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EUGENE PARDI, DO ESTRELLA MOUNTAIN COMMUNITY COLLEGE INTRODUCTION In the 19th century, microscopic studies of cells led scientists to suspect that the nucleus of the cell contained the important mechanisms of inheritance. The chromatin in the nucleus condensed to form CHROMOSOMES before cell division. With the rediscovery of Gregor Mendel’s breeding experiments, it became apparent that the chromosomes contained GENES, the basic units of inheritance. 1/30/2011 EUGENE PARDI, DO 2 INTRODUCTION The primary constituent of the chromatin is DEOXYRIBONUCLEIC ACID (DNA). Genes are composed of sequences of DNA. By serving as the blueprints of proteins in the body, genes influence all aspects of body structure and function. An error in one of these genes can lead to a recognizable genetic disease. 1/30/2011 EUGENE PARDI, DO 3 INTRODUCTION To date, more than 15,000 genetic conditions have been identified and cataloged. The proportion of beds in pediatric hospitals occupied by children with genetic diseases has risen to one third. Many common diseases that affect primarily adults are now known to have important genetic components. HTN, CAD, diabetes, cancer. 1/30/2011 EUGENE PARDI, DO 4 DNA: COMPOSITION AND STRUCTURE Genes are composed of DNA, which has three basic components: The pentose sugar molecule DEOXYRIBOSE. A phosphate molecule. One of four types of nitrogenous bases: PYRIMIDINES CYTOSINE (C) THYMINE (T) PURINES ADENINE (A) GUANINE (G) 1/30/2011 EUGENE PARDI, DO 5 1/30/2011 EUGENE PARDI, DO 6 DNA: COMPOSITION AND STRUCTURE These molecules are physically assembled together in a DOUBLE – HELIX model. DNA can be envisioned as a twisted ladder, with chemical bonds as its rungs. The two sides of the ladder are composed of the sugar and phosphate molecules, held together by strong phosphodiester bonds. 1/30/2011 EUGENE PARDI, DO 7 1/30/2011 EUGENE PARDI, DO 8 1/30/2011 EUGENE PARDI, DO 9 DNA: COMPOSITION AND STRUCTURE Projecting from each side of the ladder are the nitrogenous bases. The base projecting from one side is bound to the base projecting from the other side by a hydrogen bond. The nitrogenous bases form the rungs of the ladder. Adenine pairs with thymine. Guanine pairs with cytosine. Each DNA subunit consists of one deoxyribose molecule, one phosphate group, and one base. NUCLEOTIDE. 1/30/2011 EUGENE PARDI, DO 10 1/30/2011 EUGENE PARDI, DO 11 DNA AS THE GENETIC CODE DNA can direct the synthesis of all the body’s proteins. Proteins are composed of one or more POLYPEPTIDES, which are in turn composed of sequences of AMINO ACIDS. The body contains 20 different types of amino acids, and the amino acid sequences that make up polypeptides must be specified by the DNA molecule. Each amino acid is specified in the DNA molecule by a triplet of bases called a CODON. 1/30/2011 EUGENE PARDI, DO 12 1/30/2011 EUGENE PARDI, DO 13 1/30/2011 EUGENE PARDI, DO 14 DNA AS THE GENETIC CODE Of the 64 possible codons, three signal the end of a gene and are known as TERMINATION, or NONSENSE, CODONS. The remaining 61 all specify amino acids. Most amino acids can be specified by more than one codon. The genetic code is UNIVERSAL. All living organisms use the same DNA codes to specify proteins. 1/30/2011 EUGENE PARDI, DO 15 REPLICATION DNA must be able to replicate itself accurately during cell division. Replication consists of the breaking of the weak hydrogen bonds between the bases, leaving a single strand with each base unpaired. 1/30/2011 EUGENE PARDI, DO 16 1/30/2011 EUGENE PARDI, DO 17 REPLICATION COMPLEMENTARY BASE PAIRING is the key to accurate replication. It is the consistent pairing of adenine with thymine and of guanine with cytosine. A portion of a single strand with a sequence of bases will attract free nucleotides with the complementary bases. 1/30/2011 EUGENE PARDI, DO 18 REPLICATION When replication is complete, a new double – stranded molecule identical to the original is formed. The single strand is said to be a TEMPLATE on which a complementary molecule is built. 1/30/2011 EUGENE PARDI, DO 19 REPLICATION Several different proteins/enzymes are involved in DNA replication: DNA POLYMERASE: travels along the single DNA strand, adding the correct nucleotides to the free end of the new strand. Also proofreads the new molecule in that after the new nucleotide has been added to the chain, it checks to make sure that its base is actually complementary to the template base. 1/30/2011 EUGENE PARDI, DO 20 1/30/2011 EUGENE PARDI, DO 21 1/30/2011 EUGENE PARDI, DO 22 MUTATION A MUTATION is any inherited alteration of genetic material. Some are subtle and are not seen as chromosomal aberrations. BASE PAIR SUBSTITUTION: one base pair is replaced by another. Also called MISSENCE MUTATION in that the codon produced after transcription of the mutant gene is altered. Can result in a change in the amino acid (aa) sequence with profound effects. It may have no consequence due to redundancy of the genetic code. SILENT SUBSTITUTION 1/30/2011 EUGENE PARDI, DO 23 MUTATION FRAMESHIFT MUTATION: alteration that involves the insertion or deletion of one or more base pairs to the DNA molecule. Can change the entire “reading frame” of the DNA sequence. Can greatly alter the amino acid sequence. 1/30/2011 EUGENE PARDI, DO 24 1/30/2011 EUGENE PARDI, DO 25 MUTATION MUTAGENS: agents that are known to increase the frequency of mutations. Radiation from x-rays or nuclear fallout forms electrically charged ions that produce chemical reactions which change DNA bases. A variety of chemicals can induce mutations because they are chemically similar to the DNA bases. Some mimic the effects of ionizing radiation. Others interfere with base pairing. Some are much more potent mutagens than others. 1/30/2011 EUGENE PARDI, DO 26 MUTATION Measurement of the mutation rate is difficult because mutations are very rare events. SPONTANEOUS MUTATION: a mutation that occurs in the absence of exposure to known mutagens. MUTATIONAL HOT SPOTS: certain areas of some chromosomes that have a particularly high mutation rate. Sequences consisting of a cytosine base followed by a guanine base 1/30/2011 EUGENE PARDI, DO 27 FROM GENES TO PROTEINS The transport of the DNA code from the nucleus to cytoplasm and subsequent protein formation involves two basic processes: TRANSCRIPTION: formation of a mRNA molecule based on the DNA code. TRANSLATION: formation of a protein from the mRNA using ribosomes and tRNA. Occurs in the cytoplasm. 1/30/2011 EUGENE PARDI, DO 28 FROM GENES TO PROTEINS Both of these processes are mediated by RIBONUCLEIC ACID (RNA). Chemically similar to DNA in that RNA is also composed of a sugar molecule, phosphate group, and nitrogenous base. Differs from DNA in that the sugar molecule is ribose, not deoxyribose, and that uracil rather than thymine is one of the four bases. Structurally similar to thymine so it pairs with adenine. RNA usually occurs as a single strand instead of the double strand as DNA has. 1/30/2011 EUGENE PARDI, DO 29 TRANSCRIPTION TRANSCRIPTION is the process by which RNA is synthesized from a DNA template. The result is the formation of MESSENGER RNA (mRNA) from the base sequence specified by the DNA molecule. An enzyme DNA – DEPENDENT RNA POLYMERASE or RNA POLYMERASE binds to a PROMOTER SITE on the DNA. A promoter site is a sequence of DNA that specifies the beginning of a gene. 1/30/2011 EUGENE PARDI, DO 30 1/30/2011 EUGENE PARDI, DO 31 TRANSCRIPTION The RNA polymerase pulls a portion of the DNA strands apart from one another, allowing unattached DNA bases to be exposed. One of the DNA strands provides the template for the sequence of mRNA nucleotides. 1/30/2011 EUGENE PARDI, DO 32 TRANSCRIPTION Except for the presence of uracil, the mRNA sequence is identical to that of the other DNA strand. Transcription continues until a DNA sequence called a TERMINATION SEQUENCE is reached. RNA polymerase detaches and the transcribed mRNA moves out of the nucleus into the cytoplasm. 1/30/2011 EUGENE PARDI, DO 33 GENE SPLICING The mRNA transcribed from the DNA template reflects exactly the base sequence of the DNA. Called HETEROGENEOUS NUCLEAR RNA (hnRNA). Before migrating to the cytoplasm, many of the RNA sequences are removed by nuclear enzymes. The remaining sequences are then spliced together to form the functional mRNA. The excised sequences are called INTRONS. The sequences left to code for proteins are called EXONS. 1/30/2011 EUGENE PARDI, DO 34 TRANSLATION TRANSLATION is the process by which RNA directs the synthesis of a polypeptide. It interacts with TRANSFER RNA (tRNA). The molecule has a site for the attachment of an amino acid at one end. 1/30/2011 EUGENE PARDI, DO 35 TRANSLATION At the opposite side is a sequence of three nucleotides called the ANTICODON. Undergoes complementary base pairing with an appropriate codon in the mRNA. The mRNA specifies the sequence of amino acids by acting through the tRNA. 1/30/2011 EUGENE PARDI, DO 36 TRANSLATION The site of actual protein synthesis is the RIBOSOME. Consists of roughly equal parts of protein and RIBOSOMAL RNA (rRNA). During translation, the ribosome first binds to an initiation site on the mRNA sequence. 1/30/2011 EUGENE PARDI, DO 37 TRANSLATION It then binds tRNA to its surface so that base pairing can occur between tRNA and mRNA. The ribosome then moves along the mRNA sequence, codon by codon. 1/30/2011 EUGENE PARDI, DO 38 1/30/2011 EUGENE PARDI, DO 39 TRANSLATION As each codon is processed, an amino acid is translated by the interaction of mRNA and tRNA. The ribosome provides an enzyme that catalyzes the formation of peptide bonds between adjacent amino acids., resulting in a growing polypeptide. 1/30/2011 EUGENE PARDI, DO 40 1/30/2011 EUGENE PARDI, DO 41 TRANSLATION When the ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease. The polypeptide is released into the cytoplasm to perform its function. 1/30/2011 EUGENE PARDI, DO 42 CHROMOSOMES Human cells can be categorized into two types: GAMETES: sperm and egg cells SOMATIC CELLS: all cells other than gametes. Each somatic cell has 46 chromosomes in its nucleus. DIPLOID CELLS: the chromosomes occur in pairs. Each cell has 23 pairs of chromosomes. One member of each pair comes from an individual’s mother, and one comes from the father. 1/30/2011 EUGENE PARDI, DO 43 1/30/2011 EUGENE PARDI, DO 44 CHROMOSOMES New somatic cells are formed through mitosis and cytokinesis. The cell nucleus and cytoplasm are replicated. Gametes are HAPLOID CELLS. Have only one member of each chromosome pair, or, 23 chromosomes. MEIOSIS is the process by which these cells are formed from diploid cells. 1/30/2011 EUGENE PARDI, DO 45 CHROMOSOMES In 22 of the 23 chromosome pairs, the two members of each pair are virtually identical in appearance. Are HOMOLOGOUS to one another in both males and females. Termed AUTOSOMES. The SEX CHROMOSOMES have two homologous X chromosomes in females and a nonhomologous par, X and Y in males. Males are HEMIZYGOUS for the X chromosome. 1/30/2011 EUGENE PARDI, DO 46 1/30/2011 EUGENE PARDI, DO 47 1/30/2011 EUGENE PARDI, DO 48 CHROMOSOMES METAPHASE SPREAD: photograph of the chromosomes as they appear in the nucleus of a somatic cell during metaphase. KARYOTYPE: an ordered display of chromosomes. The chromosomes are arranged according to size, with the HOMOLOGOUS CHROMOSOMES paired together. The 22 autosomes are numbered according to length and the position of the centromere. I longest. 22 shortest. 1/30/2011 EUGENE PARDI, DO 49 1/30/2011 EUGENE PARDI, DO 50 CHROMOSOME ABERRATIONS AND ASSOCIATED DISEASES Chromosome abnormalities are the leading known cause of mental retardation and miscarriage. A major chromosome aberration occurs in at least 1 in 12 conceptions. 50% of all recovered first trimester spontaneous abortions have major chromosomal aberrations. 1 in 150 live births has a diagnosable chromosome abnormality. 1/30/2011 EUGENE PARDI, DO 51 POLYPLOIDY EUPLOID CELLS: cells that have a multiple of the normal number of chromosomes. A POLYPLOID CELL has more than the diploid number of chromosomes. TRIPLOID – 3 copies of each chromosome. TETRAPLOID – 4 copies of each chromosome. Both of these conditions are incompatible with postnatal survival. 1/30/2011 EUGENE PARDI, DO 52 ANEUPLOIDY An ANEUPLOID CELL is a somatic cell that does not contain a multiple of 23 chromosomes. TRISOMY 3 copies of one particular chromosome. MONOSOMY 1 copy of a given chromosome in a diploid cell. Among the autosomes, monosomy of any chromosome is lethal. Newborns with trisomy of some chromosomes can survive. Trisomy 21 Down’s syndrome. 1/30/2011 EUGENE PARDI, DO 53 ANEUPLOIDY In general, loss of chromosome material has more serious consequences than duplication of chromosome material. Aneuploidy of the sex chromosomes is less serious than that of the autosomes. Y chromosome very little genetic material is located on this chromosome. X chromosome inactivation of extra chromosomes diminishes their effect. A zygote with no X chromosome will not survive. 1/30/2011 EUGENE PARDI, DO 54 ANEUPLOIDY Aneuploidy is usually the result of NONDISJUNCTION. Homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis. Nondisjunction during either stage of meiosis produces some gametes that have two copies of a given chromosome and others that have no copies of the chromosome. Zygotes will either be trisomic or monosomic for the given chromosome. 1/30/2011 EUGENE PARDI, DO 55 AUTOSOMAL ANEUPLOIDY Trisomy can occur for any chromosome. Trisomies of the 13th, 18th, and 21st chromosomes are seen with any appreciable frequency in live births. Fetuses with most other chromosomal trisomies do not survive to term. PARTIAL TRISOMY: only an extra portion of a chromosome is present in each cell. Consequences are not as severe as those of complete trisomies. 1/30/2011 EUGENE PARDI, DO 56 1/30/2011 EUGENE PARDI, DO 57 This baby with trisomy 13 has cyclopia (single eye) with a proboscis (the projecting tissue just above the eye). 1/30/2011 EUGENE PARDI, DO 58 AUTOSOMAL ANEUPLOIDY Trisomies also may occur in only some cells of the body. Individuals affected are CHROMOSOMAL MOSAICS. The body has two or more cell lines, each of which has a different karyotype. Usually formed by early mitotic nondisjunction occurring in one embryo cell but not in others. 1/30/2011 EUGENE PARDI, DO 59 AUTOSOMAL ANEUPLOIDY DOWN SYNDROME: trisomy of the 21st chromosome. Seen in 1 in 800 live births. Individuals have IQs ranging from 25 – 70. Facial appearance: low nasal bridge, epicanthal folds (which produce an Asian appearance), protruding tongue, and flat, low – set ears. Poor muscle tone (hypotonia) and short stature are also characteristics. 1/30/2011 EUGENE PARDI, DO 60 1/30/2011 EUGENE PARDI, DO 61 1/30/2011 EUGENE PARDI, DO 62 1/30/2011 EUGENE PARDI, DO 63 1/30/2011 EUGENE PARDI, DO 64 1/30/2011 EUGENE PARDI, DO 65 1/30/2011 EUGENE PARDI, DO 66 AUTOSOMAL ANEUPLOIDY Congenital heart defects affect about one third to one half . A reduced ability to fight respiratory infections and an increased susceptibility to leukemia contribute to a reduced survival rate. By 40 years of age, individuals virtually always develop symptoms identical to Alzheimer’s disease. ¾ of fetuses known to have Down syndrome are spontaneously aborted. Average life expectancy is now about 60 years. 1/30/2011 EUGENE PARDI, DO 67 1/30/2011 EUGENE PARDI, DO 68 AUTOSOMAL ANEUPLOIDY The overwhelming majority of cases of Down syndrome are caused by nondisjunction during formation of the mother’s egg cell. About 1% of individuals with Down syndrome are mosaics. The effects of the trisomic cells are attenuated by the normal cells and symptoms are often less severe. 1/30/2011 EUGENE PARDI, DO 69 1/30/2011 EUGENE PARDI, DO 70 AUTOSOMAL ANEUPLOIDY Risk of having a child with Down syndrome increases with maternal age. Begins to rise after 35 years of age and reaches 3% to 5% for women older than 45 years of age. Due to age of maternal egg cells. 1/30/2011 EUGENE PARDI, DO 71 1/30/2011 EUGENE PARDI, DO 72 SEX CHROMOSOME ANEUPLOIDY Among live births, about 1 in 400 males and 1 in 650 females has a form of sex chromosome aneuploidy. Conditions are less severe than autosomal aneuploidies. All forms except complete absence of an X chromosome allow at least some individuals to survive. 1/30/2011 EUGENE PARDI, DO 73 SEX CHROMOSOME ANEUPLOIDY TRISOMY X: affecting 1 in 1000 newborn females. 3 X chromosomes in each cell. No overt physical abnormalities. Sterility, menstrual irregularity, or mental retardation is sometimes seen. 4 X chromosomes more often mentally retarded. 5 or more X chromosomes more severe retardation and various physical defects. 1/30/2011 EUGENE PARDI, DO 74 1/30/2011 EUGENE PARDI, DO 75 SEX CHROMOSOME ANEUPLOIDY TURNER SYNDROME: has a single X chromosome, karyotype designated as 45,X. Since no Y chromosome, are female. Usually sterile, have gonadal streaks rather than ovaries. These streaks of CT are susceptible to cancer in mosaics who have some cells containing a Y chromosome. 1/30/2011 EUGENE PARDI, DO 76 1/30/2011 EUGENE PARDI, DO 77 SEX CHROMOSOME ANEUPLOIDY Other features include: short stature, webbing of the neck, widely spaced nipples, coarctation of the aorta, edema of the feet in newborns, reduced carrying angle at the elbow, and sparse body hair. Not considered retarded, but, there is some impairment of spatial and mathematical reasoning ability. ¾ inherit their X chromosome from the mother. Thus, most cases are caused by a loss of the paternal X chromosome. 1/30/2011 EUGENE PARDI, DO 78 A patient with Turner syndrome is shown. This posterior view shows a low hairline and a shield-shaped chest. Note the narrow hip development. 1/30/2011 EUGENE PARDI, DO 79 SEX CHROMOSOME ANEUPLOIDY Teenagers with Turner syndrome are treated with estrogen to promote the development of secondary sexual characteristics. Dose is continued at a reduced level to maintain these characteristics and to help avoid osteoporosis. Human growth hormone is sometimes administered to increase stature. 1/30/2011 EUGENE PARDI, DO 80 SEX CHROMOSOME ANEUPLOIDY KLINEFELTER SYNDROME: have two X chromosomes and a Y chromosome in each cell. 47,XXY karyotype. Due to the presence of a Y chromosome, these individuals have a male appearance. Are usually sterile, and about half develop female – like breasts. GYNECOMASTIA 1/30/2011 EUGENE PARDI, DO 81 G-banded 47,XXY karyotype. 1/30/2011 EUGENE PARDI, DO 82 1/30/2011 EUGENE PARDI, DO 83 Adolescent male with gynecomastia and Klinefelter syndrome. 1/30/2011 EUGENE PARDI, DO 84 SEX CHROMOSOME ANEUPLOIDY Other characteristics: testes are small, body hair is sparse, voice is high pitched, stature is elevated, and a moderate degree of mental impairment may be present. Frequency is about 1 in 1000 male births. 2/3 of the cases are caused by nondisjunction of the X chromosomes in the mother. 1/30/2011 EUGENE PARDI, DO 85 Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis. 1/30/2011 EUGENE PARDI, DO 86 Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal. 1/30/2011 EUGENE PARDI, DO 87 SEX CHROMOSOME ANEUPLOIDY Frequency rises with maternal age. XXXY and XXXXY karyotypes also have Klinefelter Syndrome. Degree of physical and mental impairment increases with each additional X chromosome. All have a male appearance, no matter how many X chromosomes are present. 1/30/2011 EUGENE PARDI, DO 88 SEX CHROMOSOME ANEUPLOIDY 47,XYY syndrome: individuals tend to be taller than average, and they have a 10 to 15 point reduction in average IQ. Causes few physical problems. Incidence in prison populations was about 1 in 30 vs. 1 in 1000 in the general population. No increase in violent crimes, but there is an increase in incidence of behavioral disorders. 1/30/2011 EUGENE PARDI, DO 89 ABNORMALITIES OF CHROMOSOME STRUCTURE Parts of chromosomes can be lost or duplicated as gametes are formed. Also, the arrangement of genes on chromosomes can be altered. These changes sometimes do not have serious consequences for an individual’s health. 1/30/2011 EUGENE PARDI, DO 90 ABNORMALITIES OF CHROMOSOME STRUCTURE During meiosis and mitosis, CHROMOSOME BREAKAGE occasionally occurs. Mechanisms exist to repair these breaks perfectly with no damage to the daughter cell. Sometimes, the breaks remain, or, they heal in a fashion that alters the structure of the chromosome. The extent of chromosome breakage is increased in the presence of certain harmful agents called CLASTOGENS. Ionizing radiation, some viral infections, certain chemicals. 1/30/2011 EUGENE PARDI, DO 91 ABNORMALITIES OF CHROMOSOME STRUCTURE DELETIONS are caused by broken chromosomes and loss of DNA. Usually a gamete with a deletion unites with a normal gamete to form a zygote. The zygote has one chromosome with the normal complement of genes and one with some missing genes. A fairly large number of genes can be lost in a deletion, serious consequences can result, even though one copy of the chromosome is normal. 1/30/2011 EUGENE PARDI, DO 92 1/30/2011 EUGENE PARDI, DO 93 ABNORMALITIES OF CHROMOSOME STRUCTURE CRI DU CHAT SYNDROME: “cry of the cat” describes the characteristic cry of the affected child. Other Sx: low birth weight, severe mental retardation, microcephaly, heart defects, and the typical facial appearance. Caused by a deletion of part of the short arm of chromosome 5. 1/30/2011 EUGENE PARDI, DO 94 1/30/2011 EUGENE PARDI, DO 95 1/30/2011 EUGENE PARDI, DO 96 1/30/2011 EUGENE PARDI, DO 97 1/30/2011 EUGENE PARDI, DO 98 ABNORMALITIES OF CHROMOSOME STRUCTURE DUPLICATIONS of chromosome material are a form of chromosome aberration. Deficiency of genetic material is more harmful than an excess, so, duplications usually have less serious consequences than deletions. 1/30/2011 EUGENE PARDI, DO 99 1/30/2011 EUGENE PARDI, DO 100 ABNORMALITIES OF CHROMOSOME STRUCTURE An INVERSION is the occurrence of two breaks on a chromosome, followed by the reinsertion of the missing fragment at its original site but in an inverted order. Chromosome ABCDEFG becomes chromosome ABEDCFG. There is no loss or gain of genetic material – a “balanced” alteration of chromosome structure. Often have no apparent physical effect. 1/30/2011 EUGENE PARDI, DO 101 1/30/2011 EUGENE PARDI, DO 102 ABNORMALITIES OF CHROMOSOME STRUCTURE Genes are sometimes influenced by neighboring DNA sequences – POSITION EFFECT. Thus a change in a gene’s expression caused by a change in position can result in physical defects in persons with inversions. The serious problems caused by inversions usually occur in the offspring of individuals carrying the inversion. Prevents lining up of homologous chromosomes during prophase I of meiosis. Can result in chromosome deletions or duplications. 1/30/2011 EUGENE PARDI, DO 103 ABNORMALITIES OF CHROMOSOME STRUCTURE TRANSLOCATIONS: the interchanging of genetic material between nonhomologous chromosomes. A ROBERTSONIAN TRANSLOCATION is clinically the most important type of translocation. The long arms of two nonhomologous chromosomes fuse at the centromere, forming a single chromosome. Confined to chromosomes 13, 14, 15, 21, and 23. Short arms are small and contain no genetic material. The carriers lose no genetic material and are normal, though they only have 45 chromosomes. 1/30/2011 EUGENE PARDI, DO 104 1/30/2011 EUGENE PARDI, DO 105 ABNORMALITIES OF CHROMOSOME STRUCTURE Offspring may have serious deletions or duplications. Eg: fusion of the long arms of chromosomes 21 and 14. Offspring who receive the fused chromosome receive an extra copy of the long arm of chromosome 21 and develop Down syndrome. Parents who are carriers of this chromosome have an increased risk of having multiple offspring with Down syndrome. 1/30/2011 EUGENE PARDI, DO 106 ABNORMALITIES OF CHROMOSOME STRUCTURE A RECIPROCAL TRANSLOCATION occurs when breaks take place in two different chromosomes and the material is exchanged. The carrier of the translocation is usually normal. Gamete’s can be normal, carry the translocation, or can have duplications and deletions. 1/30/2011 EUGENE PARDI, DO 107 1/30/2011 EUGENE PARDI, DO 108 ABNORMALITIES OF CHROMOSOME STRUCTURE A number of areas on chromosomes develop distinctive breaks and gaps when the cells are cultured in a folate – deficient medium. Most of these FRAGILE SITES have no apparent relationship to disease. FRAGILE X SYNDROME: one fragile site located on the long arm of the X chromosome associated with mental retardation. Is the second most common genetic cause of mental retardation after Down syndrome. Affects 1 in 4000 males and 1 in 8000 females. 1/30/2011 EUGENE PARDI, DO 109 ABNORMALITIES OF CHROMOSOME STRUCTURE Males who inherit the mutation do not necessarily express the disease condition but they can pass it on to descendants who express it. About 1/3 of carrier females are affected, less severely than males. Unaffected transmitting males have an elevated number of repeated DNA sequences in the first exon of the fragile X gene. Affected males have a much larger number of these repeats. An increase in the number of these repeated sequences in successive generations can lead to expression of the fragile X syndrome. 1/30/2011 EUGENE PARDI, DO 110 ELEMENTS OF FORMAL GENETICS The mechanisms by which an individual’s set of paired chromosomes produces traits are the principles of genetic inheritance. Many traits are caused by single genes and are called MEDELIAN TRAITS. 1/30/2011 EUGENE PARDI, DO 111 ELEMENTS OF FORMAL GENETICS Each gene occupies a position along a chromosome known as a LOCUS. Genes at a particular locus can take different forms (have different nucleotide sequences). Called ALLELES. A locus that has two or more alleles that occur with an appreciable frequency is said to be POLYMORPHIC or POLYMORPHISM. 1/30/2011 EUGENE PARDI, DO 112 ELEMENTS OF FORMAL GENETICS At a given locus an individual has one gene whose origin is paternal and one whose origin is maternal. When the two genes are identical, the individual is HOMOZYGOUS at that locus. When the genes are not identical, the individual is HETEROZYGOUS at the locus. 1/30/2011 EUGENE PARDI, DO 113 PHENOTYPE AND GENOTYPE The composition of genes at a given locus is known as the GENOTYPE. The outward appearance of an individual is the PHENOTYPE. The phenotype reflects the interaction of the genotype with the environment. E.g. phenylketonuria 1/30/2011 EUGENE PARDI, DO 114 DOMINANCE AND RECESSIVENESS At a locus that is heterozygous for a trait, the effects of one allele can mask the effects of the other allele when the two are found together. The allele whose effects are observable is said to be DOMINANT The allele whose effects are hidden is said to be RECESSIVE. For loci having two alleles, the dominant allele is denoted by an uppercase letter and the recessive allele is denoted by a lowercase letter (e.g. A dominant; a recessive). 1/30/2011 EUGENE PARDI, DO 115 DOMINANCE AND RECESSIVENESS When one allele is dominant over another, the heterozygote genotype (Aa) has the same phenotype as the dominant homozygote (AA). For the recessive allele to be expressed, it must exist in the homozygote form (aa). When the heterozygote is distinguishable from both homozygotes, the locus is said to exhibit CODOMINANCE. E.g. ABO blood group. 1/30/2011 EUGENE PARDI, DO 116 DOMINANCE AND RECESSIVENESS A CARRIER is an individual who has a disease gene but is phenotypically normal. Most genes for recessive diseases occur in heterozygotes who carry one copy of the gene but do not express the disease. 1/30/2011 EUGENE PARDI, DO 117 DOMINANCE AND RECESSIVENESS Many recessive genes are lethal in the homozygous state, so they are eliminated from the population when they occur in homozygotes. By hiding in carriers, most recessive genes for diseases survive to be passed on to the next generation. i.e. sickle cell anemia, cystic fibrosis. 1/30/2011 EUGENE PARDI, DO 118 TRANSMISSION OF GENETIC DISEASES MODE OF INHERITANCE: the pattern in which a disease is inherited through the generations of a family. Mendel, in his studies of garden peas, proposed two basic laws of inheritance: PRINCIPLE OF SEGREGATION: homologous genes separate from one another during reproduction and that each reproductive cell carries only one of the homologous genes. 1/30/2011 EUGENE PARDI, DO 119 TRANSMISSION OF GENETIC DISEASES PRINCIPLE OF INDEPENDENT ASSORTMENT: the hereditary transmission of one gene has no effect on the transmission of another. Mendel had no knowledge of chromosomes. Geneticists have found that the behavior of chromosomes corresponds to Mendel’s laws. CHROMOSOME THEORY OF INHERITANCE. 1/30/2011 EUGENE PARDI, DO 120 TRANSMISSION OF GENETIC DISEASES Single – gene diseases can be classified into four major modes of inheritance: Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive. The first two categories involve genes known to occur on the 22 pairs of autosomes. The last two types occur on the X chromosome. 1/30/2011 EUGENE PARDI, DO 121 TRANSMISSION OF GENETIC DISEASES The PEDIGREE chart summarizes family relationships and shows which members of a family are affected by a genetic disease. The pedigree begins with one individual in the family, the PROBAND, or PROPOSITUS (MALE) or PROPOSITA (FEMALE). Usually the first person in the family diagnosed with the disease or seen in a clinic. 1/30/2011 EUGENE PARDI, DO 122 FRAGILE X INHERITANCE 123 AUTOSOMAL DOMINANT INHERITANCE Diseases caused by autosomal dominant genes are rare. Uncommon that two individuals both affected by the same autosomal dominant disease to produce offspring together. More often, affected offspring are produced by the union of an affected heterozygous parent with a normal unaffected parent. On average, half the children will be normal and half will be heterozygous and will express the disease. 1/30/2011 EUGENE PARDI, DO 124 AUTOSOMAL DOMINANT INHERITANCE Characteristics of autosomal dominant traits: The two sexes exhibit the trait in approximately equal proportions and both are likely to transmit the trait to their offspring. There is no skipping of generations. Affected heterozygous individuals transmit the trait to approximately half of their children. Due to independent assortment and chance fluctuations, it is possible that all or none of the offspring of an affected parent may have the trait. 1/30/2011 EUGENE PARDI, DO 125 1/30/2011 EUGENE PARDI, DO 126 Pedigree for achondroplasia 1/30/2011 EUGENE PARDI, DO 127 AUTOSOMAL DOMINANT: RECURRENCE RISKS RECURRENCE RISK: when one child of a family has a disease, it is the probability that subsequent children also will have the disease. In an autosomal dominant disease, when one parent is heterozygous and exhibits the disease and the other parent is normal, the recurrence risk for each child is ½ or 50%. Each birth is an independent event, so, the recurrence risk is for each pregnancy and is not dependent on the number of children in the family. 1/30/2011 EUGENE PARDI, DO 128 AUTOSOMAL DOMINANT: RECURRENCE RISKS If a child has been born with an autosomal dominant disease and there is no history of the disease in the family, the child is probably the product of a new mutation. The genes at this locus in most of the parent’s other germ cells would still be normal. In this case, the recurrence risk for the parent’s subsequent offspring is not greater than that of the general population. The offspring of the affected child, however will have an occurrence risk of ½. 1/30/2011 EUGENE PARDI, DO 129 AUTOSOMAL DOMINANT: RECURRENCE RISKS Many autosomal dominant diseases reduce the potential for reproduction. A large proportion of the observed cases are the result of new mutations. Occasionally, two or more offspring will present symptoms of an autosomal dominant disease when there is no family history of the disease. Unlikely due to multiple mutations in the same family. 1/30/2011 EUGENE PARDI, DO 130 AUTOSOMAL DOMINANT: RECURRENCE RISKS GERMLINE MOSAICISM: a mutation that occurred during embryonic development of one of the parents that affected all or part of the germline but few or none of the somatic cells of the embryo. The parent carries the mutation in his or her germline but does not actually express the disease. Can transmit the mutation to multiple offspring. 1/30/2011 EUGENE PARDI, DO 131 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY The PENETRANCE of a trait is the percentage of individuals with a specific genotype who also exhibit the expected phenotype. INCOMPLETE PENETRANCE means that individuals who have the gene for a disease may not exhibit the disease phenotype at all, even though the gene and the associated disease may be transmitted to the next generation. OBLIGATE CARRIERS: those who have an affected parent and children and therefore must carry the gene. 1/30/2011 EUGENE PARDI, DO 132 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY RETINOBLASTOMA: the most common malignant eye tumor affecting children. Exhibits incomplete penetrance in that 10% are obligate carriers and do not exhibit any symptoms of the disease. The penetrance of the gene is thus 90%. 1/30/2011 EUGENE PARDI, DO 133 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY The gene responsible has been mapped to the long arm of chromosome 13. The gene is known as a TUMOR SUPPRESSOR GENE. It is a protein that regulates the cell cycle so that cells do not grow uncontrollably. A mutation alters the protein so its tumor suppressing capacity is lost and a tumor can form. 1/30/2011 EUGENE PARDI, DO 134 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY HUNTINGTON DISEASE: another autosomal dominant disease. A neurologic disorder whose main features are progressive dementia and increasingly uncontrollable movements of the limbs. Known as CHOREA. Symptoms of the disease are not usually seen until age 40 years or later. AGE – DEPENDENT PENETRANCE. People who develop the disease often have had children before they are aware that they have the gene. 1/30/2011 EUGENE PARDI, DO 135 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY EXPRESSIVITY: the extent of variation in phenotype associated with a particular genotype. If expressivity of a disease is variable, the penetrance may be complete, but the severity of the disease can vary greatly. 1/30/2011 EUGENE PARDI, DO 136 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY Several factors cause variable expressivity: Genes at other loci sometimes modify the expression of a disease gene. Environmental factors can influence expression of a disease gene. Different mutations at a locus can cause variation in severity. 1/30/2011 EUGENE PARDI, DO 137 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY TYPE I NEUROFIBROMATOSIS or VON RECKLINGHAUSEN DISEASE: autosomal dominant disease with variable expressivity. The gene has been mapped to the long arm of chromosome 17. It is also a tumor suppressor gene. The expression of the gene varies from a few harmless café – au – lait spots on the skin to numerous neurofibromas, scoliosis, seizures, gliomas, neuromas, HTN, and mental retardation. 1/30/2011 EUGENE PARDI, DO 138 1/30/2011 EUGENE PARDI, DO 139 1/30/2011 EUGENE PARDI, DO 140 AUTOSOMAL DOMINANT: PENETRANCE AND EXPRESSIVITY A parent with mild expression of the disease can transmit the gene to a child, who may exhibit severe expression of the disease. Variable expressivity provides a mechanism by which autosomal dominant genes can be maintained at higher prevalence rates in populations. 1/30/2011 EUGENE PARDI, DO 141 AUTOSOMAL RECESSIVE INHERITANCE Autosomal recessive disorder Abnormal allele is recessive and a person must be homozygous for the abnormal trait to express the disease The trait usually appears in the children, not the parents, and it affects the genders equally because it is present on a pair of autosomes 1/30/2011 EUGENE PARDI, DO 142 AUTOSOMAL RECESSIVE INHERITANCE Autosomal recessive disorder recurrence risk Recurrence risk of an autosomal dominant trait When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25% 1/30/2011 EUGENE PARDI, DO 143 1/30/2011 EUGENE PARDI, DO 144 AUTOSOMAL RECESSIVE INHERITANCE 1/30/2011 Characteristics Condition expressed equally in males and females Affected individuals most often the offspring of asymptomatic heterozygous carrier parents Approximately 1/4 of offspring will be affected; 1/2 will be asymptomatic carriers; and 1/4 will be unaffected Individuals must be homozygous for the condition to be expressed Generational skipping may be present Consanguinity may be present EUGENE PARDI, DO 145 AUTOSOMAL RECESSIVE INHERITANCE CONSANGUINITY: refers to the mating of two related individuals. The offspring of such matings are said to be INBRED. Mating of two related individuals Dramatically increases the recurrence risk of recessive disorders 1/30/2011 EUGENE PARDI, DO 146 SEX LINKED DISORDERS Disorders involve X and Y chromosomes X-linked disorders usually expressed by males because females have another X chromosome to mask the abnormal allele Males, having only one X chromosome, are HEMIZYGOUS for genes on this chromosome. Most are recessive Y-linked disorders uncommon because Y chromosome contains relatively few genes Father-son transmission present No father-daughter transmission 1/30/2011 EUGENE PARDI, DO 147 1/30/2011 EUGENE PARDI, DO 148 X INACTIVATION X INACTIVATION: one X chromosome in the somatic cells of females is permanently inactivated. Explains why most gene products coded by the X chromosome are present in equal amounts in males and females. Called DOSAGE COMPENSATION. Observable in many interphase cells as highly condensed intranuclear chromatin bodies. BARR BODIES. Normal females have one Barr body in each somatic cell, whereas males have no Barr bodies. 1/30/2011 EUGENE PARDI, DO 149 1/30/2011 EUGENE PARDI, DO 150 1/30/2011 EUGENE PARDI, DO 151 X INACTIVATION Inactivation occurs 7 – 14 days after fertilization in embryonic development. Random selection of whether the paternal or maternal X chromosome is inactivated. Once the X chromosome is inactivated, all the descendants of that cell have the same chromosome inactivated. Inactivation is RANDOM but FIXED. 1/30/2011 EUGENE PARDI, DO 152 1/30/2011 EUGENE PARDI, DO 153 X LINKED RECESSIVE DISORDERS Characteristics Males most commonly affected Affected males cannot transmit the genes to sons, but they can to all daughters Unaffected carrier females Sons of female carriers have a 50% risk of being affected Pedigree analysis Generational skipping often present No father-to-son transmission 1/30/2011 EUGENE PARDI, DO 154 X LINKED RECESSIVE DISORDERS A. Outcomes for offspring of an unaffected father and a heterozygous unaffected carrier mother (most common scenario) B. Outcomes for offspring of an affected father and a homozygous unaffected mother C. Outcomes for offspring of an affected father and a heterozygous unaffected carrier mother 1/30/2011 EUGENE PARDI, DO 155 X LINKED RECESSIVE DISORDERS 1/30/2011 Hemophilia Bleeding disorders resulting from a congenital deficiency of coagulation factors Hemophilia A: factor VIII deficiency 20.6/100,000 male births in U.S. Hemophilia B: factor IX deficiency 5.3/100,000 male births in U.S. Mutations associated with factor VIII deficiency: Large deletions or insertions, frameshift and splice junction changes, and nonsense and missense mutations Mutations vary across families but tend to be similar within families EUGENE PARDI, DO 156 MULTIFACTORIAL INHERITANCE Characteristics of multifactorial disorders Result from hereditary and environmental factors Hereditary component is polygenic Individual involved genes follow mendelian principles Many genes act together to influence the expressed trait 1/30/2011 EUGENE PARDI, DO 157 MULTIFACTORIAL INHERITANCE Concordance and discordance Concordance Expression of the disease in two related family members Discordance Expression of the disease in one family member but not a second 1/30/2011 EUGENE PARDI, DO 158 MULTIFACTORIAL INHERITANCE Twin studies and concordance Genetic conditions Monozygotic (MZ) twins: 100% concordance Dizygotic (DZ) twins: less than 100% and similar to that among other siblings Environmental conditions Equal concordance rates among MZ and DZ twins Multifactorial conditions MZ twins with greater concordance than DZ twins, but rates are not 100% Adoption studies Gene-environment-lifestyle interaction 1/30/2011 EUGENE PARDI, DO 159 1/30/2011 EUGENE PARDI, DO 160