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More Genetics! Extensions: Going beyond Mendel… X-Linked Alleles Genes carried on autosomes are said to be autosomally linked Genes carried on the female sex chromosome (X) are said to be X-linked (or sex-linked) X-linked genes have a different pattern of inheritance than autosomal genes have The Y chromosome is blank for these genes Recessive alleles on X chromosome: Follow familiar dominant/recessive rules in females (XX) Are always expressed in males (XY), whether dominant or recessive Males said to be monozygous for X-linked genes Sex-Linked Trait If a gene is found only on the X chromosome and not the Y chromosome, it is said to be a sex-linked or X-linked trait. Because the gene controlling the trait is located on the sex chromosome, sex linkage is linked to the gender of the individual. Usually such genes are found on the X chromosome. The Y chromosome is thus missing such genes. Females will have two copies of the sex-linked gene while males will only have one copy of this gene. If the gene is recessive, then males only need one such recessive gene to have a sex-linked trait rather than the customary two recessive genes for traits that are not sex-linked. This is why males exhibit some traits more frequently than females. Sex-Linked Traits (X-linked Traits) The chromosomes that determine gender. Males XY Females XX Because the X chromosome contains many more genes than the Y chromosome, males are more likely to express any mistake that may be on the X chromosome. Red-green color blindness Hemophilia Duchenne muscular dystrophy Drosophila Chromosomes Eye Color in Fruit Flies Fruit flies (Drosophila melanogaster) are common subjects for genetics research They normally (wild-type) have red eyes A mutant recessive allele of a gene on the X chromosome can cause white eyes Possible combinations of genotype and phenotype: XR XR XR Xr XrXr XR Y Xr Y Genotype Homozygous Dominant Heterozygous Homozygous Recessive Monozygous Dominant Monozygous Recessive Phenotype Female Red-eyed Female Red-eyed Female White-eyed Male Red-eyed Male White-eyed X-Linked Inheritance Human X-Linked Disorders: Red-Green Color Blindness Color vision In humans: Depends three different classes of cone cells in the retina Only one type of pigment is present in each class of cone cell The gene for blue-sensitive is autosomal The red-sensitive and green-sensitive genes are on the X chromosome Mutations in X-linked genes cause RG color blindness: All males with mutation (XbY) are colorblind Only homozygous mutant females (XbXb) are colorblind Heterozygous females (XBXb) are asymptomatic carriers Red-Green Colorblindness Chart X-Linked Recessive Pedigree Human X-Linked Disorders: Muscular Dystrophy Muscle cells operate by release and rapid sequestering of calcium Protein dystrophin required to keep calcium sequestered Dystrophin production depends on X-linked gene A defective allele (when unopposed) causes absence of dystrophin Allows calcium to leak into muscle cells Causes muscular dystrophy All sufferers male Defective gene always unopposed in males Males die before fathering potentially homozygous recessive daughters Human X-Linked Disorders: Hemophilia “Bleeder’s Disease” Blood of affected person either refuses to clot or clots too slowly Hemophilia A – due to lack of clotting factor IX Hemophilia B – due to lack of clotting factor VIII Most victims male, receiving the defective allele from carrier mother Bleed to death from simple bruises, etc. Factor VIII now available via biotechnology Human X-Linked Disorders: Fragile X Syndrome Due to base-triplet repeats in a gene on the X chromosome CGG repeated many times 6-50 repeats – asymptomatic 230-2,000 repeats – growth distortions and mental retardation Inheritance pattern is complex and unpredictable Additional Terminology Pleiotropy Codominance A gene that affects more than one characteristic of an individual Sickle-cell (incomplete dominance) More than one allele is fully expressed ABO blood type (multiple allelic traits) Epistasis A gene at one locus interferes with the expression of a gene at a different locus Human skin color (polygenic inheritance) Incomplete Dominance The phenotype of a heterozygote (CRCW) is intermediate between the phenotypes of the two types of homozygotes (CRCR and CWCW). In incomplete dominance there will be three phenotypes, one for each possible combination, not two as in a typical dominant/recessive situation! Incomplete Dominance Example of incomplete dominance: Snapdragons! Figure 11.14 Assessment of dominance depends on the level of analysis! A heterozygote may display a dominant phenotype at the organismal level, but at a biochemical level may show incomplete dominance. Tay-Sachs disease: caused by absence of an enzyme, hexosaminidase A (Hex-A) Homozygous dominant: normal levels of Hex-A, normal development of child Homozygous recessive: no Hex-A, death of child by age 5 Heterozygote:1/2 normal levels of Hex-A, normal development of child Assessment of dominance depends on the level of analysis! Survival die live Complete Dominance HexA+/ HexA+ HexA+/ HexA- HexA-/ HexATay-Sachs live Amount of hexaminidase die HexA+/ HexA+ HexA+/ HexA- HexA- codes for a nonfunctional enzyme. Incomplete Dominance HexA-/ HexATay-Sachs Co-Dominance describes a relationship where the distinct phenotypes caused by each allele are both seen when both alleles are present. Ex. Blood Type (also shows multiple alleles) Sickle Cell Anemia Sickle Cell Anemia RBCs sickle shaped Anemia Pain Stroke Leg ulcers Jaundice Gall stones Spleen, kidney & lungs Blood cells Sickle cell anemia http://www.netwellness.org/ency/imagepages/1223.htm Blood smear (normal) http://137.222.110.150/calnet/cellbio/cellbio.htm Sickle Cell Anemia Normal red blood cells People with sickle cell conditions make a different form of hemoglobin A called hemoglobin S (S stands for sickle). Hemoglobin S red blood cells do not live as long as normal red blood cells (normally about 16 days) become stiff, distorted in shape and have difficulty passing through the body’s small blood vessels. When sickle-shaped cells block small blood vessels, less blood can reach that part of the body. Tissue that does not receive a normal blood flow eventually becomes damaged. This is what causes the complications of sickle cell disease. Normal hemoglobin: AA Sickle Cell Trait: AS contain hemoglobin A are soft and round and can squeeze through tiny blood tubes (vessels) live for about 120 days before new ones replace them Sickle Cell trait (AS) both hemoglobin A and S are produced in the red blood cells. People with sickle cell trait are generally healthy. Sickle Cell Disease: SS Multiple Alleles Genes with more then two alleles in the population any individual possesses only two such alleles (at equivalent loci on homologous chromosomes.) Alleles for Blood Type (A, B, O) Human-Leukocyte-Associated antigen (HLA) HLA genes code for protein antigens that are expressed in most human cell types and play an important role in immune responses. These antigens are also the main class of molecule responsible for organ rejections following transplantations— thus their alternative name: major histocompatibility complex (MHC) genes. There are over 100 alleles for HLA! Human ABO Blood Groups •Gene “I” specifies which sugar is found on the outside of red blood cells • 3 alleles are present in the human population: •IA = N-acetyl-galactosamine •IB = galactose •i (also referred to as o) = no sugar present • This gives us 6 possible genotypes The Human ABO Blood Group System Immunology 101 (In a nutshell) •Sugar on the blood cell is an antigen* (A, B, A and B, or none) •Your immune system thinks your own antigens are fine •Your immune system makes antibodies against non-self antigens •Antibodies recognize and target cells with antigens for destruction *something that elicits an immune response There are 3 different alleles, IA, IB, and i •Allele IA makes a cell surface antigen, symbolized with a triangle • IB makes a different antigen, symbolized as a circle • i makes no antigen A little more scientific in perspective… Multiple Alleles: ABO Blood Type Type A blood transfused into Type B personnot OK! Type B blood transfused into Type B person – OK! A medical problem - some blood transfusions produce lethal clumping of cells. The antigens (A and B) cause antibodies to be produced on by individuals who do not have them! Another Example of Multiple Alleles Polygenic Inheritance Occurs when a trait is governed by two or more genes having different alleles Each dominant allele has a quantitative effect on the phenotype These effects are additive Result in continuous variation of phenotypes Polygenic inheritance: additive effects (essentially, incomplete dominance) of multiple genes on a single trait (phenotypic appearance) AA = dark Aa = less dark aa - light Think of each “capital” allele (A, B, C) as adding a dose of brown paint to white paint. Each dominant allele contributes a small but equal effect to the phenotype. By the way… The genetics of human eye color is actually complicated and is not dictated solely by the simple dominant-recessive actions of two alleles of one gene. There are multiple genes (with multiple alleles of each gene) involved, and the interactions of these genes have not been clearly elucidated (understood/explained). This is clearly evidenced by the enormous variation in human eye color that does not always follow the simplified model. People generally have flecks, rays and “splotches” of browns, blues, ambers and greens that overlay the background color. Inheritance of Eye Color in Humans The inheritance of brown or blue eyes in humans is a result of two copies of a gene that codes for pigment production. There are four alleles for eye pigmentation, two that code to produce pigment and two that code for "no pigment". We have an increase in variation within the population because the heterozygotes phenotypes of the genes involved are expressed (codominance). The eye color alleles code for the production of a yellow-brown pigment* *There is also a yellow overlay gene which, when combined with the basic pigment gene, alters light brown to hazel and light blue to green. First Iris Layer Pigment • AA = Produce lots of pigment • Aa = Produce some pigment • aa = Do not produce pigment Second Iris Layer Pigment • BB = Produce lots of pigment • Bb = Produce some pigment • bb = Do not produce pigment Eye Color What does this tell you about the inheritance of height? Birds of a Feather? Pleiotropy From the Greek words meaning “many” and “influences” The impact of a single gene on more than one characteristic Mendel also recognized this effect. He observed that pea plants with red flowers had red coloration where the leaf joined the stem, but that their seed coats were gray in color. Plants with white flowers had no coloration at the leaf-stem juncture and displayed white seed coats. These combinations were always found together, leading Mendel to conclude that they were likely controlled by the same hereditary unit (i.e., gene). Examples of pleiotropy include: The albino condition lack pigment in their skin and hair Affects eye and skin sensitivity to light in many animals Also have crossed eyes at a higher frequency than pigmented individuals. This occurs because the gene that causes albinism can also cause defects in the nerve connections between the eyes and the brain. These two traits are not always linked, again showing the complexity of genetic interactions in determining phenotypes. Even the environment has an impact on some genes! Environmental effects environment often influences phenotype the norm of reaction = phenotypic range due to environmental effects norms of reactions are often broadest for polygenic characters. Flower color in hydrangia determined by pH of soil! •Blue hydrangia require acidic pH •Pink hydrangia require basic pH Temperature can affect gene expression! Let’s Experiment The classic study on environmental control of gene expression was done with the pigmentation gene of Siamese cats and Himalayan cats and rabbits. Typically, the animal's extremities are pigmented while the body core remains unpigmented or cream colored. The pigmentation gene is activated when the temperature falls below a certain point. To demonstrate that the pattern was temperature controlled, the backs of rabbits were shaved and ice packs placed on the shaved portion. When new fur grew, it was pigmented. Cold controls melanin production the Himalayan rabbits… why go black in the cold? Temperature Environmental effects: effect of temperature on pigment expression in Siamese cats Burrrrrr It’s getting hot in here…. Even diet can make a difference! Where’s the beef? Caterpillar fed Oak flowers Caterpillar fed Oak leaves Got Air? Epistasis Genes whose actions are required for other genes to be expressed. This has an effect on mammalian hair color. The dominant allele of this gene allows pigment to be produced, while the recessive allele does not. A second gene controls the distribution of the pigment in the hair. Example: Coat color in Labrador Retrievers BB or Bb-----------> Black bb-------------------->Chocolate Where do Yellow Labs come from? Yellow vs. Dark (Black or Chocolate) is controlled by the Extension Gene (E) EE or Ee--------->dark color ee------------------>yellow (regardless of BB or bb) Practice Problem… BbEe X BbEe Set up this cross and determine the ratios of the offspring Epistatis in Mice: Mice also have black or brown-pigmented fur depending on the inheritance of a gene for pigmentation. A second, independent gene prevents the distribution of any pigment in the fur. This gene, when recessive, results in white mice. Epistasis in horses In horses, brown coat color (B) is dominant over tan (b). Gene expression is dependent on a second gene that controls the deposition of pigment in hair. The dominant gene (C) codes for the presence of pigment in hair, whereas the recessive gene (c) codes for the absence of pigment. If a horse is homozygous recessive for the second gene (cc), it will have a white coat regardless of the genetically programmed coat color (B gene) because pigment is not deposited in the hair. A Comparison More Mostly Human Genetics Chromosome Number: Polyploidy Polyploidy Occurs when eukaryotes have more than 2n chromosomes Named according to number of complete sets of chromosomes Major method of speciation in plants Diploid egg of one species joins with diploid pollen of another species Result is new tetraploid species that is self-fertile but isolated from both “parent” species Some estimate 47% of flowering plants are polyploids Often lethal in higher animals Human Triploidy Triploidy is the third most frequent chromosomal anomaly and is responsible for 15-18% of spontaneous abortions (Dyban and Baranov, 1990). Only 1 in 1,200 triploid fetuses live after birth, although for a very short time. The frequency of triploidy in live births is 1/10,000 (Jacobs et al., 1974), and males represent 51-69% of the cases (McFadden and Langlois, 2000). Most common cause is double fertilization. Chromosome Number: Aneuploidy Monosomy (2n - 1) Diploid individual has only one of a particular chromosome Caused by failure of synapsed chromosomes to separate at Anaphase I (nondisjunction) Trisomy (2n + 1) occurs when an individual has three of a particular type of chromosome Diploid individual has three of a particular chromosome Also caused by nondisjunction This usually produces one monosomic daughter cell and one trisomic daughter cell in meiosis I Down syndrome is trisomy 21 Nondisjunction Trisomy 21 a.k.a. Down’s Syndrome Chromosome Number: Abnormal Sex Chromosome Number Result of inheriting too many or too few X or Y chromosomes Caused by nondisjunction during oogenesis or spermatogenesis Turner Syndrome (XO) Female with single X chromosome Short, with broad chest Can be of normal intelligence and function with hormone therapy Chromosome Number: Abnormal Sex Chromosome Number Klinefelter Syndrome (XXY) Male with underdeveloped testes and prostate; some breast overdevelopment Long arms and legs; large hands Near normal intelligence unless XXXY, XXXXY, etc. No matter how many X chromosomes, presence of Y renders individual male Turner and Klinefelter Syndromes Chromosome Number: Abnormal Sex Chromosome Number Poly-X females XXX simply taller & thinner than usual Some learning difficulties Many menstruate regularly and are fertile More than 3 Xs renders severe mental retardation Jacob’s syndrome (XYY) Tall, persistent acne, speech & reading problems Abnormal Chromosome Structure Deletion Missing segment of chromosome Lost during breakage Translocation A segment from one chromosome moves to a non-homologous chromosome Follows breakage of two nonhomologous chromosomes and improper re-assembly Deletion, Translocation, Duplication, and Inversion Abnormal Chromosome Structure Duplication A segment of a chromosome is repeated in the same chromosome Inversion Occurs as a result of two breaks in a chromosome The internal segment is reversed before reinsertion Genes occur in reverse order in inverted segment Inversion Leading to Duplication and Deletion Abnormal Chromosome Structure Deletion Syndromes Williams syndrome - Loss of segment of chromosome 7 Cri du chat syndrome (cat’s cry) - Loss of segment of chromosome 5 Translocations Alagille syndrome Some cancers Williams Syndrome Williams Syndrome Williams syndrome is a genetic disorder characterized by mild mental retardation, distinctive facial appearance, problems with calcium balance, and blood vessel disease. Caused by missing part of the genetic material on one copy of chromosome 7, deleting approximately 25 genes. Alagille Syndrome Alagille Syndrome Reciprocal translocation. The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Mutations in either the JAG1 gene or NOTCH2 gene probably disrupt the signaling pathway. As a result, errors may occur during development, especially affecting the heart, bile ducts in the liver, spinal column, and certain facial features. Liver problems most common issue. The End…