Lecture 7.pptx

General Genetics (GEN-626) Lecture 7 Sex Dependent Pattern of Inheritance Pattern of Inheritance The inheritance patterns observed will depend on whether the allele is found on an autosomal chromosome or a sex chromosome, and on whether the allele is dominant or r...

General Genetics (GEN-626) Lecture 7 Sex Dependent Pattern of Inheritance Pattern of Inheritance The inheritance patterns observed will depend on whether the allele is found on an autosomal chromosome or a sex chromosome, and on whether the allele is dominant or recessive. There are five basic modes of inheritance for single-gene : Autosomal dominant inheritance Autosomal recessive X-linked dominant X-linked recessive Y-linked and mitochondrial  Homogametic and heterogametic Because they are homologous, the sex chromosomes are separated during meiosis into different gametes. 44 + XX 44 + XY 22 + X 22 + X 22 + X 22 + Y Human females produce all gametes with the same combination of chromosomes = homogametic. Human males produce gametes with two possible combinations of chromosomes = heterogametic. Non-Mendelian inheritance patterns Complex and multifactorial inheritance Some traits or characteristics display continuous variation, a range of phenotypes that cannot be easily divided into clear categories. In many of these cases, the final phenotype is the result of an interaction between genetic factors and environmental influences. An example is human height and weight. A number of genetic factors within the individual may predispose them to fall within a certain height or weight range, but the observed height or weight will depend on interactions between genes, and between genes and environmental factors (for example, nutrition). Traits in which a range of phenotypes can be produced by gene interactions and gene-environment interactions are known as complex or multifactorial. Autosomal Inheritance Autosomal dominant: If the phenotype associated with a given version of a gene is observed when an individual has only one copy, the allele is said to be autosomal dominant. The phenotype will be observed whether the individual has one copy of the allele (is heterozygous) or has two copies of the allele (is homozygous). Autosomal recessive If the phenotype associated with a given version of a gene is observed only when an individual has two copies, the allele is said to be autosomal recessive. The phenotype will be observed only when the individual is homozygous for the allele concerned. An individual with only one copy of the allele will not show the phenotype, but will be able to pass the allele on to subsequent generations. As a result, an individual heterozygous for an autosomal recessive allele is known as a carrier. Sex-linked Inheritance X-linked Inheritance Y-linked Inheritance Because little genetic information exists on the Y chromosome in many organisms, most sex-linked characteristics are X linked. Males and females differ in their sex chromosomes; so the pattern of inheritance for sex-linked characteristics differs from that exhibited by genes located on autosomal chromosomes. Linked inheritance is mostly used to study disease patterns Sex-linked or X-linked inheritance The X chromosome carries hundreds of genes, and many of these are not connected with the determination of sex. The smaller Y chromosome contains a number of genes responsible for the initiation and maintenance of maleness, but it lacks copies of most of the genes that are found on the X chromosome. As a result, the genes located on the X chromosome display a characteristic pattern of inheritance referred to as sex-linkage or X-linkage. Females (XX) have two copies of each gene on the X chromosome, so they can be heterozygous or homozygous for a given allele. However, males (XY) will express all the alleles present on the single X chromosome that they receive from their mother, and concepts such as 'dominant' or 'recessive' are irrelevant. A number of medical conditions in humans are associated with genes on the X chromosome, including haemophilia, muscular dystrophy and some forms of colour blindness.  History 4.11 Thomas Hunt Morgan’s work with Drosophila helped unravel many basic principles in genetics, including X-linked inheritance. (a) Morgan. (b) The Fly Room, where Morgan and his students conducted genetic research. (Part a: AP/Wide World Photos. Part b: American Philosophical Society.) Sex linked inhertance (White-eyed males) In the early 1900s, T. H. Morgan studied inheritance in Drosophila melanogaster to try to disprove Mendel’s theory of the 3:1 ratio It took two years to find any variation in his vast fly breeding programme. Eventually a male fly was found which XrY XRXR had white eyes. This white-eyed male was crossed with XR a normal red-eyed female. We will use the notation XR to show the Xr XRXr red eye allele is on the X-chromosome and is dominant to white eye, Xr. Y XRY  Carrier females All the flies in the F1 had red eyes. Flies with genotype XRXr XRY XRXr are carrier females. Morgan crossed the F1 with XR Xr each other. XRXr F2 came out with a 3:1 XRXR Red-eyed ratio of red-eyed flies to XR Red-eyed carrier white-eyed flies. female female But all the white-eyed flies were males. XRY XrY Y Red-eyed White- male eyed male X-Linked White Eyes in Drosophila To investigate the inheritance of the white-eyed characteristic in fruit flies, Morgan systematically carried out a series of genetic crosses. First, he crossed pure-breeding, red-eyed females with his white-eyed male, producing F1 progeny of which all had red eyes (In fact, Morgan found 3 white eyed males among the 1237 progeny, but he assumed that the white eyes were due to new mutations.) His results suggested that white eyes are a simple recessive trait. However, when Morgan crossed the F1flies with one another, he found that all the female F2 flies’ possessed red eyes but that half the male F2 flies had red eyes and the other half had white eyes. This finding was clearly not the expected result for a simple recessive trait, which should appear in ¼ of both male and female F2 offspring. To explain this unexpected result, Morgan proposed that the locus affecting eye color is on the X chromosome (i.e., eye color is X linked). He recognized that the eye-color alleles are present only on the X chromosome; no homologous allele is present on the Y chromosome. Because the cells of females possess two X chromosomes, females can be homozygous or heterozygous for the eye-color alleles. The cells of males, on the other hand, possess only a single X chromosome and can carry only a single eye-color allele. Males therefore cannot be either X-Linked Inheritance X-Linked Recessive Inheritance 1. Human traits involving recessive alleles on the X chromosome are X-linked recessive traits. 2. X-linked recessive traits occur much more frequently among males, who are hemizygous. A female would express a recessive X-linked trait only if she were homozygous recessive at that locus. 3. X-linked recessive traits are Duchenne muscular dystrophy and two forms of color blindness. Some characteristics of X-linked recessive inheritance: a. Affected fathers transmit the recessive allele to all daughters (who are therefore carriers), and to none of their sons. b. Father-to-son transmission of X-linked alleles generally does not occur. c. Many more males than females exhibit the trait. d. All sons of affected (homozygous recessive) mothers are expected to show the trait. e. With a carrier mother, about 1⁄2 of her sons will show the trait and 1⁄2 will be free of the allele. f. A carrier female crossed with a normal male will have 1⁄2 carrier and 1⁄2 normal daughters.  X-Linked Dominant Inheritance 1. Only a few X-linked dominants are known. 2. Examples include: a. Hereditary enamel hypoplasia (faulty and discolored tooth enamel) b. Webbing to the tips of toes. c. Constitutional thrombopathy (severe bleeding due to lack of blood platelets). 3. Patterns of inheritance are the same as X-linked recessives, except that heterozygous females show the trait (although often in a milder form).  Y linked inheritance (Holandric traits) There are far fewer Y-linked than X-linked genetic disorders This is not surprising given that the Y chromosome is smaller and has many less genes than the X chromosome. Y-linked inheritance shows a pattern of transmission of the mutant phenotype from father to son, and it is never observed in females. An example of a Y linked phenotypic trait is hairy ears.  Pedigree Analysis The technique of looking through a family tree (of humans or other organisms) for the occurrence of a particular characteristic in one family over a number of generations. Can be used to determine the likely mode of inheritance: Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive When looking at pedigrees, incomplete penetrance is occasionally observed. Incomplete penetrance describes the situation where a proportion of a population with a particular genotype does not show the expected phenotype. Complete penetrance of a phenotype means that all individuals with a particular genotype will show the affected phenotype. Symbols used in drawing pedigrees X linked Recessive Pattern Examples include:  Ichthyosis, an inherited skin disorder  One form of red–green colour-blindness  One form of severe combined immunodeficiency disease  Haemophilia  Fragile X syndrome  Duchene muscular dystrophy  X linked Dominant Pattern An idealised pattern of inheritance of an X-linked dominant trait includes the following features: a male with the trait passes it on to all his daughters and none of his sons a female with the trait may pass it on to both her daughters and her sons every affected person has at least one parent with the trait if the trait disappears from a branch of the pedigree, it does not reappear over a large number of pedigrees, there are more affected females than males Examples include:  Vitamin D resistant rickets  Incontinentia pigmenti, a rare disorder that results in the death of affected males before birth  Autosomal Recessive Pattern An idealised pattern of inheritance of an autosomal recessive trait includes the following features: both males and females can be affected two unaffected parents can have an affected child all the children of two persons with the condition must also show the condition the trait may disappear from a branch of the pedigree, but reappear in later generations over a large number of pedigrees, there are approximately equal numbers of affected females and males. Examples include:  Albinism  Cystic fibrosis  Thalassaemia  Tay-Sachs disease  Phenylketonuria  Red hair colour  Autosomal Dominant Pattern An idealised pattern of inheritance of an autosomal dominant trait includes the following features: both males and females can be affected all affected individuals have at least one affected parent transmission can be from fathers to daughters and sons, or from mothers to daughters and sons once the trait disappears from a branch of the pedigree, it does not reappear in a large sample, approximately equal numbers of each sex will be affected. Examples include:  Huntington disease  Achondroplasia (a form of dwarfism)  Familial form of Alzheimer disease  Defective enamel of the teeth  Neurofibromatosis (the ‘Elephant man’ disease)  Sex limited inheritance Y-linked inheritance is often confused with sex- limited inheritance. Sex-limited traits can only occur in one sex because the feature affected is unique to that sex. For example, premature baldness is an autosomal dominant trait, but presumably as a result of female sex hormones, the condition is rarely expressed in the female, and then usually only after menopause. Mitochondrial inheritance Animal and plant cells contain mitochondria that have their evolutionary origins in protobacteria that entered into a symbiotic relationship with the cells billions of years ago. The chloroplasts in plant cells are also the descendants of symbiotic protobacteria. As a result, mitochondria and chloroplasts contain their own DNA.  X-inactivation (Dosage Compensation) During the growth and development of females’ cells, one X chromosome is inactivated in each body cell. The inactivated X chromosome is visible in a female’s cells as a Barr body. Which of the two X chromosomes becomes inactive in a cell is a matter of chance, therefore heterozygous females express different alleles in different cells. This is generally not noticeable in the phenotype – for example a woman heterozygous for the recessive condition haemophilia A will produce sufficient clotting factor VIII. Tortoise shell cats are an example where X inactivation is visible in the phenotype as one of the genes which controls coat colour is sex- linked.  X-inactivation One of the genes that controls coat colour in cats is sex-linked. It has alternative alleles Xo (orange) and Xb (black) If Xo are inactivated will produce dark fur. If Xb is inactivated will produce orange fur. Genomic imprinting The expression of a small number of human genes is influenced by whether the gene has been inherited from the mother or father. This process - called genomic (or parental) imprinting - usually means that the organism expresses one of its alleles but not both. In many cases the non-expressed allele is inactivated - for example, by DNA methylation. (High levels of DNA methylation are known to inhibit gene activity.) Imprinting involves three stages: the inactivation of an allele in the ovaries or testes before or during the formation of egg cells or sperm the maintenance of that inactivation in the somatic cells of the offspring organism the removal, then re-establishment, of the inactivation during the formation of egg cells or sperm in the offspring organism The pattern of imprinting is maintained in the somatic cells of the organism but can alter from generation to generation. Assignment Q.1: The parents of a child with severe sensorineural hearing loss are referred to the genetics clinic. They indicate that they have had three children: a son, a daughter and then another son, and that it is their daughter who was found at the age of 9 months to have severe hearing loss. The father of these children has two sisters both of whom have two sons. His parents are both well. No-one in his family has ever had a child with hearing loss before. The mother of the three children has a brother who has one son and one daughter. Her parents are also well and once again there is no known history of severe hearing loss in childhood. However, her maternal grandfather developed moderate hearing loss in his sixties. On specific questioning the mother recalls that her maternal grandmother was the sister of her husband’s paternal grandmother. Now draw up the family tree. What is the most likely genetic explanation for the daughter’s severe hearing loss?