Chapter 5 Inheritance Patterns PDF

Chapter 5 Inheritance Patterns Dra Verónica Veses Jiménez Chapter overview Mendelian Inheritance – Historical Antecedents – Mendel´s work – Mendelian inheritance – Punnet square Variation of Mendelian inheritance Atypical inheritance patterns...

Chapter 5 Inheritance Patterns Dra Verónica Veses Jiménez Chapter overview Mendelian Inheritance – Historical Antecedents – Mendel´s work – Mendelian inheritance – Punnet square Variation of Mendelian inheritance Atypical inheritance patterns 2 Historical antecedents Aristotle, in his book ”the Generation of Animals” describes the theory of Epigenesis. It is the process by which each embryo or organism is gradually produced from an undifferentiated mass by a series of steps and stages during which new parts are added. 1590 Janssen (father and son) invented the microscope. After the appearance of the microscope Preformationist theory re- appears: instead of assembly from parts, preformationists believed that the form of living things exist, in real terms, prior to their development. It suggests that all organisms were created at the same time, and that succeeding generations grow from homunculi, or animalcules, that have existed since the beginning of Creation. They believed that generation of offspring occurs as a result of an unfolding and growth of preformed parts. 3 The birth of Genetics Mendel carried out his experiments with pea plants (1856-1863). At first, his work was ignored by the scientific community. In 1900 Carl Correns, Hugo de Vries and Eric Von Tschermak, independently corroborate the findings of Mendel In 1902 Boveri and Sutton independently describe the paralelism between the mendelian principles and the chromosome behaviour during meiosis. In 1905 Bateson establishes the term Genetics as “the science devoted to the study of heredity and variation” 4 Gregor Mendel: the father of Genetics Until the work of Mendel, inheritance was considered as a mixture of both parents. He hypothesized that parents pass on to their offspring separate and distinct (now called genes) factors that are responsible for inherited traits Mendel pioneered applying an experimental approach to the question of inheritance. For seven years, he crossed pea plants and recorded the patterns of inheritance in the offspring Each pea plant has a "particulate inheritance", which Mendel called gametes. Each plant has two copies of these particules, which influences the type of plant 5 Genetic principles discovered by Mendel He crossed different strains of pea plants of "pure race" and study its progeny (true-breeding). In their studies he used common pea plants because: They allow you to analyze a single trait or characteristic at a time. The plants were available and easy to grow They reproduced quickly and allow self- reproduction Differences in traits could be observed directly 6 What is meant by “true breeding?” 7 Mendel studied seven different characteristics in pea plants 8 Monohybrid crossings: flower color For each monohybrid cross, Mendel cross- fertilized true-breeding plants that were different in just one character—in this case, flower color. He then allowed the hybrids (the F1 Characteristics do not blend, as generation) to self- had been previously believed, fertilize. and can reappear in later generations. 9 Monohybrid crossing: seed shape Mendel repeated the experiment with another trait: "smooth / rough" and observed the same phenomenon. The rough feature was missing in the first generation (F1) and reappeared in the F2 offspring He noted that the resulting second-generation ratio seemed to be 3:1 (smooth: rough). He repeated the experiments many times and always came to similar results: – 3.15:1 ratios – 3,01:1 – 2,95:1 etc.. Based on these findings, Mendel formulated the notion of "units of inheritance" and constructed a model: Each pea plant has a "particulate inheritance", which Mendel called gametes. Each plant has two copies of these gametes, which influence the type of plant (smooth or wrinkled peas). 10 Dihybrid cross In these experiments are analyzed simultaneously two characters Plants used as parental lines produced smooth yellow seeds and wrinkled green seeds The first-generation plants were allowed to self-pollinate and the ratios obtained were: 9:3:3:1, which is the result of multiplying two ratios 3:1, one refers to the character color (3 Yellow: 1 green) and one for the form (3 smooth: 1 rough) Mendel explained this as a result of the existence of two legacy systems that are combined at random (independently). 11 Dominance and recessiveness Recessive traits are not expressed in heterozygotes. – For a recessive allele to be expressed, there must be two copies of the allele. Dominant traits are governed by an allele that can be expressed in the presence of another, different allele. – Dominant alleles prevent the expression of recessive alleles in heterozygotes. 12 Law of Segregation Genes occur in pairs (like chromosomes). During gamete production, members of each gene pair separate. During fertilization, the full number of chromosomes is restored (allele pairs are reunited). Homozygous- same allele at same locus on both members of a chromosome pair. (i.e.TT, tt) Heterozygous- two different alleles at the same locus on a chromosome pair. 13 Law of Uniformity When two homozygotes with different alleles are crossed, all the offspring in the F1 generation are identical and heterozygous. In other words, the characteristics do not blend, as had been previously believed, and can reappear in later generations. 14 Law of Independent Assortment The distribution of one pair of alleles into gametes does not influence the distribution of another pair. The genes controlling different traits are inherited independently of one another. 15 Mendelian Inheritance in Humans Mendelian principles apply to over 16,000 human traits or disorders. The human ABO blood system is an example of a simple Mendelian inheritance. – The A and B alleles are dominant to the O allele. – The A or B allele are codominant (both traits are expressed). 16 Types of Mendelian inheritance There are four models of Mendelian inheritance, based on: – The chromosomal location of the gene locus autosomal Sex-linked (X and Y) – The character of the resulting phenotype dominant recessive 17 Autosomal dominant An autosomal trait (or disorder) is one that manifests in the heterozygous state That is, in a person possessing both an abnormal or mutant allele and the normal allele It is called vertical transmission Any child born to a person affected with a dominant trait or disorder has a 1 in 2 (50%) chance of inheriting it and being similarly affected 18 Autosomal recessive Recessive traits and disorders are manifest only when the mutant allele is present in a double dose (homozygosity) Individual heterozygous for such mutant alleles show no features of the disorder and they are healthy. They are described as carriers The offspring of two heterozygotes have a 1 in 4 chance (25%) of being homozygous affected, a 1 in 2 (50%) of being heterozygous unaffected and a 1 in 4 (25%) chance of being homozygous unaffected 19 Sex-linked inheritance Refers to the pattern of inheritance shown by genes that are located on either of the sex chromosomes Genes carried on the X chromosome are referred to as being X-linked and those carried on the Y chromosome are referred to as Y-linked or holandric inheritance 20 X-linked inheritance Because males have one chromosome but females have two, there are only two possible genotypes in males and three in females with respect to a mutant allele at an X- linked locus A male with a mutant allele at an X-linked locus is hemizygous for that allele A female can be: Homozygote for the normal allele Homozygote for the mutant allele Heterozygote (can be affected or unaffected: see X inactivation) 21 Inactivation pattern of X It is a normal physiological process in which one of the X chromosome is practically inactivated in somatic cells of normal women This process balances the expression of X-linked genes in both sexes Inactivation is random (a chromosome) and is maintained in each clonal lineage (mosaic) Exceptions: alterations of one X chromosome involve a nonrandom inactivation 22 X-linked dominant Because the gene is located on the X chromosome, there is no transmission from father to son, but it can be transmitted from father to daughter (all daughters of an affected male will be affected because the father has only one X chromosome). Children of an affected woman have a 50% chance of inheriting the X chromosome with the mutant allele. Dominant X-linked disorders clinically manifest in all males and in females depending on the X inactivation pattern. 23 X-linked recessive Recessive X-linked traits are not clinically manifested when a normal copy of the gene is present. All X-linked recessive traits are fully evident in men, since they have only one copy of the X chromosome. In contrast, women are rarely affected by X-linked recessive diseases. They are only affected if they are homozygous for the mutant allele. Because the gene is on the X chromosome there is no transmission from father to son, but there is from father to daughter and from mother to daughter and son. 24 Y-linked inheritance There are very few Y-linked genes, and the majority are involved in primary sex determination or the development of secondary male characteristics A Y-linked gene will manifest in all men carrying it, and only in men, regardless of whether is a dominant or recessive gene Amongst the few known cases of hereditary abnormality linked to the Y chromosome we have hypertrichosis of the ear. This is a character whose gene determines the appearance of hair on the pinna. 25 Punnett square We use the Punnett square to predict the genotypes and phenotypes of the offspring. 26 Using a Punnett Square STEPS: 1. determine the genotypes of the parent organisms 2. write down your "cross" (mating) 3. draw a p-square Parent genotypes: TT and t t Cross TT  tt 27  Punnett square 4. "split" the letters of the genotype for each parent and put them "outside" the p-square 5. determine the possible genotypes of the offspring by filling in the p-square 6. summarize results (genotypes & phenotypes of offspring) T T TT  tt Genotypes: t Tt Tt 100% T t Phenotypes: t Tt Tt 100% Tall plants 28 VARIATION OF MENDELIAN INHERITANCE ATYPICAL INHERITANCE PATTERNS Section overview Variations of Mendelian inheritance – Intermediate or incomplete dominance – Codominance – Influenced dominance – Penetrance – Expresiveness – Lethal genes – Pleiotrophy Atypical inheritance – Genetic anticipation – Mosaicism – Uniparental disomy – Imprinting disorders 30 VARIATIONS OF MENDELIAN INHERITANCE 31 Intermediate or incomplete dominance Heterozygous phenotype is intermediate between the two homozygous phenotypes Neither allele is dominant or recessive Nomenclature corresponds to a letter followed by a number 32 Example of incomplete dominance: carnation flowers 33 Codominance In this case the phenotype of heterozygous is a cross of the homozygous phenotypes without any mixture of them, giving a separate result. Example: blood groups 34  Influenced dominance Baldness is a dominant trait in men and a recessive trait in women Changes in the pattern of dominance are due to the presence of sex hormones Genotype Male Female c1c1 bald bald c1c2 bald Not bald c2c2 Not bald Not bald 35 Penetrance It is the probability that a gene presents any level of phenotypic expression. If the frequency of expression of a phenotype is less than 100% it is called reduced penetrance Sometimes there is age-dependent penetrance. 36 Example of reduced penetrance Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. 37 Expressivity It is the severity of the expression of the phenotype in individuals with the same genotype Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition 38 Examples Marfan syndrome: some patients have only mild symptoms (such as being tall and thin with long, slender fingers), while others experience life- threatening complications involving the heart and blood vessels. Polydactyly has also variable expressivity. Some individuals have an extra toe and others have an extra toe and an extra finger 39 Lethal genes Genes which result in the premature death of the organism Types of lethal alleles: – Recessive lethals – Dominant lethals – Conditional lethals 40 Recessive lethal alleles Recessive lethal may encode for dominant or recessive traits, however they are only fatal in the homozygous condition. Heterozygotes will sometimes display a form of disease phenotype, as in the case of achondroplasia. One mutant lethal allele is tolerated, but having two results in death. Not all heterozygotes for recessive lethal alleles will show a mutant phenotype, as is the case for cystic fibrosis carriers. 41 Dominant lethal alleles Alleles that need only be present in one copy in an organism to be fatal. These alleles are not commonly found in populations because they usually result in the death of an organism before it can transmit its lethal allele on to its offspring. An example in humans of a dominant lethal allele is Huntington's disease, a rare neurodegenerative disorder that ultimately results in death. 42 Conditional lethal alleles Alleles that will only be fatal in response to some environmental factor are referred to as conditional lethals. One example of a conditional lethal is favism, a sex- linked inherited condition that causes the carrier to develop hemolytic anemia when they eat fava beans 43 Pleiotrophy The ability of a single gene to have multiple phenotypic effects (alleles at a single locus may have effects on two or more traits) Classic example is the effects of the mutant allele at the beta-globin locus that gives rise to sickle-cell anemia, which causes multiple symptoms, only one of which is the actual sickle celled condition. 44 45 ATYPICAL INHERITANCE 46 Genetic anticipation The tendency for some genetic disorders to manifest at an earlier age and/or to increase in severity with each succeeding generation. The mechanism of anticipation is associated with a particular type of DNA change - areas of DNA which contain trinucleotide repeats. The disease manifests itself when the number of repeats has increased above a particular number. For some of these conditions the age of onset or severity is associated with the number of trinucleotide repeats. This expansion causes the features of some disorders to become more severe with each successive generation. Disorders caused by this type of mutation include myotonic dystrophy, fragile-X syndrome and Huntington disease. 47 Mosaicism An individual, or a particular tissue of the body can consist of more than one cell type or line, through an error occured during mitosis at any stage after conception 48 Somatic Mosaicism Explains why the features of a single-gene disorder being less severe in an individual than is usual Also, when features are confined to a particular part of the body in a segmental distribution. 49 Germline Mosaicism Two or more genetic or cytogenetic cell lines confined to the precursor (germline) cells of the egg or sperm It explains cases of families where the parents have normal phenotypes and more of one of their children is affected by a autosomal dominant disease or an X- linked recessive disorder. 50 Imprinting People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. 51 Mechanism of imprinting In genes that undergo genomic imprinting, the parent of origin is often marked on the gene during the formation of egg and sperm cells. The marking is done through methylation. This mechanism identifies which copy of a gene was inherited from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. 52 53 Frequency of Imprinting Only a small percentage of all human genes undergo genomic imprinting. Imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 and another on the long (q) arm of chromosome 15. 54 Imprinting disorders: Angelman syndrome It is a complex genetic disorder that primarily affects the nervous system. Symptoms include delayed development, intellectual disability, severe speech impairment, and ataxia. Most affected children also epilepsy and microcephaly It is due to the inactivation of the maternal copy of the UBE3A gene. 70 % of cases occur when a segment of the maternal chromosome 15 containing this gene is deleted 11 % of cases are caused by a mutation in the maternal copy of the UBE3A gene 55 Patient with Angelman syndrome https://elpais.com/e lpais/2020/02/14/m amas_papas/158166 0502_886470.html 56 Imprinting disorders: Prader-Willi syndrome It is a complex genetic condition characterized hypotonia, feeding difficulties, poor growth, and delayed development in childhood, and hyperphagia and obesity in adulthood 70 % of cases occur when a segment of the paternal chromosome 15 is deleted and the genes on the maternal copy are inactive. 25 % of cases, the patient has two copies of chromosome 15 inherited from his or her mother instead of one copy from each parent (maternal uniparental disomy). 57 Uniparental disomy Occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD has no effect on health or development, because most genes are not imprinted. If the affected gene is imprinted, this loss of gene function can lead to delayed development, intellectual disability, or other health problems. 58 MITOCHONDRIAL INHERITANCE 59 Mitochondria Each cell has hundreds of mitochondria in the cytoplasm. The main function of mitochondria is to convert molecules into usable energy. Thus, many diseases transmitted by mitochondrial inheritance affect multiple organs with high energy use such as the heart, blood, skeletal muscle, liver and kidneys. 60 Mitochondrial inheritance Mitochondria are inherited only from the mother's egg, so only women can pass the trait to their offspring. Mitochondrial disorders are therefore transmitted from an affected mother to all of the children but to none of those of an affected father 61 Mitochondria have multiple copies of a circular chromosome Each mitochondria contains 10 copies of the circular chromosome Therefore, each human cell contains thousands of copies of mtDNA 62 Homoplasmy and Heteroplasmy In most people mitochondrial DNA from different mitochondria is identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mutations of mtDNA can accommodate a mixture of mutant and wild- type mtDNA within each cell (heteroplasmy) 63 POLYGENIC INHERITANCE 64 Historical antecedents The first scientist to study multifactorial inheritance was Francis Galton, Charles Darwin's cousin. Like his contemporary, Gregor Mendel, Galton studied the inheritance of traits. However, unlike Mendel, Galton observed what he called "blending" characters (Galton, 1897). Blending is now known as continuous variation, describing a gradation in expression in which phenotypes do not fall into distinct categories, unlike Mendel´s peas. 65 Polygenic inheritance Polygenic traits are governed by more than one gene pair (e.g., several pairs of genes may be involved in determining the phenotype). The inheritance of skin color, determined by an unknown number of gene pairs, is a classic example of polygenic inheritance. A range of phenotypes exist from very dark to very light. 66 Resulting phenotypes – discontinuous: phenotypes corresponding to two or more classes, which are distinct and do not overlap (such as Mendel´s peas) – continuous: phenotypic characters which are distributed from one end to another in an overlapping fashion (as height in humans). 67 Example of a continuous phenotype 68 What is known as polygenic or quantitative inheritance? This involves the inheritance and expression of a phenotype being determined by many genes at different loci and each gene exerting a small additive effect, in a continuous distribution mode. Effects of the genes are cumulative , with each gene contributing a small amount to the final expressed phenotype. No one gene is dominant or recessive to another. Several human characteristics show a continuous distribution in the population that closely resembles a normal distribution. Traits with continuous variation are also called quantitative traits Approximately 68%, 95% and 99.7% of observations fall within the mean plus or minus one, two or three standard deviations respectively. 69 The normal (Gaussian) distribution When a trait that exhibits continuous variation is plotted on a graph, the phenotypic distribution forms a bell-shaped curve. Accordingly, most individuals have an intermediate phenotype, and the majority of individuals group at the mean (Mossey, 1999) 70 Human characteristics that show a continuous normal distribution, and are therefore polygenic. Blood pressure Dermatoglyphics (ridge count) Head circumference Height Intelligence Skin color Heart disease 71 Regression to the mean In reality, human characteristics such as height and intelligence are also influenced by environment, and possibly also by genes that are not additive in that they exert a dominant effect. These factors probably account for the observed tendency of offspring to show what is known as a “regression to the mean”. This is demonstrated by tall or intelligent parents having children whose average height or intelligence is slightly lower than average or mid-parental value. Similarly, parents who are very short or of low intelligence tend to have children whose average height or intelligence is lower than the general population average, but higher than the average value of the parents. 72 Correlation Is a statistical measure of the degree of resemblance or relationship between two parameters First-degree relatives share on average 50% of their genes If a parameter such as height is polygenic, then the correlation between first-degree relatives such as siblings should be 0.5. Several studies have shown this to be true. 73  Degrees of relationship Relationship Proportion of genes shared ------------------------------------------------------------------------ First degree {1/2} Parents, Siblings, Children ------------------------------------------------------------------------------------- Second degree {1/4} Uncles and aunts, nephews and nieces Grandparents, grandchildren, half-siblings ------------------------------------------------------------------------------------- Third degree {1/8} First cousins, Great- grandparents, Great- grandchildren ------------------------------------------------------------------------------------- 74 Multifactorial inheritance Efforts have been made to extend the polygenic theory for the inheritance of quantitative or continuous traits to try to account for discontinuous multifactorial disorders 75 The liability/threshold model According to this model all of the factors which influence the development of a polygenic disorder, whether genetic or environmental, can be considered as a single entity known as liability. The liabilities of all individuals in an population form a continuous variable, which has a normal distribution in both the general population and in relatives of affected individuals However, the curves for these relatives will be shifted to the right, with the extent to which they are shifted being directly related to the closeness of their relationship to the affected index case. 76 Liability curves Hypothetical liability curves in the general population and in relatives for a hereditary disorder in which the genetic predisposition is polygenic. 77 Presentation of abnormal phenotype A threshold exists above which the abnormal phenotype is expressed. In general population the proportion beyond the threshold is the phenotypic incidence in the population, and among relatives the proportion beyond threshold is the familial incidence. It is important to emphasize, that exceeding the liability includes all factors that contribute to the cause of the condition. 78 References Robert L. Nussbaum, 2007. Thompson & Thompson Genetics in Medicine. 7th Edition. Saunders. Peter D Turnpenny, 2011. Emery's Elements of Medical Genetics. 14th Edition. Churchill Livingstone. Saunders Elsevier , 2007​. Genetics Home Reference (http://ghr.nlm.nih.gov/handbook/inheritance) Lobo, I. (2008) Multifactorial inheritance and genetic disease. Nature Education 1(1):5 79