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  3. 3. Introduction: The science of genetics is concerned with the inheritance of traits, whether normal or abnormal, and with the interaction of genes and the environment. Inheritance has always interested man. Carvings in stone – 6000 years old – showing family trees and patterns of certain inheritance have been found. The first mention of the heritability of Haemophillia can be traced to writings 1500 years ago. The question of whether environment or genetics exerts the greater influence in the aetiology of malocclusion has been a matter of debate since the origin of orthodontics. As far back as 1891, Kingsley was unequivocal in his views in describing inheritance as a major factor in producing malocclusion. Edward H. Angle (1907) was equally adamant in his belief that malocclusions arise from local causes. None the less, the modern knowledge of genetics and patterns of inheritance have been explained only relatively recently.
  4. 4. • In the early 1700s Pierre Louis Moreau de Maupertuis was the first to propose that there were certain hereditary particles. Each body part is formed by 2 such particles – one from each parent. One particle might dominate the other, so that the trait of the offspring may resemble one parent more than the other. • But our present idea of genetics starts with the work of Gregor Mendel, and his work on various varieties of garden peas (Pisum sativum). • His work was not something that was never done, but he was the first to notice that the inheritance units obeyed certain statistical laws.
  5. 5. • Mendel selected 7 pairs of contrasting characteristics in the garden pea. (Eg. Tall or dwarf, yellow or green seeds, violet or white flowers etc.) • The two contrasting varieties were crossed and the first set of offspring was known as the first filial (or F1) generation. The next was known as the F2 generation, and so on. • In the F1 generation, the offspring always resembled only one parent. The character which was manifested was referred to as the dominant, and the other as the recessive
  6. 6. When these were self pollinated, the offspring were seen to have both characteristics- in the ratio 3:1. When the F2 was self pollinated, the result was as follows- Recessive character - all recessive Dominant character – 1/3rd all dominant 2/3rd both characters in the ratio 3:1 Hence the ratio of the off spring in F2 is actually 1:2:1 (Dominant : hybrid : recessive).
  7. 7. This lead Mendel to conclude:- • That there are 2 factors which determine a specific character • The parent transmits only one of the pair to the offspring. • It is only a matter of chance as to which of the transmitted pairs unite. This is referred to as Mendel’s 1st law, or the Law of Segregation.
  8. 8. The law of Unit Inheritance – Before Mendel’s time it was believed that the characteristics of parents blended into the offspring. Mendel clearly stated that blending did not occur. Also, that the characteristics of one parent may not appear in one generation (F1) but may reappear in the next generation (F2). Law of Independent assortment – Members of different gene pairs assort to the gametes (sex cells) independently of one another. There is a random recombination of paternal and maternal chromosomes in the gametes.
  9. 9. Nevertheless, Mendel’s contribution went unnoticed for a long time. Even though Charles Darwin put forth his theory of hereditary nature of variations, which lead to the evolution of species, the actual mechanism of inheritance was unknown. At the beginning of the 20th century, 3 independent workers *Vries in Holland, *Correns in Germany and *Tschermak in Austria rediscovered Mendel’s laws, and that heralded the beginning of genetics as a science.
  10. 10. Terminology GeneticsTour A gene is a unit of information and corresponds to a discrete segment of DNA with a base sequence that encodes the amino acid sequence of a polypeptide. The genes responsible for contrasting characters are called alleles Genome all the genes carried by a cell
  11. 11. Genotype is defined as the genetic constitution of an individual, and may refer to specified gene loci or to all loci in general. An individual’s phenotype is the final product of a combination of genetic and environmental influences. Phenotype may refer to a specified character or to all the observable characteristics of the individual. Trait is any detectable phenotypic property Homozygous – an individual who has the same factors for a particular characteristic. (eg-TT or yy) Heterozygous – individual with different factors (Tt or Yy) In a heterozygous individual the character that is manifested is the dominant, and the other is the recessive character.
  12. 12. History of Human Genetics The human genome contains approximately 3 billion nucleotides, making up about 100,000 alleles, which in turn are contained on 46 chromosomes. Transcription of these chromosomes releases the information necessary to synthesize some 6000 proteins. These proteins make up the trillion cells giving rise to the nearly 4000 anatomical structures that constitute a single human being. Mutation, the accidental alteration of the genome, may result in heritable conditions or syndromes affecting any aspect of growth and development.
  13. 13. Interest in human genetics started by following various hereditary conditions through family trees, or pedigrees. The earliest diseases to be studied were albinism, polydactyly (early 1700s) and hemophilia (early 1800s). Another aspect that received some attention was consanguineous marriages. The effects of “Nature and Nurture” were studied from the mid 1800s by Galton. He also was interested in the hereditary improvement if men and animals by selective breeding – and coined the term eugenics for
  14. 14. In the early 1900s Sir Garrod discovered that some families had a condition known as alkaptonuria - in which the affected individual secretes dark urine. He found that it was found in families. But it was not simply passed from parent to child. The children were usually normal, but the disorder could reappear later in the descendents. Although it had been long since Mendel had done his experiments, it was around this time that they were being rediscovered. Garrod realized that this is a Mendelean recessive type of inheritance. It occurs due to excretion of homogentisic acid which is usually metabolized in normal individuals. So the genes seemed to have something to do with the production of the enzyme. This was the first time that the idea that genes control the synthesis of enzymes arose.
  15. 15. But even though he gained recognition, Garrod’s contemporaries did not realize that this does not apply only to rare inherited disorders, but was actually the basis of life. At around the same time, Landsteinter discovered the ABO blood groups, and that gave rise to the branch of blood group genetics.
  16. 16. The Chromosome Theory of Inheritance It was well known for a long time that cells contained a nucleus and that the nucleus had threadlike substances called chromosomes (chroma = colour, chromosomes took up certain stains very easily). In 1903, Sutton and Boveri , independently, proposed that it was the interaction between these chromosomes that lead to the phenomenon of inheritance. They behaved just like Mendel’s factors – occur in pairs and come one from each parent.
  17. 17. Structure of Nucleic Acid Nucleic acid was first isolated as early as 1869 by a Swiss doctor named Meicher, from pus soaked bandages of wounded solders. He found a compound which was very rich in phosphorous, which was quite unique. Initially, he named it nuclein. He had even postulated in 1892 that this might be the actual hereditary factor. But few people believed in this, as they thought it was not possible, until the structure of DNA was proposed in 1953. For many years it was felt that protein was the basic substance of life. Although nucleic acid had been discovered, its importance in protein formation was not appreciated until the work of Griffith and later Avery Macleod and McCarthy (on pneumococci) and Hershey and Chase (using bacteriophages).
  18. 18. Nucleic acid It is composed of long chains of molecules called nucleotides. Each nucleotide is composed of :- A nitrogenous base A sugar molecule, and A phosphate molecule
  19. 19. • The nitrogenous bases are of 2 types – purines and pyrimidines. • The purines include – • adenine and guanine • The pyrimidines include – • cytosine, thymine and uracil. • The nucleic acids can further be of 2 types depending on the sugar molecule – • Sugar – ribose  Ribonucleic acid or RNA • Sugar – deoxyribose  Deoxyribonucleic acid or DNA
  20. 20. Structure of DNA The structure of DNA was suggested by Wilkins, Watson and Crick. The DNA molecule is composed of 2 chains of nucleotides arranged in a double helix. The backbone of each chin is formed by the sugar-phosphate molecules and the 2 chains are held together by hydrogen bonds between the nitrogenous bases which point in towards the centre of the
  21. 21. COMPLEMENTARY BASE PAIRING The bases of the two polynucleotide chains interact with each other. Thymine always interacts with adenine and guanine with cytosine (i.e. A-T and G-C). The way in which the bases form pairs between the two DNA strands is known as complementary base pairing. Complementary base pairing is essential for the expression of genetic information and is central to the way DNA sequences are transcribed into mRNA and translated into protein.
  22. 22. X-ray diffraction pictures of the double helix show repeated patterns of bands that reflect the regularity of the structure of the DNA. The double helix executes a turn every 10 base pairs. The pitch of the helix is 34A so the spacing between bases is 3.4A. The diameter of the helix is 20A. The double helix is said to be antiparallel. One of the strands runs in the 5’→3’ direction and the other 3’→5’ direction. The double helix is not absolutely regular and when viewed from the outside a major groove and a minor groove can be seen. These are important for interaction with proteins, for replication of the DNA and for expression of the genetic information. .
  23. 23. TYPES OF DNA SEQUENCES Analysis of human DNA have shown that approximately 60-70% of the human genome consists of single or low copy number DNA sequences. The remainder of the genome, some 30-40% consists of either moderately or highly repetitive DNA sequences. NUCLEAR DNA (A) Nuclear genes (i) Unique single copy genes (ii) Multigene families – e.g. the HOX homeobox gene family. -Classical gene families -Gene super families (B) Extragenic DNA (i) Tandem repeat Satellite Minisatellite -Telomeric -Hypervariable Microsatellite (ii) Interspersed *Short interspersed nuclear elements *Long interspersed nuclear
  24. 24. MITOCHONDRIAL DNA Two rRNA genes 22 tRNA genes 13 genes coding for proteins involved in oxidative phosphorylation.
  25. 25. 1) Replication Replication of the DNA molecule occurs in what is termed as the semi-conservative method. The individual chains divide at multiple sites, and, on account of the specific base pairing, the complementary chain is formed. So the daughter cell has one parent strand and one new strand. 2) Genetic code within the DNA molecule. The Watson and Crick model of the DNA molecule also helps to explain the genetic code. There are 20 different amino acids. Since the function of genes is to synthesize proteins, it is safe to assume that the genes actually code the sequence of the amino acids needed to produce each protein. The arrangement of the nitrogenous bases is what gives the code for the amino acids. Since there are 4 bases and 20 amino acids, it can be calculated that groups of 3 bases are essential for coding the amino acids. The triplet code for one amino acid is called a codon.
  26. 26. Transcription and translation The information in the DNA is transmitted to a particular type of RNA called the messenger – RNA. This occurs in a similar way to DNA replication. Complementary bases are found in the RNA. Cytosine with guanine, thymine with adenine, and adenine with uracil. Nucleus DNA TRANSCRIPTION mRNA TRANSLATION (rRNA, tRNA) Cytoplasm ) Protein
  27. 27. The m-RNA is then associated with Ribosome, which are actually the sites for protein synthesis. The m-RNA forms a template for the synthesis of the protein. In the cytoplasm, there is another form of RNA called transfer- RNA. For the incorporation on amino acids into a polypeptide chain, the amino acid must first be activated by reacting with ATP. Then the activated amino acid attaches itself to one end of a particular transfer RNA. The other end of the transfer RNA combines with the m-RNA. Thus a particular triplet on the m-RNA is related through transfer RNA to a specific amino acid. The ribosome moves along the messenger – RNA in a zipper – like fashion, the amino acids linking up to form the polypeptide chain. The rule that there is transfer of genetic information from DNA to RNA to the protein is called the “CENTRAL DOGMA” of molecular genetics.
  28. 28. Gene Structure The term gene, coined by a Danish botanist Johannsen, represents the hereditary factors. A gene is a unit of information and corresponds to a discrete segment of DNA with a base sequence that encodes the amino acid sequence of a polypeptide. Genes vary greatly in size from less than 100 base pairs to several million base pairs. In humans there are an estimated 50-100000 genes arranged on 23 chromosomes.
  29. 29. The genes are very dispersed and are separated from each other by sequences that do not contain genetic information.; this is called intergenic DNA. The intergenic DNA is very long, such that in humans gene sequences account for less than about 30% of the total DNA. Only one of the two strands of the DNA double helix carries the biological information and this is called the template strand or sense or coding strand, which is used to produce an RNA molecule of complementary sequence which directs the synthesis of a polypeptide. The other strand is called the nontemplate strand or antisense or noncoding strand.
  30. 30. Gene promoters Expression of genes is regulated by a segment of DNA sequence present upstream of the coding sequence known as the promoter. Conserved DNA sequences in the promoter are recognized and bound by the RNA polymerase and other associated proteins called transcription factors that bring about the synthesis of RNA transcript of the gene.
  31. 31. Introns and Exons In genes coding information is usually split into a series of segments of DNA sequence called exons. These are separated by sequences that do not contain useful information called introns. The length of exons and introns varies but the introns are usually much longer and account for the majority of the sequence of the gene. Before the biological information in a gene can be used to synthesize a protein, the introns must be removed from RNA molecules by a process called splicing which leaves the exons and the coding information continuous.
  32. 32. DEVELOPMENTAL GENE FAMILIES Several gene families have been identified in vertebrates any mutations occurring in various members of these families ca result in either isolated malformations or multiple congenital anomaly syndromes . 1. Segmentation genes 2. Paired-box genes (PAX) 3. Zinc finger genes 4. Signal transduction (‘Signalling’) genes 5. Homeobox genes (HOX)
  33. 33. SEGMENTATION GENES Insect bodies consist of series of repeated body segments which differentiate into particular structures according to their position. Three main groups of segmentation determining genes have been classified on the basis of their mutant phenotypes. (A) Gap mutants – delete groups of adjacent segments (B) Pair-rule mutants – delete alternate segments (C) Segment polarity mutants – cause portions of each segment to be deleted and duplicated on the wrong side. (i) Hedgehog (Vertebrates) • Sonic Hedgehog • Desert Hedgehog • Indian Hedgehog (ii) Wingless
  34. 34. Hedgehog morphogens are involved in the control of left- right asymmetry, the determination of polarity in the central nervous system, somites and limbs, and in both organogenesis and the formation of the skeleton. In humans, Sonic hedgehog (SHH) plays a major role in development of the ventral neural tube with loss-of- function mutations resulting in a serious and often lethal malformation known as holoprosencephaly where the facial features shows eyes close together and there is a midline cleft lip due to failure of normal prolabia development.
  35. 35. PAIRED-BOX GENES (PAX) The mammalian Pax gene family consists of nine members that can be organized into groups based upon sequence similarity, structural features, and genomic organization. The four groups include 1. Pax1 and Pax9 2. Pax2, Pax5, and Pax8 3. Pax3 and Pax7 and 4. Pax4 and Pax6
  36. 36. ZINC FINGER GENES The term zinc finger refers to a finger-like loop projection which is formed by a series of four amino acids which form a complex with a zinc ion. Genes, which contain a zinc finger motif, act as transcription factors through binding of the zinc finger to DNA. SIGNAL TRANSDUCTION GENES Signal transduction is the process whereby extracellular growth factors regulate cell division and differentiation by a complex pathway of genetically determined intermediate steps. Mutations in many of the genes involved in signal transduction can cause developmental abnormalities. Fibroblast growth factor receptors (FGFRs) belong to the category of signal transduction genes.
  37. 37. HOMEOBOX GENES (HOX) AND ITS IMPORTANCE Since their discovery in 1983, the homeobox genes were originally described as a conserved helix-turn-helix DNA motif of about 180 base pair sequence, which is believed to be characteristic of genes involved in spatial pattern control and development. The protein domain encoded by the homeobox, the homeodomain, is thus about 60 amino acids long. Proteins from homeobox containing, or what are known as HOX genes, are therefore important transcription factors which specify cell fate and establish a regional anterior/posterior axis. The first genes found to encode homeodomain proteins were Drosophila developmental control genes, in particular homeotic genes, from which the name "homeo"box was derived. However, many homeobox genes are not homeotic genes; the homeobox is a sequence motif, while "homeotic" is a functional description for genes that cause homeotic transformations.
  38. 38. Four homeobox gene clusters (HOXA, HOXB, HOXC, and HOXD) that comprise a total of 39 genes have been identified in humans. Each cluster contains a series of closely linked genes. In each HOX cluster there is a direct linear correlation between the position of the gene and its temporal and spatial expression. These observations indicate that these genes play a crucial role in early morphogenesis. Lower number HOX genes are expressed earlier in development and more anteriorly and proximally than are the higher number genes.
  39. 39. Homeobox gene clusters in humans Cluster Number of genes Chromosome location HOXA (=HOX1) 11 (1-7, 9-11, 13) 7p HOXB (=HOX2) 10 (1-9, 13) 17q HOXC (=HOX3) 9 (4-6, 8-13) 12q HOXD (=HOX4) 9 (1, 3, 4, 8-13) 2q In humans each branchial arch exhibits a specific combination of Hox gene expression. So far no Hox genes been detected in the brain, and researchers claim that this is due to the highly evolved nature of the human brain.
  40. 40. Examples of Homeobox genes, and their effects in humans – Msx -1  involved in the development of secondary palate and tooth. Failure to express this gene results in familial tooth agenesis – features - missing 2nd premolar and 3rd molar (Studies in Finnish families by Nieminen et al 1995). Msx- 2  Disruption of this gene causes Craniosynostosis SHH (Sonic hedgehog gene)  involved in the patterning of Neural crest and neural tube – deficiency in expression of SHH affects midline structures – which are underdeveloped. Excess expression of SHH results in Hytertelorism
  41. 41. HOMEODOMAIN The homeodomain is a DNA-binding domain, and many homeobox genes have now been shown to bind to DNA and regulate the transcription of other genes. Thus homeodomain proteins are basically transcription factors, most of which play a role in development. The homeodomain is a common DNA-binding structural motif found in many eukaryotic regulatory proteins. Homeodomain proteins are involved in the transcriptional control of many developmentally important genes, and 143 human loci have been linked to various genetic and genomic disorders.
  42. 42. X-ray crystallographic and NMR spectroscopic studies on several members of this family have revealed that the homeodomain motif is comprised of three α-helices that are folded into a compact globular structure. Helices-I and II lie parallel to each other and across from the third helix. This third helix is also referred to as the “recognition helix”, as it confers the DNA binding specificity if individual homeodomain proteins. The homeodomain has been evolutionarily conserved at the structural level. This is most evident upon examination of divergent members of the homeodomain family.
  43. 43. MUTATION A mutation is defined as a heritable alteration or change in the genetic material. A mutation arising in a somatic cell cannot be transmitted to offspring, whereas if it occurs in gonadal tissue or a gamete it can be transmitted to future generations. Herman Muller went on to use x-rays to cause mutations in fruit flies – for which he won the Nobel Prize.
  44. 44. TYPES OF MUTATIONS Mutations occur in two forms: Point mutations - involve a change in the base present at any position in a gene Gross mutations - involve alterations of longer stretches of DNA sequence. The location of the mutation within a gene is important. Only mutations that occur within the coding region are likely to affect the protein. Mutations in noncoding or intergenic regions do not usually have an effect.
  45. 45. Point mutations 1. Missense mutations 2. Nonsense mutations 3. Frameshift mutations 4. Silent mutations Gross mutations 1. Deletions 2. Insertions 3. Rearrangements
  46. 46. Missense mutations These point mutations involve the alteration of a single base which changes a codon such that the encoded amino acid is altered. Such mutations usually occur in one of the first two bases of a codon. The redundancy of the genetic code means that mutation of the third base is likely to cause a change in the amino acid. The effect of a missense mutation on the organism varies. Most proteins will tolerate some change in their amino acid sequence. However, alterations of amino acids in parts of the protein that are important for structure or function are more likely to have a deleterious effect and to produce a mutant phenotype.
  47. 47. Nonsense mutations These are point mutations that change a codon for an amino acid into a termination codon. The mutation causes translation of the messenger RNA to end prematurely resulting in a shortened protein which lacks part of its carboxyl-terminal region. Nonsense mutations usually have a serious effect on the activity of the encoded protein and often produce a mutant phenotype.
  48. 48. Frameshift mutations These result from the insertion of extra bases or the deletion of existing bases from the DNA sequence of a gene. If the number of bases inserted or deleted is not a multiple of three the reading frame will be altered and the ribosome will read a different set of codons downstream of the mutation substantially altering the amino acid sequence of the encoded protein. • Frameshift mutations usually have a serious effect on the encoded protein and are associated with mutant phenotypes.
  49. 49. Silent mutations Mutations may occur at the third base of a codon and, due to the degeneracy of the genetic code, the amino acid will not be altered. Silent mutations have no effect on the encoded protein and do not result in a mutant phenotype. They tend to accumulate in the DNA of organisms where they are known as polymorphisms. They contribute to variability in the DNA sequence of individuals of a species.
  50. 50. Deletions These involve the loss of a portion of the DNA sequence. The amount lost varies greatly. Deletions can be as small as a single base or much larger in some cases corresponding to the entire gene sequence. Insertions In this case the mutation occurs as a result of insertion of extra bases, usually from another part of a chromosome.
  51. 51. Rearrangements These mutations involve segments of DNA sequence within or outside a gene exchanging position with each other. A simple example is inversion mutations in which a portion of the DNA sequence is excised then re-inserted at the same position but in the opposite orientation. Gross mutations, because they involve major alterations to gene sequences, invariably have serious effect on the encoded protein and are frequently associated with a mutant phenotype.
  52. 52. FUNCTIONAL EFFECTS OF MUTATIONS ON THE PROTEIN Mutations exert their phenotypic effect in one of two ways, either through loss or gain of function. Loss-of-function mutations Loss-of-function mutation can result in either reduced activity or complete loss of the gene product. The former can be the result of either reduced activity or of decreased stability of the gene product and is known as a hypomorph, the latter being known as a null allele or amorph. Loss-of function mutations in the heterozygous state would, at worst, be associated with half normal levels of the protein product.
  53. 53. Haploinsufficiency Loss-of function mutations in the heterozygous state in which half normal levels of the gene product result in phenotypic effects are termed haploinsufficiency mutations. There are number of autosomal dominant disorders where the mutational basis of the functional abnormality is the result of haploinsufficiency, in which, homozygous mutations result in more severe phenotypic effects.
  54. 54. Gain-of-function mutations Gain-of-function mutations, as the name suggests, result in either increased levels of gene expression or the development of a new function(s) of the gene product. Mutations which alter the timing or tissue specificity of the expression of a gene can also be considered to be gain-of- function mutations. Gain-of-function mutations are dominantly inherited and the rare instances of gain-of-function mutations occurring in the homozygous state are associated with a much more severe phenotype, which is often a prenatally lethal disorder.
  55. 55. Structure of Chromosomes Each chromosome is not composed of a single Watson-Crick double helix. The width of a chromosome is much greater than the diameter of the helix. There are several meters of DNA in a human body, and the total length of the chromosomes is less than a millimeter. Finch and Klug suggested the “SOLENOID MODEL” of chromosome structure.
  56. 56.
  57. 57. Each DNA duplex is coiled around itself – primary coiling This is coiled around histone ‘beads’ – secondary coiling – called nucleosomes Nucleosomes are coiled to form chromatin fibres, around a protein matrix or scaffold – tertiary coiling Chromatin fibres are coiled to form loops – quaternary coiling The loops are further wound in a tight helix to form the chromosome – that can be seen under a microscope. The clusters of chromomeres can be seen as darkly staining bands, or G bands on the the chromosomes.
  58. 58. Human Chromosomes There are 46 chromosomes in the normal human – 23 pairs. The members of each pair match with respect to the genetic information they carry. One chromosome of the pairis inherited from the father, and one from the mother, and further, one is transmitted to the child. 22 pairs are alike in males and females – known as autosomes 1 pair differs – the sex chromosomes.
  59. 59. The members of a pair of chromosomes are microscopically indisdtinguishable, and the same is true for the female sex chromosomes – the X chromosome. In the male, there is one X chromosome and one Y chromosome which is smaller than the X chromosome, but it is thought that the two have a shout homologous segment. There are 2 types of cell division – Mitosis – normal cell division, by virtue of which the body grows – it results in 2 daughter cells, identical to the parent cell in genetic makeup, and number of chromosomes. Meiosis – This results in the production of reproductive cells (gametes). Each of which have only 23 chromosomes.
  60. 60. Classification of Chromosomes When prepared for analysis, the chromosomes appear under the microscope as a chromosome spread. The chromosomes are then cut out from a photomicrograph and arranged in pairs in a standard classification. This process is called karyotyping, and the complete picture is called the karyotype. In 1960, at a conference in Denver a classification system was devised to distinguish 7 chromosome groups (A through G) based on length and centromere position. But with more advanced staining, other methods of classification have arisen. Each chromosome has been identified by its banding pattern and each band numbered according to a standard system. The Paris classification is currently in use.
  61. 61. The chromosomes have a primary constriction known as the centromere. The location of the centromere can be used to classify the chromosomes • Metacentric – central centromere • Submetacentric - off –centre • Acrocentric – towards one end • Telocentric – terminal centromere CHROMOSOME NOMENCLATURE Each chromosome arm is divided into regions and each region is subdivided into bands numbering always from the centromere outwards. A given point on a chromosome is designated by the chromosome number, the arm (p or q), the region and the band, e.g. 15q12. Sometimes the word region is omitted so that 15q12 would be referred to simply as band 12 on the long arm of chromosome15.
  62. 62. Chromosome Analysis For chromosome analysis, the cells to be studied must be able to grow and divide rapidly. White blood cells are readily obtainable. WBCs are separated from blood by centrifugation, and placed in a suitable culture medium with phytohemagglutinin, a mitogenic agent. When the cultured cells are dividing rapidly, a very dilute solution of colchicine is added to the medium. This stops mitosis in the metaphase, and metaphase cells accumulate in the culture. A hypotonic solution is then added to swell the cells and to separate the chromatids while leaving the centromeres intact. The cells are fixed, spread on a slide and stained. They can then be examined under a microscope, stained and then photographed. The individual chromosomes are then cut from the photo, and arranged according to a particular manner (ie- karyotyped). After this, the karyotype can be examined for abnormalities of number or structure. WBC cultures are usually short lived, and skin cultures are usually used for biochemical and histochemical
  63. 63. • Staining methods • Autoradiography – The cultures are exposed to radioactive thymidine, and then after a given time, the cell divisions are stopped. The chromosomes which replicate, incorporated the thymidine. This procedure has shown that not all chromosomes replicate at the same time. But this process is laborious and time consuming, and is rarely used. • After 1970, several special staining techniques have developed for staining chromosomes in banded patterns. Some are:- • Q banding – the chromosomes are stained with quinacrine mustard or related compounds and examined by fluroscence microscopy. Each pair stains with a specific pattern of bright and dim bands – the Q bands. • G banding – widely used. Chromosomes treated with tripsin to denature the protein, and then stained with Giemsa stain. The chromosomes develop bright and dark bands – G bands. The dark bands correspond to the bright Q bands. • R banding – less widely used. The chromosomes are heat treated, and then stained with Giemsa – the results are the REVERSE of G and Q banding, and gives much the same information.
  64. 64. • C banding – This results in staining the centromere and other regions of the chromosome containing constrictive heterochromatin, ie- secondary constrictions of chromosomes 1, 9, 16 and the distal segment of the long arm of the chromosome. (heterochromatin is chromatin that stains differently from other chromatin). • NOR staining – This refers to the use of ammoniacal silver to stain the “nucleolar organizing regions, ie – The stalks of the chromosomes which contain the ribosomal genes • High resolution banding ­– used for staining cells in prophase – shows much more bands than the metaphase staining.
  65. 65. Medical applications of Chromosome analysis • Clinical diagnosis – in patient with congenital malformations, mental retardation disorders of sexual development etc. • Linkage and Mapping – Assignment of specific human genes to their chromosomal positions. • Polymorphisms – Minor heritable differences in chromosomes are common, especially in chromosomes 1, 9, and 16 and the Y chromosome. These can be used to trace individual chromosomes through families, and hence serve as markers to trace certain genetic defects and determine their source.
  66. 66. • Chromosomes and Neoplasia – The relation of chronic myelogenous leukemia to the Philadelphia chromosome. Chromosomal defects are present in most neoplasias. • Reproductive problems – A small proportion of parents experiencing spontaneous abortions or infertility have some chromosomal abnormality. • Prenatal Diagnosis – Amniocentesis is used to obtain fetal cells, and analyze the chromosomes for abnormalities. This is particularly useful in older pregnant women, and families with a history of chromosomal abnormalities.
  67. 67. Genetic disorders and inheritance Genetic disorders can be of 3 main types :- • Single gene disorders – these occur due to mutations of single genes. They show typical pedigree patterns and are rare - 1 in 2000 or less. • Chromosome disorders – the disorder occurs due to an excess or deficiency of whole chromosomes or chromosome segments. They show characteristic features, and are relatively more common than single gene disorders - 7 in 1000 births. • Multifactorial inheritance – These are caused due to a combination of genetic and environmental factors. They are the most common of the genetic disorders and do no show the typical pedigree patterns on single gene disorders.
  68. 68. Indications that a condition has a genetic etiology (Neel and Schull 1954) • Occurrence of a disease in definite proportions in families when environmental factors can be ruled out. • Absence of disease in unrelated lines like spouses or in-laws. • Characteristic age of onset, and course in the absence of precipitating factors • More in monozygotic than dizygotic twins. • Demonstration of characteristic phenotype and chromosomal abnormality, with or without family history.
  69. 69. Single Gene disorders. These can be – Autosomal dominant Autosomal recessive Sex linked (gonosomal) dominant Sex linked (gonosomal) recessive
  70. 70. Autosomal dominant • In this the mutant gene manifests itself in the homozygote as well as the heterozygote. These disorders are quite rare – Eg:- Osteogenesis imperfecta, Achondoroplasia. • The person is usually heterozygous, and one of the parents is affected. It is inherited as a simple mendellian dominant factor. • Autosomal dominant characteristics can also occur as new mutations in some children whose parents are not affected by the disorder. The possibility of a new mutation should always be kept in mind when considering a genetic etiology.
  71. 71. • Another characteristic of many autosomal dominant disorders is expressivity. This is a variability in clinical manifestation. In polydactyly, there may be no more than a small wartlike appendage in the side of the hand but at the other extreme, another affected person may have an entire extra finger. • Sometimes the gene may not express itself at all, which is known as non penetrance. This explains why sometimes the disorder may skip a generation. • Some autosomal genes are expressed more frequently in one sex than another. This is called sex influence. Eg – gout and pre senile baldness in males. The influence of sex is probably due to the influence of sex hormones. • Some disorders which have an apparent autosomal dominant type of inheritance have been postulated, in recent times to have a viral etiology. Eg – Alzheimer’s disease.
  72. 72. Autosomal Recessive inheritance • These are only expressed when the gene is present in a homozygous genotype. The heterozygote is healthy, because the normal gene is expressed rather than the mutant gene. The disorder is normally expressed if a heterozygote marries another heterozygote, but due to the rarity of the mutant gene, this possibility is remote. But the chances are much higher in cases of consanguineous marriages – the chances that cousins will posses the recessive mutant gene is 1 in 8. • So the rarer the mutant gene, the more the chances that the affected individual has parents who are cousins. Eg of autosomal recessive disorders – alkaptonuria. The most common autosomal recessive disorder is cystic fibrosis.
  73. 73. Intermediate inheritance • Some mutant genes are only partially expressed in the heterozygote. This is known as incomplete dominance, or intermediate inheritance. An example is sickle cell anaemia. A person homozygous for the mutant gene, shows typical sickling of the RBCs. The heterozygote on the other hand shown normal RBCs in normal condition. But if the heterozygote is exposed to low oxygen tension, as in high altitude travel etc, the RBCs change from the normal shape to sickle shape. These people are said to have the sickle cell trait. • Codiminance. • In some cases, the alleles for a particular characteristic may be different, but both may be expressed. This is known as co- dominance. Eg – both the antigens A and B are present is blood group AB.
  74. 74. Sex linked inheritance. • This refers to the pedigree pattern of genes carried on either the X chromosome or the Y chromosome. X-Linked recessive • This gene manifests in the female only if she is homozygous for the gene, but always manifests in the male as he has only one X chromosome (said to be hemizygous). • If the female is heterozygous, she is healthy but said to be a carrier. • The disorder is passed from a healthy female carrier to all her sons. An affected male has healthy sons, and females who are carriers. Eg - hemophillia • Some cases in which females may be affected – – Turner’s syndrome – the female has only 1 X chromosome – Manifesting heterozygote - the gene manifests even in the heterozygous state.
  75. 75. X linked Dominant • The expression of these disorders is similar to autosomal dominant – the heterozygote and homozygote are both affected. Additionally, an affected male transmits this disorder to all his daughters, but the sons are always healthy. A female hetrozygote has a 50% chance of having an affected child Y linked inheritance • These disorders are transmitted directly from father to son. All the sons are affected. Females are not affected as they do not have a Y chromosome
  76. 76. Chromosomal abnormalities Chromosomal abnormalities can be of the following types:- Abnormality in Number Autosomes Sex chromosomes Abnormality in - Structure Autosomes Sex chromosomes
  77. 77. Numerical Abnormalities in Autosomes Loss or gain of a single chromosome is known as aneuploidy Polyploidy – is a gain of the whole chromosome set – ie – 3N or 4N number of chromosomes. While this is common in plants, it is lethal in humans. Monosomy – is the loss of a single chromosome. This is also a lethal condition in man. Trisomy – This is the gain of a single chromosomy. Lejeune (1959) was the first to show that patients with Down’s syndrome had an extra Chromosome 21. The main cause of trisomy is the failure of homologous chromosomes to separate during meiosis. This is known as non-disjunction. Other syndromes caused due to trisomy are Edward’s syndrome – Trisomy 18 Patau’s syndrome – Trisomy 13
  78. 78. Structural abnormalities in Autosomes2 types – Translocations – exchange of segments between non homologous chromosomes. Deletions – Loss of a segment of a chromosome. Translocations Translocations can further be of 2 types -Robertsonian - Reciprocal.
  79. 79. An example of Robertsonian translocation is a case in which the long arms of chromosome 14 and 21 get translocated, and the short arms are lost. In this person there will be – 1 normal Chromosome 14 1 normal Chromosome 21 1 abnormal chromosome (14/21) But since the amount of genetic material is still the same (there are still 2 chromosome 14s and 2 chromosome 21s) the affected person is still normal. But the gametes of this person will not be normal – (14/21) 14 21 14/21 14
  80. 80. The possible combinations of these chromosomes and their outcomes after combining with normal chromosomes 14 and 21 are shown below – 14/ 21 21 downs syndrome 14/21 carrier 14 21 normal 14 monosomy (death) In case of reciprocal translocation, since the amount of DNA is conserved, again, the person affected will be normal, but the gametes will be abnormal
  81. 81. Deletions Although monosomy is lethal, some people with genetic disorders have been found to have partial monosomy. This is due to removal or deletion of a part of a chromosome. Eg – Deletion of the short arm of chromosome 5 – causes ‘cri du chat’ – characterized by a cat like cry at birth. Also, if a deletion occurs at 2 ends of a chromosome, such that the resultant ends have complementary base pairs, they tend to join, and form a ring chromosome.
  82. 82. Sex chromosome abnormalities Abnormality of number Seen in many syndromes – • Klinefelter’s syndrome – XXY • Turner’s syndrome – females with only 1 X chromosome • Multiple X – females with 3 or 4 X chromosomes XYY males Abnormalites of Structure Isochromosome X – a long X chromosome – which results from deletion of the short arms of the X chromosome and duplication of the long arm.
  83. 83. Multifactorial Inheritance These disorders are the most common type of genetic disorders. They occur due to the effect of many genes, and also have a component of environmental influence. These disorders show a definite familial tendency, the incidence among relatives being greater than that of the general population, but less than that of a single gene disorder. Normal traits having a multifactorial influence are - intelligence, skin colour, blood pressure, etc.
  84. 84. Relatives have a higher incidence of these disorders, because their genetic makeup is such, that they are more prone to the disorder. The graph below shows the liability to a particular disorder. (Liability = the sum total of genetic + environmental factors influencing a disorder.) It can be seen that the threshold for a disease occurring in the general population is much higher than that of the relatives. This indicates the increases risk of relatives to the disorder.
  85. 85. • It is also seen that if an individual is affected by a severe form of a disorder, the chances that someone else in the family has it, or will develop it in the future, is greater. • Eg- – Pt. with bilateral cleft lip – 6% chance of another relative having it – Pt. with unilateral cleft lip – 2.5% chance.
  86. 86. Heritability Defined as – proportion of the total variation of a character which can be attributed to genetic factors. In other words, it is an estimate of how much of the etiology of a disorder can be ascribed to genetic influences rather than environmental factors. Greater the heritability, greater the genetic component.
  87. 87. TWINNING Twins can be identical or non-identical → monozygotic (MZ) or dizygotic (DZ) – depending on whether they originate from a single conception or from two separate conceptions. MONOZYGOTIC TWINS Monozygotic twins originate from a single egg which has been fertilized by a single sperm. A very early division, occurring in the zygote before separation of the cells which make the chorion, results in dichorionic twins. Division during the blastocyst stage from days 3 to 7 results in monochorionic diamniotic twins. Division after the first week leads to monoamniotic
  88. 88. DIZYGOTIC TWINS Dizygotic twins result from the fertilization of two ova by two sperm and are no more closely related genetically than brothers and sisters. Hence they are sometimes referred to as fraternal twins. Dizygotic twins are dichorionic and diamniotic although they can have a single fused placenta if implantation occurs at closely adjacent sites.
  89. 89. The classical twin approach for separating the effects of nature and nurture involves comparing identical (monozygous) and non-identical (dizygous) twins. Differences between monozygous (MZ) twin pairs reflect environmental factors, whereas differences between dizygous (DZ) twin pairs are due to both genetic and environmental factors. Therefore, greater similarities between MZ twin pairs compared with DZ twin pairs can be interpreted as reflecting genetic influences on the feature(s) being studied. SIGNIFICANCE OF TWIN STUDIES
  90. 90. Apart from comparisons of monozygous and dizygous twins, there are other twin models that provide insights into the contributions of genetic and environmental factors to observed variability. The monozygous co-twin model involves comparisons of monozygous twins where each member of a pair has been exposed to different environmental effects. For example, identical twins might be treated with different appliances to correct similar malocclusions and the outcomes compared. Monozygous twins are assumed to have identical genotypes, so their offspring are genetically related as half-sibs but are socially first cousins. A nested analysis of variance similar to that used in analysing data from half and full-sibling litters in animal studies can be applied to provide estimates of genetic and environmental effects.
  91. 91. Genetic influence on tooth number size, morphology,position Various developmental dental disorders, which are under the influence of genes, include Disorders in tooth morphogenesis. Amelogenesis imperfecta (AI): this is a group of genetically heterogeneous disorders affecting enamel formation. It is clinically heterogeneous in that hypoplastic, hypocalcified and hypomaturation forms have been described and genetically heterogeneous with families exhibiting autosomal dominant, autosomal recessive and X-linked inheritance. In humans, two amelogenes, AMGX and AMGY, have been cloned and mapped to the X and Y chromosomes, respectively (Lau et al., 1989) and in 1997 MacDougall et al. mapped the ameloblastin gene within the critical region for autosomal dominant AI at chromosome 4q21. It is likely, however, that mutations in several genes may be involved in the aetiology of different forms of autosomally inherited AI
  92. 92. Dentinogenesis imperfecta (DI): this is autosomal and occurs in approximately 1:8000 live births. It presents with brownish discoloration of the teeth, crowns susceptible to rapid attrition, fragile roots and pulp chamber obliteration due to abnormal continuous production of dentine matrix (Shields, 1973). DI also presents a number of sub-types, one of which is coupled with osteogenesis imperfecta in which there is an alteration in type 1 collagen genes. Most patients with this type of dentinogenesis imperfecta have mutations and deletions for amino acid substitutions in genes with encode for sub-units of type 1 collagen (Bonadio et al., 1990). The structural defects in the collagen type 1 molecules affects the extra cellular matrix formation, resulting in the pathogenesis of DI.
  93. 93. Hypodontia The congenital absence of teeth may be referred to as hypodontia, when one or several teeth are missing, or anodontia when there is a complete absence of one or both dentitions. Features include, 1. More common in permanent than primary dentition 2. Absence of primary teeth associated with absence of permanent successors 3. May be associated with other developmental anomalies • Grahnen (1956) in his familial and twin studies revealed the hereditary nature of hypodontia and concluded that in children with missing teeth, up to half of their siblings or parents also had missing teeth. • Osborne et al (1958) in his twin studies have shown that tooth crown dimensions are strongly determined by heredity. The molecular genetics of tooth morphogenesis with the homeostatic Hox 7 and Hox 8 (now referred as Msx-1 and Msx-2) genes are being responsible for stability in dental patterning.
  94. 94. Clinical evidence suggests that congenital absence of teeth and reduction in tooth size are associated e.g., hypodontia and hypoplasia of maxillary lateral incisors frequently present simultaneously. Numerous pedigrees have been published linking the two characteristics and implying that they are different expressions of the same disorder. • Gruneberg (1965) suggested that a tooth germ must reach a critical size during a particular stage of development or the structure will regress, and Suaraz and Spence (1974) showed that hypodontia and reduction in tooth size are in fact controlled by the same or related gene loci. It is apparent from all the evidence in this respect that tooth size fits the polygenic multifactorial threshold model. • Markovic (1982) found a high rate of concordance for hypodontia in monozygous twin pairs, while zygous twin pairs he observed discordant. These and other previous studies concluded that a single autosomal dominant gene could explain the mode of transmission with incomplete penetrance.
  95. 95. • Vastardis (Nature Genetics 1996) studied the cause for selective tooth agenesis in human, where missense mutation occurred in the MSX-1 homeodomain. This occurs as a consequence of replacement of arginine with proline protein (Arg196Pro mutation) in the homoedomain of MSX- 1. Tooth agenesis was reported in a family with a ser 105 stop mutation of MXS-1 gene. • Dermaut and Smith (AJO1997) studied the prevalence of tooth agenesis correlated with jaw relationship and dental crowding in 185 patients and found that, 1. Hypodontia occurred more often in girls than in boys. 2. The upper lateral incisors and lower premolars were the most frequently missing teeth. 3. Class I skeletal relationships were found more often in patients with agenesis than in patients without missing teeth and are associated with deep-bite growth patterns.
  96. 96. • Research work by Cobourne (BJO 1999) on families affected with hypodontia has revealed that it is transmitted as an autosomal dominant disorder with variable expressivity and incomplete penetrance. Missing maxillary laterals and mandibular second premolars have been associated with defects in MSX-1and MXS-2 genes. • Van den Boogard et al (Nature Genetics 2000) observed a genetic aberration in a Dutch family with tooth agenesis. A stop codon in MSX-1 mutation was identified implying the involvement of this gene in tooth agenesis. • Nieminen (Eu J of Human Genetics 2001) found that, a non-sense mutation in the PAX-9 gene was associated with molar tooth agenesis in a Finnish family. The A340T transversion creates a stop codon at lysine 114, and truncates the coded PAX-9 protein at the end of the DNA-binding paired box. The tooth agenesis phenotype involved all permanent second and third molar and most of the first molars.
  97. 97. • Lidral (JDR 2002) concluded that a mutation in MSX-1 gene in chromosome 4 has been identified as the causative factor for oligodontia involving the absence of all second premolar and third molar. Missing first molar and second molars have been linked with a substitution mutation of MSX-1 gene. • With the help of molecular genetics techniques, Peck and Peck (AJO 2002) assessed a family exhibiting an autosomal dominant trait of missing second premolar and third molars. The affected chromosome was isolated to be in a chromosome 4p and many genes were considered to be responsible for this tooth agenesis. A point mutation was detected in the MSX 1 gene in all affected family. Also mutation of PAX-9 transcription factors has been observed in familial tooth agenesis and also in missing mandibular second premolars and central incisors.
  98. 98. ECTOPIC ERUPTION AND TRANSPOSITION OF CANINES Various studies in the past have indicated a genetic tendency for ectopic maxillary canines. • Zilberman et al (1990) and Peck et al (1994) concluded that palatally ectopic canines were an inherited trait, being one of the anomalies in a complex of genetically related dental disturbances often occurring with missing teeth, tooth size reduction, and other ectopically positioned teeth. • Previous studies by Mossey et al (1994) have also shown an association between ectopic-maxillary canine and Class II div 2 malocclusion, a genetically inherited trait. • Peck et al (1997) classified a number of different types of tooth transposition in both maxillary and mandibular arches, with maxillary canine/first premolar class position being the most common.
  99. 99. They also provided strong evidence of a significant genetic component in the cause of this most common type of transposition in that there was • A familial occurrence • Bilateral occurrence in a high percentage of cases • Female predominance and a difference in different ethnic groups An increased frequency of associated dental anomalies; tooth agenesis and peg-shaped maxillary lateral incisors were also reported. Neubuser et al (1995) found that PAX-9 transcription factor is associated the genetic mechanism for tooth displacement anomalies, such as palatally displaced canines and canine transposition.
  100. 100. FAMILY AND TWIN STUDIES FOR HERITABILITY OF DENTOFACIAL PHENOTYPESThe twin method, when appropriately applied, provides geneticists with one of the most informative technique available for analysis of complex genetic traits. Alternative method for investigating the role of heredity in determining craniofacial and dental morphology is by familial studies. Heritability in such studies is normally expressed in terms of parent/offspring correlation coefficients or correlation coefficients with sibling pairs, of which twins are a special kind. The study of craniofacial relationship in twins has provided much useful information concerning the role of heredity in malocclusion. The procedure is based on the underlying principle that observed differences within a pair of monozygotic twins (whose genotype is identical) are due to environment and those differences within a pair of dizygotic twins (who share 50% of their total gene complement) are due to both genotype and environment.
  101. 101. A comparison of the observed within-pair differences for twins in the two categories should be provide a measure of the degree to which monozygotic twins are more alike than dizygotic twins. The larger this differences between the two twin categories, the greater the genetic difference effect on variability of the trait. This model implies the zygosity is accurately determined and that environment effects are equal in the two twin categories The bulk of the evidence for the heritability of various types of malocclusion arises from family and twin studies.
  102. 102. CLASS II MALOCCLUSION Class II Division I Malocclusion: Extensive cephalometric studies have been carried out to determine the heritability of certain craniofacial parameters in class II division I malocclusion (Harris 1975). These investigation have shown that in the class II patients, the mandible is significantly more retruded than in class I patients, with the body of the mandible length smaller and overall mandibular length reduced. These studies also showed a higher correlation between the patient and his immediate family that data from random pairings of unrelated siblings, thus supporting the concept of polygenic inheritance for class II division I malocclusion
  103. 103. Class II Division 2 malocclusion Class II division 2 is a distinct clinical entity and is a more consistent collection of definable morphometric features occurring simultaneously i.e., syndrome than the other malocclusion types put forward by Angle in the early 1900’s. Class II division-2 malocclusion along with characteristic skeletal features is often accompanied by particular morphometric dental feature also, such as a poorly developed cingulum on the upper incisors and a characteristic crown angulation. Markovic 1992 carried out a clinical and cephalometric study of 114 Class II division-2 malocclusions, 48 twin pairs and six sets of triplets. Intra- and Inter- pair comparisons were made to determine concordance-discordance rate for monozygotic and dizygotic twins. Of the monozygotic twin pairs, 100% demonstrated concordance for the Class II division-2 malocclusion, whilst almost 90% of the dizygotic twin pairs were discordant. This is strong evidence for genetics as the main etiological factor in the development of class II division2 malocclusion.
  104. 104. The studies point to incontestable genetics influences probably autosomal dominant with incomplete penetrance and variable expressivity. It could also possibly be explained by a polygenic model with a simultaneous expression of a number of genetically determined morphological traits acting addictively, rather than being the effect of a single controlling gene for the entire occlusal malformation. Aspects of skeletal and muscle morphology are genetically determined and there is some recent experiment evidence from a twin study (Lauweryns et al 1995) indicating strong genetic factors in certain aspects of masticatory muscle behavior.
  105. 105. CLASS III MALOCCLUSION Probably the most famous example of a genetic trait in humans passing through several generations is the pedigree of the so- called HAPSBURG JAW. This was the famous mandibular prognathism demonstrated by several generations of the Hungarians/Austrian dual monarchy. • Strohmayer (1937) concluded from his detailed pedigree analysis of the Hapsburg family line that the mandibular prognathism was transmitted as an autosomal dominant trait. This could be regarded as an exception and in itself, does not provide sufficient information to predict the mode of inheritance of mandibular prognathism. • Suzuki (1961) studied 1362 persons from 243 Japanese families and noted that, while the index cases and mandibular prognathism; there was a significantly higher incidence of this trait in other members of his family (34.4%) in comparison of families of individuals with normal occlusion (7.5%).
  106. 106. Schulze and Weise (1965) also studied mandibular prognathism in monozygotic and dizygotic twins. They reported that concordance in monozygotic twins was six times higher than among dizygotic twins. Both of the above studies reported a polygenic hypothesis as the primary cause for mandibular prognathism (Litton et al 1970). A class III malocclusion resulting from a skeletal imbalance between the maxillary and mandibular bases may result from deficiency in maxillary growth, excessive mandibular growth, or a combination of both. Various studies have also highlighted the influence of a distinct cranial base morphology with a more acute cranial base angle and shortened posterior cranial base resulting in a more anterior position the gleniod fossa, thus contributing to the mandibular prognathism (Ellis and Mcnamara, 1984; Singh et al 1997).
  107. 107. Various models have been suggested, such as autosomal dominant with incomplete penetrance (Stiles and Luke1953), simple recessive (Downs 1928), variable both in expressivity and penetrance with differences in different racial populations (Kraus et al 1959). Litton et al (1970) carried out an analysis of the literature to that date and also analyzed a group of probands, siblings and parents with Class III malocclusion, and analyzed the results in an effort to determine a possible mode of transmission. Both autosomal dominant and autosomal recessive transmission were ruled out and there was no association with gender (male or female). The polygenic multifactorial threshold model put forward by Edward et al 1960, however, did fit the data and accordingly proposed a polygenic model with a threshold for expression to explain familial distribution, and the prevalence both within general population and in siblings of affected persons
  108. 108. Soft tissues do not generally play a part in the etiology of Class III malocclusion, and in fact there is a tendency for lip and tongue pressure to compensate for a skeletal Class III discrepancy by retroclining lower incisors and proclining upper incisors. Polygenic inheritance implies that there is scope for environmental modification and many familial and twin studies bear this out. Watnick (1972) studied 35 pairs of monozygotic and 35 pairs of dizygotic like-sexed twins using lateral cephalometry. He concluded that the analysis of unit areas with the craniofacial complex represents local growth sites and revealed different modes of control within the same bone. Certain areas, such as the lingual symphysis, lateral surface of the ramus and frontal curvature of the mandible are predominantly under genetic control. Other areas, such as the antegonial notch, are predominantly affected by environmental factors.
  109. 109. Hughes and Moore 1942 suggested that the mandible and maxilla are under separate influence of genetics control, and that certain portions of individual bones, such as the ramus, body, and symphysis of the mandible are under different genetic and environmental influences. Nakasima and Nakata (AJO 1982) assessed the craniofacial morphologic differences between parents of Class II patients and parents of Class III patients, as well as parent-offspring correlations, and the genetic and environmental components of variation within the craniofacial complex in these malocclusions. ,
  110. 110. The results showed that The parents of Class II patients had a convex profile with a distoclusion type of denture pattern, while the parents of Class III patients had a concave profile with a mesioclusion type of denture pattern. This suggests that both Class II and Class III malocclusions have a genetic basis. The skeletal pattern was more directly related to genetic factors. Parent-offspring correlation data were in good agreement with the expected level under the polygenic model of inheritance.
  111. 111. HERITABILITY OF LOCAL OCCLUSAL VARIABLES • It has been thoroughly documented that measurements of the skeletal craniofacial complex have moderate to high heritability, while measures of the dento-alveolar portions of the jaws i.e., tooth position and dental relationships are given much less attention in the literature. • Because of the adaptability of the dentoalveolar region when subjected to environmental factors, local malocclusions are primarily acquired and would be expected to have low heritablities • In an analysis of the nature versus nurture in malocclusion Lundstrom (1984) concluded that the genetic contribution to anomalies of tooth position and jaw relationship overall is only 40%, with a greater genetic influence on the skeletal pattern than on the dental features.
  112. 112. • Lundstrom (1984) studied 50 pairs of monozygotic and 50 pairs of dizygotic twins and concluded that heredity played a significant role in determining, among other factors, width and length of the dental arch, crowding and spacing of the teeth and degree of overbite. • A study by Hu et al (1992) also reported familial similarity in dental arch form and tooth position. • In a recent study by King et al (1993), initial treatment records of 104 adolescent sibling pairs, all whom subsequently received orthodontic treatment, were examined. Heritability estimates for occlusal variations such as rotations, crossbites and displacements were significantly higher than in a comparable series of adolescents with naturally good occurring occlusions. The explanation offered was that a genetically influenced facial types and growth patterns of the siblings are likely to respond to environment factors e.g., chronic mouth breathing and reduced masticatory stress similar fashions. • It is also important to remember the soft tissue morphology and behaviour have a genetic component and they have a significant influence on the dentoalveolar morphology.
  113. 113. Bolton's ratio Bulent Baydas et al (EJO 2005) : Sample size = 106 FM and 78 M. These were patients and their siblings who reported for orthodontic treatment. Bolton's ratio has a high heritability in siblings of same gender, in siblings of different gender ,the anterior and overall ratios did not show any heritability.
  114. 114. GENETIC FACTORS AND EXTERNAL APICAL ROOT RESORPTIONAnalysis of the genetic basis for variable response to treatment has been applied to the specific adverse outcome sometimes associated with orthodontic treatment called external apical root resorption (EARR). The degree and severity of EARR associated with orthodontic treatment is multifactorial, involving host and environmental factors. An association of EARR exists, in those who have not received orthodontic treatment, with missing teeth, increased periodontal probing depths, and reduced crestal bone heights. Individuals with bruxism, chronic nailbiting, and anterior open bites with concomitant tongue thrust also may show an increased extent of EARR before orthodontic treatment Genetic variation accounts for 50% to 64% of the variation in EARR of the maxillary Incisors.
  115. 115. Variation in the interleukin-lb gene (IL-1B) in orthodontically treated individuals accounts for 15% of the variation in EARR. Persons in the orthodontically treated sample who were homozygous for IL-1B allele "1" were estimated to be 5.6 times more likely to experience EARR of 2 mm or more than those who were heterozygous or homozygous for allele "2. Iwasaki et al found individual differences in a ratio of IL-l b to IL-l RA (receptor antagonist) cytokines in crevicular fluid that correlated with individual differences in canine retraction using identical force Although the relation to genetic markers was not undertaken, this study indicates a variable individual response to orthodontic force that may be mediated at least in part by IL-l b and IL-l RA cytokines. This supports the hypothesis that bone modeling mediated, at least in part, by IL-l b as an individual response to orthodontic force can be a factor in EARR
  116. 116. Further testing of another candidate gene using nonparametric sibling pair linkage analysis with the DNA microsatellite marker D18S64 (tightly linked to the gene TNFRSFllA) identified evidence of linkage of EARR affecting the maxillary central incisor This indicates that the TNFRSFllA with EARR.The TNFRSFllA gene codes for the protein RANK, part of the osteoclast activation pathway.
  117. 117. GENOMICS AND OROFACIAL CLEFTS • Orofacial clefts, the most common craniofacial malformation ranks second among all the craniofacial anomalies, among all the congenital malformation affecting human. These include, • Cleft lip and Cleft palate Cleft lip with or without cleft palate Cleft palate only • Median clefts • Alveolar clefts • Facial clefts • Etiology of orofacial clefts appears to be complex with involvement of genetic, environmental and tetragenic factors complicating the process
  118. 118. CLEFT LIP AND CLEFT PALATE Etiological factors: 1. Monogenic or single gene disorder 2. Polygenic or multifactorial inheritance 3. Chromosomal abnormalities 4. Familial 5. Sex predominance 6. Racial incidence
  119. 119. Monogenic or single gene disorders Approximately half of the recongnized syndromes associated with cleft lip and palate are due to single gene disorders with equal distribution between autosomal dominant and autosomal recessive. Single gene defect may give rise to Mendelian pattern of inheritance, either of isolated cleft lip (palate) or in multiple malformations associated with cleft lip with or without cleft palate. Polygenic or multifactorial inheritance Several genes, each with a relatively small effect, act in concert with poorly defined environmental triggering mechanisms leading to the expression of the abnormality. Thus, such cases show a slight familial tendency but do not confirm to simple Mendelian inheritance patterns. Chromosomal abnormalities Chromosomal abnormalities account for 18% of the clefting syndromes and would invariably be associated with other malformations, delayed development and poor prognosis. Chromosomal abnormalities notably trisomy D and also less frequently trisomy E, may cause multiple malformations including cleft lip (palate).
  120. 120. Familial Fogh-Anderson’s family studies showed that siblings of patient with cleft lip had increased frequency of cleft lip and cleft palate, but no increased frequency of cleft palate alone. Siblings of patients with cleft palate had increased frequency of cleft palate, but not CL and CP. Sex predominance More males are born with cleft lip and cleft palate than females and more females than males have cleft palate alone. Racial incidence The incidence of cleft lip and cleft palate is greatest in the Mongoloid population being greater than that in the Caucasian population, which is in turn greater than in the Negroid population. In contrast, the racial differences for cleft palate or not significant.
  121. 121. Over 300 syndromes are known to have clefting of the lip or palate as an associated feature Some of the syndromes associated with CLP are, • Pierre Robin syndrome • CLP-ectodermal dysplasia syndrome (CLPED-1) • Ectrodactyly, ectodermal dysplasia, orofacial cleft (EEC syndrome) In addition to syndromic CLP, progress has also been made in elucidating the genetic mechanisms behind several syndromic causes of isolated CP. Some of the syndromes associated with CP are, • Mandibulofacial dysostosis (Treacher Collins syndrome) • Holoprosencephaly, type-3 • Stickler syndrome
  122. 122. CRANIOFACIAL SYNDROMES A syndrome is recognised to represent multiple malformations occuring in embryonically non- contiguous areas. more than 40 syndromes known to include malocclusion as one of their features. Some of the syndromes with dental importance are,  Crouzons syndrome  Aperts syndrome  Treacher Collins syndrome  Pfeiffer syndrome  Craniofacial microsomia  Williams Syndrome
  123. 123. CROUZONS SYNDROME It is a frequent form of craniofacial dysostosis. It is characterized by multiple anomalies of the craniofacial skeleton with an autosomal dominance inheritance pattern Genetic etiology: Caused by multiple mutations in the fibroblast growth factor receptor2 gene (FGFR2). Mutation in Tyrosine kinase receptor, at Ig II – Ig III domain Chromosome and region: 10q 253-q26
  124. 124. Clinical features: They are limited to the head and neck region in contrast to other craniosynostosis syndrome in which hand, feet involvement or both are common. Forehead is often high and prominent There is hypertelorism, strabismus, midface hypoplasia, a prominent beaked nose, high arched palate, mandibular prognathism and dental malocclusion.
  125. 125. TREACHER COLLINS SYNDROMETREACHER COLLINS SYNDROME Treacher collins syndrome is characterized by bilaterally symmetrical abnormalities of structures within the first and second branchial arches. It is inherited as autosomal dominant trait. Genetic etiology: Treacher collins syndrome occurs as result of mutation of Treacle gene (TCOF1 gene) located in chromosome 5q 32 – q 33.1. TCOF1 encodes a protein that is 1411 amino acids in length and has been named ‘treacle
  126. 126. Clinical features: The facial appearance is downward slanting palpaberal fissures, depressed zygoma, displastic ears and receding chin. Zygomatic arches may be absent but more often are symmetrically underdeveloped.
  127. 127. WILLIAMS SYNDROME (EJO2004) Williams syndrome is a genetic desorder caused by a hemizygose micro deletion of chromosome 7(7q11.23) affecting multiple organ system WS first reported by william(1961)Bverine(1962) independently. Clinical features are ; Cardiac anomalies Mental retardation Distinctive facial features and dental abnormalities