Counselors Communicate Modes of Inheritance 15 24.3: Factors That Affect Expression of Single Genes • Most genotypes vary somewhat from person to person, due to the effects of the environment and other genes • Penetrance, expressivity, and pleiotropy describe distinctions of genotype 16 Penetrance and Expressivity • Complete penetrance • Everyone who inherits the disease causing alleles has some symptoms • Incomplete penetrance • Some individuals do not express the phenotype even though they inherit the alleles • An example is polydactyly • Variable expression • Symptoms vary in intensity in different people • For example, two extra digits versus three extra digits in polydactyly 17 Pleiotropy • Pleiotropy • A single genetic disorder producing several symptoms • Marfan syndrome (an autosomal dominant defect) is an example • People affected produce several symptoms that vary 18 Genetic Heterogeneity • Genetic heterogeneity • The same phenotype resulting from the actions of different genes • Hereditary deafness is an example 19 24.4: Multifactorial Traits • Most if not all characteristics and disorders considered “inherited” actually reflect input from the environment as well as genes • Polygenic traits • Determined by more than one gene • Examples include height, skin color, and eye color • Blood type O without genotype ii. Due to homozygous recessive expression of another gene, therefore blood types A and B are not possible – called Bombay phenotype • Multifactorial traits • Traits molded by one or more genes plus environmental factors • Examples include height and skin color • Common diseases such as heart disease, diabetes mellitus, hypertension, and cancers are multifactorial 20 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (a) 21 (b) a: © Library of Congress; b: © Peter Morenus/University of Connecticut at Storrs Frequency Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. aabbcc Aabbcc aaBbcc aabbCc 0 1 AaBbcc AabbCc aaBbCc AAbbcc aaBBcc aabbCC AaBbCc aaBbCC AAbbCc AabbCC AABbcc aaBBCc AaBBcc aaBBCC AAbbCC AABBcc AaBbCC AaBBCc AABbCc 2 3 4 Number of dominant alleles AaBBCC AABbCC AABBCc AABBCC 5 6 22 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. AaBb AB Ab aB ab AABB AABb AaBB AaBb AB Number of Phenotype dominant frequency alleles Ab AABb AAbb AaBb Aabb 1/16 0 4/16 1 6/16 2 4/16 3 1/16 4 Light blue AaBb aB AaBB AaBb aaBB aaBb Deep blue or green Light brown ab AaBb Aabb aaBb aabb Medium brown Dark brown/black 23 24.5: Matters of Sex • Human somatic (nonsex) cells include an X and a Y chromosome in males and two X chromosomes in females • All eggs carry a single X chromosome • Sperm carry either an X or Y chromosome • Sex is determined at conception: a Y-bearing sperm fertilizing an egg conceives a male, and an X-bearing sperm conceives a female 24 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. X Y X-bearing sperm Y-bearing sperm + + X X Egg Egg XX female XY male 25 Sex Determination Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Maleness derives from a Y chromosome gene called SRY • The SRY gene encodes a type of protein called a transcription factor • The SRY activates transcription of genes that direct development of male structures in the embryo, while suppressing formation of female structures SRY gene X chromosome Y chromosome © Biophoto Associates/Photo Researchers, Inc. 26 Genes of the Sex Chromosomes • X chromosome • Has over 1,500 genes • Most genes on the X chromosome do not have corresponding alleles on the Y chromosome • Y chromosome • Has only 231 protein-encoding genes • Some genes are unique only to the Y chromosome 27 Hemophilia • Passed from mother (heterozygote) to son • Each son has a 50% chance of receiving the recessive allele from the mother • Each son with one recessive allele will have the disease • Each son has no allele on the Y chromosome to mask the recessive allele • Each daughter has a 50% chance of receiving the recessive allele from the mother • Each daughter with one recessive allele will be a carrier • Each daughter with one recessive allele does not develop the disease because she has another X chromosome with a dominant allele 28 Gender Effects on Phenotype • Sex-limited trait • Affects a structure or function of the body that is present in only males or only females • Examples are beards or growth of breasts • Sex-influenced inheritance • An allele is dominant in one sex and recessive in the other • Baldness is an example • Heterozygous males are bald but heterozygous females are not 29 24.6: Chromosome Disorders • Deviations from the normal chromosome number of 46 produce syndromes because of the excess or deficit of genes • Chromosome number abnormalities may involve single chromosomes or entire sets of chromosomes • Euploid is a normal chromosome number 30 Polyploidy • Polyploidy • The most drastic upset in chromosome number • This is an entire extra set of chromosomes • Results from formation of a diploid, rather than a normal haploid, gamete • Most embryos or fetuses die, but occasionally an infant survives a few days with many abnormalities 31 Aneuploidy • Aneuploidy • Cells missing a chromosome or having an extra chromosome • Results from meiotic error called nondisjunction • Here a chromosome pair fails to separate, either at the first or at the second meiotic division, producing a sperm or egg that has two copies of a particular chromosome or none, rather than the normal one copy • When a gamete fuses with its mate at fertilization, the resulting zygote has either 47 or 45 chromosomes, instead of 46 • Trisomy is the condition of having an extra chromosome • Monosomy is the condition of missing a chromosome 32 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. A A a a A A a a Primary spermatocyte First division nondisjunction A A a Meiosis I a A Secondary spermatocyte a A a Second division nondisjunction Meiosis II Sperm A a A a A A Euploid Euploid a a Fertilization of euploid egg Zygotes Monosomic (a) Monosomic Trisomic Trisomic (b) Monosomic Trisomic 33 34 24.2 Clinical Application Down Syndrome 35 Prenatal Tests Detect Chromosome Abnormalities Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chorionic villi Uterus Placenta Amniotic membrane Fetus Catheter Rare fetal cells Cervix Fetus 15–16 weeks Vagina (b) Amniocentesis Syringe (a) Chorionic villus sampling (c) Fetal cell sorting 36 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 37 © Bernard Bennot/SPL/Photo Researchers, Inc. 38 24.7: Gene Expression Explains Aspects of Anatomy and Physiology • Gene expression patterns can add to what we know about structure and function of the human body • Identifying which genes are active and inactive in particular cell types, under particular conditions, can add to our understanding of physiology • Gene expression monitors the proteins that a cell produces • The technology used is termed gene expression profiling, and identifying the sets of proteins in a cell is proteomics • DNA microarrays or DNA chips profile gene expression • This is valuable in anatomy and physiology when it allows medical researchers see distinctions their eyes cannot detect 39 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ALL MLL -3σ -2σ -1σ 0 +1σ σ = standard deviation from mean AML +2σ +3σ 40 © S.A. Armstrong et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genetics Vol. 30, Fig. 5, p. 41-47, January 2002 Important Points in Chapter 24: Outcomes to be Assessed 24.1: Introduction Distinguish among genome, gene, and chromosome. Define genetics. Explain how genetic information passes from generation to generation. Explain how the human genome is an economical storehouse of information. 24.2: Modes of Inheritance State the two bases of genetic predictions. Define the two types of chromosomes. Explain the basis of multiple alleles of a gene. 41 Important Points in Chapter 24: Outcomes to be Assessed Distinguish between heterozygous and homozygous; genotype and phenotype; dominant and recessive. Distinguish between autosomal recessive and autosomal dominant inheritance. 24.3: Factors That Affect Expression of Single Genes Explain how and why the same genotype can have different phenotypes among individuals. 24.4: Multifactorial Traits Describe how traits determined by genes and the environment are inherited. 42 Important Points in Chapter 24: Outcomes to be Assessed 24.5: Matters of Sex Describe how and when sex is determined. Explain how X-linked inheritance differs from inheritance of autosomal traits. Discuss factors that affect how phenotypes may differ between the sexes. 24.6: Chromosome Disorders Describe three ways that chromosomes can be abnormal. Explain how prenatal tests provide information about chromosomes. 43 Important Points in Chapter 24: Outcomes to be Assessed 24.7: Gene Expression Explains Aspects of Anatomy and Physiology What type of information does gene expression profiling provide? Explain how a DNA microarray works. 44