Molecular Genetics The Objective : To give information about : 1- Mendelian genetics and how Gregor Mendel proved that transmission genetics is the general process by which traits controlled by factors ( genes on chromosome ) are transmitted through gametes from generation to generation. 2- What crossing over means and how it occurs in meiosis. 3- What X- linked inheritance means and how X- linked conditions are inherited through recessive or dominant mutations. 4- Types of X- linked genetic diseases caused by X- linked mutations. Definition : Genetics : The study of inherited variation. Gene : A sequence of DNA that instructs a cell to produce a particular protein. Allele : An alternate Forms of a gene that occur at a given locus in chromosome.Allele are symbolized with the same basic symbol ( eg. T for tall peas and t for dwarf ). Homozygous : Having two identical alleles of a gene. TT or tt. Heterozygous : Having two different alleles of a gene. Tt. Genotype : The alleles combinations in an individual that cause particular traits or disorders. Phenotype : The expression of a gene in traits or symptoms. Dominant : A gene variant expressed when present in even one copy. TT, T t. Recessive : An allele whose expression is masked by another allele. tt. Diploid : A cell containing two sets of chromosomes. Haploid : A cell containing one sets of chromosomes. Gamete : A sex cell sperm or ovum. Mendelian Genetics : Mendels Experiments : Mendel is called the Father of Genetics ( 1822 1884 ). His precedent setting experiments with garden peas ( Pisum sativum ). 1- The First Experiment : Mendel took Tall plants and crossed them with dwarf plants. Mendel found that first generation offspring or F1 were all Tall ( Tt ) We will specifically refer to the offspring of Tall and dwarf peas as Monohybrids because they are Hybrid for only one characteristics (height ). Since all the F1 offspring plants were Tall Tt, Mendel referred to Tallness as Dominant Trait. The alternative dwarfness, he referred to as Recessive. When the F1 plants were self fertilized to form F2 generation, both Tall and dwarf offspring occurred, the dwarf characteristics reappeared. Among the F2 offspring Mendel observed 3 Tall and 1 dwarf,then the Ratio : 3 : 1. ( Figure 1 ). Figure (1) Monohybrids Cross Mendel assumed the first Law of Inheritance : Law of Segregation : Segregation : The distribution of alleles of a gene into separate gametes during meiosis. ( Mendels first law ). The Genotype TT is called Homozygous Dominant. The Genotype tt is called Homozygous Recessive. The Genotype Tt is called Heterozygous. Both Genotypes TT and Tt show dominant phenotype Tall and Genotype tt shows recessive phenotype dwarf. This Experiment involves crossing organisms that differ in two Traits, shape and color of the seeds So it is called Dihybrid Cross. Mendel crossed plants having Round, Yellow seeds with plants having Wrinkled, Green seeds. F1 offspring are Dihybrid Round and Yellow seeds ( Dominant Trait). When F1 plants were self -fertilized, they produced an F2 generation that had all four possible combinations of the seeds characteristics : Round Yellow, Round Green, Wrinkled Yellow and Wrinkled Green seeds with 9 : 3 : 3 : 1 ratio. ( Figure 2 ). 2- Second Experiment : Figure (2) Dihybrid Cross Therefore, Mendel formulated his second Law of Heredity Mendels Law of Independent Assortment : Independent Assortment : The random arrangement of homologous chromosome pairs, in terms of maternal or paternal origin, down the center of a cell in metaphase 1 of meiosis. Inheritance of a gene on one chromosome does not influence inheritance of a gene on a different chromosome. (Mendels second law ). Trihybrid : The offspring from Homozygous Parents differing in three pairs of genes. The Trihybrid cross is illustrated in ( Figure 3 ). 3- Trihybrid Cross : Figure (3) Trihybrid Cross Crossing Over : Crossing over : an event during prophase 1 of meiosis when homologous chromosomes exchange parts, that mixes up maternal and paternal gene combinations. Progeny that exhibit this mixing of maternal and paternal alleles on single chromosome are called recombinant. 1.The probability that crossing over will occur between two Loci increase with increasing distance between the two Loci on the chromosome. 2.Crossing Over involves the breakage of each of two Homologous chromosomes by Endonuclease Enzymes and then exchange parts and reunion by Ligase Enzymes. 3.Crossing Over occurs during Profase 1 of Meiosis in the post Replication Tetrad stage ( 4 chromatids are present for each pair of Homologous chromosomes ). ( Figure 7 ). Features of Crossing Over : Crossing Over Sex Determination : Sex chromosome : A chromosome containing genes that specify sex. X and Y chromosome. Autosome : A chromosome that does not have a gene that determine sex. Eggs produced by the Female in Oogenesis have 23 chromosomes ( autosomes ( 22 ) plus an X chromosome). Sperm from the Male have the same autosomal number and either an X or Y. Eggs fertilized with sperm containing a Y chromosome result in Zygotes that develop into Males ; those fertilized with sperm containing an X develop into Females. ( Figure 4 ). Figure (4) Sex Determination Human cell include 46 chromosomes (( 44 autosomes and XX ( Homogametic in Female )) or (( 44 autosomes and XY ( Heterogametic) in Male )). X chromosome has many genes that are important for growth and development. Y chromosome is much smaller and has fewer genes. ( Figure 5 ). XX- XY Mechanism of Sex Determination : XX- Zygote became Females and XY- Zygotes became Males. Figure (5) Sex Linked Inheritance : Sex Linked : refers to aTrait determined by a gene Located on Sex chromosome, usually the X chromosome. Because of there location on the X chromosome as Sex determiners they are said to be Sex Linked. Sex-Linked Diseases are inherited through one of the sex chromosomes the X or Y chromosomes. Autosomally Inherited Diseases are inherited through the non-sex chromosomes ( Autosomes ), pairs 1 through 22. X- Linked Inheritance : X- linked diseases are single gene disorders that reflect the presence of defective genes on the X chromosome. This chromosome is present as two copies in females but only as one copy in males. X- Linked inheritance are complicated by the fact that : 1- Males ( XY ) always pass their X chromosome to their daughters but never to their sons, whereas females (XX) pass their X chromosomes to daughters and sons with equil. 2- X- linked inheritance refers to the pattern of inheritance of a condition caused by mutation on the X chromosome. The mutation may be recessive or dominant. 3- Conditions that follow a pattern of X- Linked recessive inheritance include Hemophilia, Colourblindness. X- Linked Inheritance : 4- The chance that a child will inherit an X- Linked recessive condition in every pregnancy is different for sons and daughters and depends on whether the mother or father has a mutation : A - When the mother is a carrier of an X- linked recessive mutation there is 1 chance in 2 ( 50% ) that a son will be affected and a 1 chance 2 in ( 50% ) that a daughter will be a carrier. Since the normal gene on the second X chromosome counteracts the defect, the daughters can only be carriers. Since the Y chromosome of the son cannot offset the defective gene from his X chromosome a son will be affected. X- Linked Inheritance A A A- when the mother is a carrier of an X- linked recessive mutation there is 1 chance in 2 ( 50% ) that a son will be affected and a 1 chance 2 in ( 50% ) that a daughter will be a carrier. ( Figure 7A and 8A) B B B -When the father is affected by a condition due to an X- Linked recessive mutation, non of his sons will be affected but all of his daughters will be carriers. ( Figure 7 B and 8 B) X- Linked Inheritance : 5- X- linked recessive diseases are much more common in males than in females because 2 copies of the mutant allele are required for the disease to occur in females, while only one copy is required in males. 6- Affected males never pass the disease to their sons because there is no male to male transmission of X chromosome. C C 7- There are very few conditions that have been shown to follow a pattern of X- linked dominant inheritance : A - When the mother has the mutated X- linked dominant gene and is affected : both daughters and sons will have 50% probability to be affected. ( Figure 7 C and 8 C) X- Linked Inheritance : D D B - When the father has X- linked dominant condition : all daughters will be affected and all sons are normal. ( Figure 7 D and 8 D) X- Linked Inheritance : 8- X- Linked dominant inheritance Expressed in female in one copy. 9- X- Linked dominant inheritance Much more severe effects in males. 10- Conditions that follow a pattern of X- Linked dominant inheritance incontinentia pigmenti. ( Figure 9 ) Sex Linked Recessive Traits in Humans : 1- Colour Blindness : Is the redused ability to distinguish between certain colours. Its usually inherited and is more common in men, affecting about one in 20. Far fewer women around one in 200 are affected.The gene for red-green colourblindness lies on the X-chromosome. Inheritance : Colourblindness follow a pattern of X linked recessive inheritance. 1- Colour Blindness A B- A- Inheritance of Colour Blindness Diagnosis : Test for colourblindness : which consists of aseries of pictures of colored spots, is the most often used to diagnose red-green color deficiencies. Afigure is embedded in the picture as anumber of spots in aslightly different color, and can be seen with normal color vision, but not with aparticular color defect 2-Hemophilia : Is a rare genetic disorder that almost always occurs in males. Aperson has hemophilia when he or she inherits problems with certain blood- clotting factors, making them unable to work properly. Blood clotting factors are needed to help stop bleeding after acut or injury and to prevent spontaneous bleeding. Hemophilia gene can contain many different errors, leading to different degrees of abnormality in the amount of clotting factor produced. About 1 in every 5000 boys is born with Hemophilia ; girls are more rarely affected by this genetic condition linked to gender. There are two major types of Hemophilia : 1- Hemophilia A : Is caused by adeficiency of active clotting factor V111. Factor V111: a protein that participates in acascade of reactions that result in formation of blood clot ( Figure 9 ). The disease arises from amutation in gene for Factor V111 which located on X-chromosome. Is the cause of about 80% of cases. 2- Hemophilia B : Is caused by alack of active clotting Factor 1X.Which makes up the majority of the remaining 20 % of cases. Inheritance : Hemophilia follow a pattern of X- linked recessive inheritance. A B A H Inheritance of Hemophilia