1B Inheritance Patterns - PDF

Text Introduction Monogenic inheritance refers to the kind of inheritance whereby a trait is determined by the expression of a single gene or allele, not by several genes as in polygenic inheritance. It is the inheritance of characteristics that are determined by a single gene pair. These are charac...

Text Introduction Monogenic inheritance refers to the kind of inheritance whereby a trait is determined by the expression of a single gene or allele, not by several genes as in polygenic inheritance. It is the inheritance of characteristics that are determined by a single gene pair. These are characteristics showing discontinuous variation i.e., those represented by two or more contrasting characteristics. There are few easily visible, normal external characteristics that show monogenic inheritance. Examples are eye color, large or small ear lobes, sticky or dry earwax, ability or inability to curl the tongue (tongue rolling), ability or inability to taste the substance PTC, ability or inability to hyperextend the thumb (hitch hiker's thumb). However, there are numerous examples of diseases that follow a monogenic pattern of inheritance. In humans, most visible characteristics such as stature, blood pressure and intelligence show continuous variation. Each of these characteristics is represented by a range of values. Such characteristics are determined by several genes, which also interact with the environment, and therefore show polygenic inheritance. For example stature is determined by a number of inherited genes, but a high nutritional level during childhood also contributes to increase stature. Inherited genetic diseases are examples of discontinuous variation. The disease is either present or is not, and there is no intermediate range. They show monogenic inheritance. 1.1) AUTOSOMAL DOMINANT INHERITANCE: Patterns of inheritance: Autosomal dominant inheritance manifests itself in the heterozygote. The trait is equally represented in males and females. The trait shows vertical inheritance through generations i.e. transmission from parent to offspring. Affected parents have 50% chance that their offspring will be similarly affected. The trait does not skip generations. It is transmitted by either sex. EXAMPLES OF AUTOSOMAL DOMINANT DISORDERS: Achondroplasia: a type of dwarfism characterised by short limbs, a normal-sized trunk and various skeletal abnormalities. Adult polycystic kidney disease: multiple cysts in the kidneys and liver causing symptoms and complications in adult life and leading to progressive renal failure. Brachydactyly: meaning short fingers or toes. Usually, the middle phalanx is short. There are several varieties. In most cases it causes no inconvenience to affected individuals. Congenital Spherocytosis: the red blood cells are in the form of spheres rather than flat biconcave discs; they cause anaemia. Familial Adenomatous Polyposis (FAP): numerous polyps in the large intestine becoming cancerous in most cases. Familial Hyperlipidaemia: elevated blood levels of low-density lipoproteins predisposing to coronary heart disease at a young age. This is the commonest autosomal dominant disorder. Huntington's disease: a late-onset neurological disorder, appearing usually around the age of 35 years and characterized by abnormal, involuntary writhing movements (chorea) and behaviour and personality disorders. It is a severely incapacitating and progressive disorder resulting in early death. Marfan's syndrome: a disorder of connective tissue. It causes abnormalities of the skeleton including tall stature, wide arm span, spidery fingers and deformities of the sternum; cardiovascular abnormalities such as aortic aneurysm or heart valve incompetence and subluxation of the lens. Neurofibromatosis: characterized by numerous cafe-au-lait pigmented patches and multiple benign tumours of the nerve sheaths (neurofibromas) causing irregular swellings in the skin Postaxial Polydactyly: characterized by an extra digit on the side of the little finger or little toe, this may vary from a small tag to a well-developed digit. The extra digit is usually removed in early infancy and forgotten. Tuberous sclerosis (adenoma sebaceum): characterised by an adenomatous rash on the cheeks, calcifications in the brain and fits. 2 Situations that may modify the pattern of autosomal dominant inheritance: Some autosomal dominant disorders do not always appear to follow the general rules stated above. Some cases do not have the characteristic pedigree and have a negative family history. This may be due to one of the following phenomena: a) Conditions that manifest themselves late in life: The typical example is Huntington's disease. Although the gene for Huntington's disease is present from the time of conception, affected individuals are normal until symptoms appear, usually around the age of 45 years. Many individuals who carry the abnormal gene marry and have children before the disease appears. The age at onset of the disease is very variable ranging from 20 to 70 years. Some individuals who have the abnormal gene might die from unrelated causes before the disease appears. Thus the pedigree may show an unaffected person who has affected offspring. b) New Mutations: Autosomal dominant conditions that have a negative family history are usually the results of new mutations. Individuals with a severe disorder such as achondroplasia often have reduced chances of getting married and having children, because of medical or social reasons. Achondroplastic dwarfs have 50% of their children similarly affected. Most cases of achondroplasia, however, have normal parents. These cases are the result of new mutations. For a normal couple who had a child with achondroplasia arising as a new mutation, there would be no increased recurrence risk for their other children. However, the affected child would have a 50% chance of having affected offspring. c) Variable Expressivity: There is often a considerable variation in the severity of the disorder or in the type of abnormalities present although the genetic defect is the same. This is referred to as variable expressivity. Most genetic diseases show some degree of variable expressivity. For example, in postaxial polydactyly the extra digit may vary from a small skin tag to a fully formed digit. In Marfan's syndrome affected individuals often do not have all the characteristics - one individual may be present with tall stature and subluxated lens, another with an aortic aneurysm. Sometimes the variability may be so great that there may be little resemblance in phenotypic manifestations of an affected individual and his affected 3 offspring. For example, in one type of limb reduction deformity the disorder may be expressed to variable degrees from a missing finger to a missing leg. d) Penetrance: In some cases individuals who carry an abnormal gene do not appear to manifest any symptoms of the disease, although their offspring may be affected and it would appear in the pedigree that the disease has "skipped a generation". The reason for this could be reduced penetrance. Penetrance is a measure of how frequently a gene is expressed. It is the proportion of heterozygotes who manifest the disorder. Some autosomal dominant conditions e.g. achondroplasia have 100% penetrance i.e. when the gene is present the disease always express itself. In other conditions there may be reduced penetrance. Retinoblastoma is an autosomal dominant condition that has 85% penetrance i.e. only 85% of persons carrying the abnormal gene show symptoms of the condition; the remaining 15% never develop retinoblastoma but can still transmit the gene to their offspring. Penetrance is important in the assessment of recurrence risks. 1.2) AUTOSOMAL RECESSIVE CONDITIONS: Patterns of inheritance: The condition manifests itself only in homozygotes; The parents of an affected individual are both heterozygous (carriers) but are phenotypically normal; The condition is often present among sibs but is not usually transmitted through generations. The offspring of heterozygous parents have a 1 in 4 chance of being affected; the ratio of affected to normal offspring is 1: 3. An almost equal number of affected males and females. In case both the parents are affected, all children would be affected. EXAMPLES OF AUTOSOMAL RECESSIVE DISEASES: Albinism: There is lack of pigment in the skin, hair and eyes due to a deficiency in one of the enzymes (e.g. tyrosinase) that is necessary for the formation of melanin 4  pigment from tyrosine. Lack of pigment may cause visual problems and sensitivity of the skin to sunlight. Beta Thalassaemia: The adult type of haemoglobin (HbA) is not produced or is produced in very small amounts due to a defect in the production of beta-globin. This causes severe anaemia beginning in early childhood and requiring frequent blood transfusions. The bone marrow increases greatly in amount, trying to compensate for the anaemia, causing a thickening of the bones of the skull and face. Congenital Hypothyroidism: This is due to lack of secretion of the hormone thyroxine. Severe mental retardation results unless replacement therapy with thyroxine is started in early infancy. Cystic Fibrosis: A disorder in the secretions of glands affecting mainly the respiratory system, pancreas and sweat glands; death in infancy may result from recurrent severe pulmonary infections. Galactosaemia: This is due to lack of an enzyme required to metabolise galactose. High levels of galactose are present causing mental retardation, cataracts and cirrhosis of the liver. These consequences can be prevented if the disorder is recognised and treated in early infancy using special milk substitutes that do not contain galactose and lactose. Gangliosidosis: Deficiency of the enzyme beta galactosidase causes accumulation of ganglioside in the tissues including the brain, bone marrow, liver and spleen; involvement of the brain causes fits, severe mental deterioration. Death usually occurs in infancy. Phenylketonuria: A defect in phenylalanine metabolism causing mental retardation unless a special diet is started early enough in infancy. Sickle cell anaemia: A disorder of the haemoglobin molecule causing the red blood cells to become sickle shaped and rupture under conditions of low oxygen tension. This results in severe haemolytic anaemia. 2) SEX-LINKED INHERITANCE: The sex chromosomes(X and Y) besides carrying the sex-determinant genes also bear genes for several other characters. These additional genes travel along with the sex 5 controlling genes from generation to generation, and are, therefore called sex-linked genes. The characters controlled by the sex linked genes are termed sex-linked characters. Inheritance of sex-linked genes or traits is known as Sex-linked inheritance. Their location in the sex chromosome is called sex-linkage. Most sex-linked genes are located on X- chromosome, forming X-linkage. A few genes occur on the Y-chromosome, forming Y- linkage. The Y-linked traits are transmitted only through the male, for example, gene for sex determination in mammals. The Y-chromosome carries so few genes that it is described as genetically inert or genetically empty. The sex-linkage was first discovered by Morgan in 1910 in the fruit fly, Drosophila melanogaster. This fly, has XX and XY sex chromosomes in the female and male respectively. Its eye color gene is located in the X-chromosome, and there is no corresponding allele in the Y-chromosome. The male expresses a sex-linked recessive trait even if it has a single gene for it, whereas the female expresses such a trait only if it has two genes for it. The normal eye colour is red and is dominant over the mutant white eye colour. The following crosses illustrate the inheritance of X-linked eye colour in Drosophila. i. Red-eyed Female X White-Eyed Male: If a homozygous red-eyed female fly is mated with a hemizygous (having a single allele for a trait) white-eyed male fly, all the F1 flies irrespective of their sex, are red eyed. When the red eyed male and female flies of F1 are intercrossed, the F2 flies are in the ratio of 2 red-eyed females to 1 red- eyed male to 1 white-eyed male. Thus, the red-eyed and white-eyed flies are in the ratio of 3:1 in F2 generation (Mendelian monohybrid ratio). The above cross shows that a recessive X-linked trait follows criss-cross inheritance i.e., transmission from the father to the grandsons through the daughters. The latter are called carriers because they have a trait but do not express it. ii. White-eyed Female X Red-eyed Male: In this cross, a homozygous white-eyed female fly is mated with a hemizygous red-eyed male fly. This cross is reciprocal (opposite) of the previous cross and should yield the same result. But in its F1progeny, all the males are white-eyed, and all the females are red-eyed. This result shows that eye colour and sex are linked. When a red-eyed female fly and a white- eyed male fly of F1 are intercrossed, F2 progeny comprises approximately equal numbers of red-eyed females, white-eyed females, red-eyed males and white-eyed 6  males. The above cross shows that the father transmits its dominant sex-linked trait (red eyes) to his grandsons as well as granddaughters through daughters. This proves that the eye-colour gene lies in the X-chromosome. The sex-linked inheritance can be studied in following three headings:- 2.1) Patterns of X-linked recessive inheritance: Most affected individuals are males Usually none of the offspring of the affected male will be affected, but all his daughters will carry the gene in masked heterogygous condition. None of the sons of an affected male will be affected. Affected males result from mothers who are affected or who are known to be carriers (heterozygotes). Affected females come from affected fathers and affected or carrier mother. The sons of effected females should be affected. Approximately half the sons of carrier mother should be affected. EXAMPLES OF X-LINKED RECESSIVE INHERITANCE DISORDERS Duchenne muscular dystrophy: Occurs due to the deficiency of protein dystrophin, dystrophin is a protein of high molecular weight that is associated with a transmembrane glycoprotein complex of skeletal muscle cells. It is characterized by muscular degeneration and weakness and sometimes also associated with mental retardation. Hemophilia A: Classical form of blood clotting deficiency; deficiency of clotting factor VIII. Hemophilia B: Christmas disease, deficiency of clotting factor IX. Glucose 6-phosphate dehydrogenase deficiency: Deficiency of glucose 6- phosphate dehydrogenase enzyme, severe anemic reaction following the intake of primaquines in drugs and certain foods, including fuva beans. Lesh-Nyhan syndrome: Deficiency of hypoxanthiane-guanine phosphate ribosyl transferase enzyme. It leads to motor and mental retardation, self mutilation and early death. Colour blindness, protan type: Insensitivety to red light. Colour blindness, deutan type: Insensitivety to green light. 7 2.2) Patterns of X-linked dominant inheritance: It is frequently found in females than in males. Affected females come from affected mothers or fathers. Affected males come from affected mothers. Approximately half of the children of an affected heterozygote female are affected. All daughters, but none of the sons, of an affected father are affected. The trait usually does not skip generations. EXAMPLE: Hypophosphatemia (Vit. D resistant rickets) Hereditary enamel hypoplasia 2.3) Patterns of Y-linked inheritance Genes in the non-homologus region of Y- chromosome pass directly from male to male and show following pattern of inheritance: Affects only males Affected males always have an affected father All sons of an affected male are affected EXAMPLE: Ichthyosis hystrix gravis hypertrichosis 3) SEX-LIMITED INHERITANCE: Certain genes produce characters in one sex only, but not in both even though they are present in both the sexes. Such characters are called sex-limited characters. The genes of these characters are located in the autosomes instead of in the sex chromosomes. So, the sex limited traits are the autosomal traits in which the dominant expression depends on the sex hormones of the individuals. The sex-limited characters develop only in the presence of sex hormones. Sex-limited genes are genes that are present in both sexes of sexually reproducing species but are expressed in only one sex and remain 'turned off' in the other. In other words, sex- limited genes cause the two sexes to show different traits or phenotypes, despite having the 8 same genotype. This term is restricted to autosomal traits, and should not be confused with sex-linked characteristics, which have to do with genetic differences on the sex chromosomes. Sex-limited genes are also distinguished from sex-influenced genes, where the same gene will show differential expression in each sex. Sex-influenced genes commonly show a dominant/recessive relationship, where the same gene will have a dominant effect in one sex and a recessive effect in the other (for example, male pattern baldness). Sex-limited genes are responsible for sexual dimorphism, which is a phenotypic (directly observable) difference between males and females of the same species. These differences can be reflected in size, color, behavior (e.g., levels of aggression), and morphology. An example of sex-limited genes are genes which instruct the male elephant seals to grow big and fight, at the same time instructing female seals to grow small and avoid fights. These genes are also responsible for some female beetles' inability to grow exaggerated mandibles. The overall point of sex-limited genes is to resolve intralocus sexual conflict. In other words, these genes try to resolve the "push-pull" between males and females over trait values for optimal phenotype. Without these genes, organisms would be forced to settle on an average trait value, incurring costs on both sexes. With these genes, it is possible to 'turn off' the genes in one sex, allowing both sexes to attain (or at least, approach very closely) their optimal phenotypes. Many studies have been published exploring the genetic basis of sex-limited genes. One paper, published in Evolution, evaluates the hypothesis that sex-limited traits can arise in two ways. The alleles responsible for sexual dimorphism can be limited to expression in only one sex when they first appear, or the alleles could begin by being expressed in both sexes then become modified (repressed or promoted) in one sex by modifier genes or regulatory elements. The concept of this study was to examine female hybrids from species where males displayed different types of ornamental traits (elongated feathers, wattles, color patches). The assumption is that different hypotheses about male-specific expression will yield different results in female hybrids. The most likely genomic explanation for initial expression in both species then modification is involvement of cis-dominance, where the factors that modify the gene are located next to the gene on the chromosome. (This is in contrast to trans- dominance, where mobile products that can affect distant genes are produced.) These factors can be in the form of promoter regions, which can be either be suppressed or 9 activated by hormones. This experiment also demonstrates that these alleles come under regulatory control very quickly. This is because none of the ornamentation seen in males is seen in the very next generation. These conclusions make it likely that at least some male- specific (thus, sex-limited) genes cue their expression by hormone levels - the absence of estrogen or the presence of testosterone. Because sex-limited genes are present in both sexes but only expressed in one, this allows the unexpressed genes to be hidden from selection. On a short-term scale, this means that during one generation, only the sex that expresses the sex-limited trait(s) of interest will be affected by selection. The remaining half of the gene pool for these traits will be unaffected by selection because they are hidden (unexpressed) in the genes of the other sex. Since a portion of the alleles for these sex- limited traits are hidden from selection, this occurrence has been termed 'storage-effect'. On a long-term scale, this storage effect can have significant effects on selection, especially if selection is fluctuating over a long period of time. It is inarguable that selection will fluctuate over time with varying levels of environmental stability. For example, fluctuations in population density can drive selection on sex-limited traits. In less dense populations, females will have less opportunity to choose between males for reproduction. In this case, attractive males may experience both reduced reproductive success and increased predation pressure. Thus, selection on males for sex-limited traits such as increased size (elephant seals) and weaponry (claws on fiddler crabs, horns on rhinoceros beetles) will change direction with fluctuation in population density. EXAMPLES OF SEX LIMITTED INHERITANCE: Bright plumage in some male birds Milk secretion in female mammals. The bulls have the genes for the milk production which they transmit their daughters but they or their sons are unable to express this trait. The production of milk is, therefore, limited to variable expression only in the female sex. Beard development in human beings is a sex limited trait as men normally have beards, whereas women normally do not. Likewise, the genes for male voice, body hair and physique are autosomal in human beings, but they are expressed only in the presence of androgens which are absent in females. 10 4) SEX-INFLUENCED INHERITANCE: In sex influenced traits an allele is dominant in one gender but recessive in the other gender. In such type of inheritance the dominance is influenced by the sex of the bearer. Thus male and female may be similar for a particular trait but give different phenotypic expression of the same trait. EXAMPLES OF SEX INFLUENCED INHERITANCE: Harelip is more common and more severe in males than in females. Pattern baldness in man is also a sex-influenced trait. In pattern baldness, hair is lost on the head top but persist as a fringe low on the head. It is more common in males than in females. Women who have genotype for pattern baldness typically show only thinning of hair. Moreover, man becomes bald if he has only one allele for baldness; whereas a woman needs two alleles for baldness to lose hair. This is the reason why bald woman are rare. 11 Genotype Phenotype: Male Female BB Bald Bald Bb Bald No bald Bb No bald No bald 5.) MITOCHONDRIAL INHERITANCE: Mitochondrion: Fig: mitochondrial DNA Mitochondrial inheritance Mitochondrial genes show maternal inheritance because all the mitochondria a zygote has come from the cytoplasm of the ovum. Thus, in most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). This pattern of inheritance is also known as extra chromosomal inheritance. Mutations in the mitochondrial genes cause some rare human disorders. For example, a person with the disease named mitochondrial myopathy suffers weakness, intolerance of exercise and muscle deterioration. Mechanisms for this include simple dilution (an egg contains on average 200,000 mtDNA molecules, whereas a healthy human sperm was reported to contain 12 on average 5 molecules), degradation of sperm mtDNA in the female genital tract, in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Patterns of Mitochondrial inheritance Female inheritance In sexual reproduction, mitochondria are normally inherited exclusively from the mother; the mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells; sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo. Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this. The fact that mitochondrial DNA is maternally inherited enables genealogical researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paternally inherited, is used in an analogous way to determine the patrilineal history.) This is usually accomplished on human mitochondrial DNA by sequencing the hypervariable control regions (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a genealogical DNA test. HVR1, for example, consists of about 440 base pairs. These 440 base pairs are then compared to the control regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. mtDNA is highly conserved, and its relatively slow mutation rates (compared to other DNA regions such as microsatellites) make it useful for studying the evolutionary relationships—phylogeny—of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined. However, due to the slow mutation rates it experiences, it is often hard to distinguish between closely related species to any large degree, so other methods of analysis must be used. 13 The mitochondrial bottleneck Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell. Male inheritance Doubly uniparental inheritance of mtDNA is observed in bivalve mollusks. In those species, females have only one type of mtDNA (F), whereas males have F type mtDNA in their somatic cells, but M type of mtDNA (which can be as much as 30% divergent) in germline cells. Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies, honeybees, and periodical cicadas. Male mitochondrial inheritance was recently discovered in Plymouth Rock chickens. Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice, where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep, and in cloned cattle. It has been found in a single case in a human male. Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo inheritance and persistence under lab conditions. Three-parent inheritance An artificial reproductive process known as mitochondrial donation or Three Parent InVitro Fertilization (TPIVF) results in offspring containing mtDNA from a donor female, and nuclear DNA from another female and a male. In the spindle transfer procedure, the nucleus of an egg is inserted into the cytoplasm of an egg from a donor female which 14 has had its nucleus removed, but still contains the donor female's mtDNA. The composite egg is then fertilized with the male's sperm. The procedure is used when a woman with genetically defective mitochondria wishes to procreate and produce offspring with healthy mitochondria. The first known child to be born as a result of spindle transfer TPIVF was a boy born to a Jordanian couple in Mexico on April 6, 2016. 15