Genes and Genetic Diseases PDF

GENES AND GENETIC DISEASES Derek Owens DrAP, CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable genetic diseases. McCance c...

GENES AND GENETIC DISEASES Derek Owens DrAP, CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable genetic diseases. McCance chapter 4 Chromosomes Two types of cells 1. Germline Mutations can be transmitted to the next generation 2. Somatic Diploid cells- 23 pairs of chromosomes – Homologous- 22 of the 23 pairs are virtually identical – The remaining pair, the sex chromosomes consist of two homologous X chromosomes in females and a non-homologous pair X and Y in males 3 Polyploidy When a germ line or somatic cell has more than the diploid number of chromosomes (46) Several types of body tissue including liver, bronchioles and epithelial tissue are normally polyploid – Triploidy- is when a zygote has three copies of each chromosome rather than usual two Nearly all triploid conceptions are spontaneously aborted or stillborn Accounts for 10% of all known miscarriages 4 Aneuploidy Those cells that do not contain a multiple of 23 chromosomes – Monosomy- a diploid cell which contains only one copy of a given chromosome Always lethal – Trisomic is an aneuploid cell containing three copies of one chromosome Trisomy of 13, 18 and 21 can survive Normally a result of non-disjunction – Homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis 5 Abnormalities of the chromosome structure Parts of chromosomes can be lost or duplicated as gametes are formed and the arrangement of genes on chromosomes can be altered – Deletions- a gamete with a deletion unites with a normal gamete to form a zygote one chromosome with a normal compliment of genes and one with missing genes – Cri du chat syndrome – Duplications- duplications usually have less serious consequences a deficiency of genetic material is more harmful than excess – Inversions- the occurrence of two breaks on a chromosome followed by the reinsertion of the missing fragment at the original site but in inverted order “Balanced”- no loss or gain of genetic material – Can often have deletions and duplications so does sometimes result in disease 6 Abnormalities of chromosome structure (cont) – Translocations- the interchanging of genetic material between non-homologous chromosomes Robertsonian translocation- the long arms of two nonhomologous chromosomes fuse at the centromere forming a single chromosome Reciprocal translocation- occurs when breaks take place in two different chromosomes and the material is exchanged – Fragile sites A number of areas on chromosomes to develop microscopically observable breaks and gaps Most have no apparent relationship to disease Fragile X syndrome- a fragile site is located on the long arm of the X-chromosome which has considerable clinical and genetic importance – Associated with cognitive impairment – Affects 1 in 4000 males and 1 in 8000 females which is the second most common genetic cause of intellectual disability after down syndrome 7 Down syndrome The most well-known example of aneuploidy chromosomal cells – 10 in 800 live births – Typically have low IQ quotients The risk greatly increases with maternal age Approximately 97% are caused by nondisjunction during formation of one of the parents gametes or during early embryonic development – The remaining 3% result from translocations The facial appearance is distinctive – low nasal bridge, epicanthal folds, large protruding tongue, and flat low set ears – Congenital heart defects in about 1/3 to ½ By 40 years old almost always develop symptoms nearly identical to Alzheimer’s disease – One of the genes that can cause Alzheimer’s is located on chromosome 21 8 Turner syndrome One of the most common single chromosome aberrations – 15 to 20% of spontaneous abortions – One in 2500 newborn females is affected The presence of a single X chromosome – Results in a total of 45 chromosomes and no homologous X or Y chromosome – Since they have no Y-chromosome they are always female but usually sterile Physical characteristics 1. Short in stature 2. Webbing of the neck 3. Widely spaced nipples 4. Corotation of the aorta (15-20%) 5. Edema of the feet in newborns 6. Sparse body hair 9 Klinefelter syndrome 2 X chromosomes and a Y – Due to the presence of a Y chromosome have a male appearance but usually sterile Physical characteristics 1. 50% develop gynecomastia 2. The testes are small and the body hair is sparse 3. Statures elevated 4. Voice is somewhat high-pitched 5. A Moderate degree of mental impairment is often present About 1 in 1000 male births 10 Elements of formal genetics Locus- the location each gene occupies on a chromosome Alleles- genes at a particular locus can take different forms – Can determine the difference between hemoglobin S (sickle) and hemoglobin A Polymorphic- when two or more alleles each occur with appreciable frequencies in a population Genotype- the composition of genes at a given locus Phenotype- the result of both genotype and environment Dominant- the allele whose affects mask another on a heterozygote Recessive- to be expressed must exist in homozygote form Carrier- an individual who has a disease causing allele but is phenotypically normal 11 Transmission of genetic diseases Mode of inheritance- the pattern in which a disease is inherited through the generations of a family – Once this is known much can be learned about the gene causing the disease Mendelian traits (after Gregor Mendel) – Principal of segregation- homologous genes separate from one another during reproduction and each reproductive cell carries only one of the homologous genes. – Principle of independent assortment- hereditary transmission of one gene has no effect on the transmission of another The known single gene diseases can be classified in the four major modes of inheritance 1. Autosomal dominant 2. Autosomal recessive 3. X-linked dominant 4. X-linked recessive – Only a few disease causing genes found on the Y chromosome and those primarily affect male fertility 12  Pedigree chart Important in the analysis of modes of inheritance Summarizes family relationships and shows which family members are affected by a genetic disease – Proband- the individual affected by a genetic disease Propositus (male) or Proposita (female)- the first person in the family diagnosed or seen in a clinic Pedigree chart showing achondroplasia 13 Autosomal dominant inheritance 1. Both sexes exhibit the trait in equal proportion 2. No skipping generations 3. Affected heterozygous individuals transmit the trait to approximately 50% of their children – It is uncommon for two individuals both affected by the same autosomal dominant disease to produce offspring together (Homozygous affected) More common affected off-spring are produced by the union of a normal parent with an affected heterozygous parent – Diseases caused by Autosomal dominant genes are relatively rare 14  Genetic disease characteristics Recurrence risk- The chance that a child will have the disease – When one parent is a heterozygous affected and the other is unaffected recurrence risk for each child is 50% Each birth is an independent event If a child has been born with an autosomal dominant disease and there’s no history of disease in the family the child is probably the product of a new mutation 15 Genetic disease characteristics Penetrance- the percentage of individuals with a genotype who also exhibit the expected phenotype – Incomplete penetrance- the individuals who have a disease causing allele may not exhibit the disease phenotype at all The allele in the associated disease may be transmitted to the next generation Age dependent penetrance- symptoms of the disease are not seen until 40 years of age – Breast cancer, colon cancer, hemochromatosis and polycystic kidney disease – Should I have children knowing there’s a 50-50 chance they will have this disease? Obligate carrier- individuals who have an affected parent and an affected child and therefore must themselves carry the allele but do not have the disease 16  Autosomal recessive inheritance Diseases caused by autosomal recessive alleles are rare – Frequency of carriers can be high Individuals must be homozygous for recessive allele to express the disease Carriers are phenotypically normal Can be characterized by incomplete or age dependent penetrance as well as variable expressivity, the same as autosomal dominant diseases The most common lethal recessive disease in white children is cystic fibrosis which occurs in about 1 in 2500 births – Defective Cl transporter which leads to a salt imbalance resulting in and abnormally thick dehydrated mucus secretions Death from lung disease or heart failure occurs at about 40 years of age on average 17 Autosomal recessive inheritance Consanguinity- the marriage between related individuals is often a factor in producing recessive disease – Related individuals are more likely to share the same recessive disease causing alleles Important criteria for discerning autosomal inheritance 1. Males and females are affected in equal proportions 2. Consanguinity is sometimes present 3. The disease is seen in siblings but usually not in their parents 4. On average ¼ of the offspring of carrier parents will be affected 18 X-linked inheritance The Y chromosome contains only a few dozen genes, so most sex linked traits are located on the X chromosome with the exception of fragile X syndrome Females receive two X chromosomes and therefore can be homozygous for disease, homozygous for the normal allele or heterozygous A male who inherits a recessive disease on the X chromosome will be affected by the disease because the Y chromosome does not carry a normal allele to counteract the effects of the disease causing a allele – Males are more frequently affected by X-linked recessive diseases 19 Characteristics of X-linked recessive conditions 1. The trait will be seen much more often in males – Females must inherit two copies of the recessive allele to express the disease – Males need only inherit one recessive allele from their mother 2. Never transmitted from father to son – Sons only receive a Y chromosome from their father 3. The Gene can be transmitted through a series of carrier females causing the appearance of skipped generations 4. Affected Fathers will transmit to all daughters who then will be phenotypically normal carriers – Transmitting the gene to approximately half of their sons who are affected The most common and severe of all X-linked recessive disorders is Duchenne muscular dystrophy (DMD) – Affects approximately 1 in 3500 males 20 X-Linked recurrence risk Most common mating type is the combination of a carrier female and a normal male – The mother will transmit the disease causing allele to half their offspring Half the daughters will be carriers, half will be normal Has the sons will be normal, half will have the disease 21 Sex determination Begins during the sixth week of gestation One Y chromosome is sufficient to initiate the process of gonadal differentiation – The number of X-chromosomes does not alter this process – An individual two X chromosomes and one Y chromosome is still phenotypically male The SRY (Sex determining region on the Y) has been located on a short arm of the Y chromosome – Appears to act as a trigger that initiates the action of genes on other chromosomes 22 Sex linked traits Sex limited trait- a trait that can occur in only one of the sexes often because of anatomic differences Sex influenced trait- a trait that occurs much more often in one sex than the other – Male pattern baldness 23 Gene identification Locating the positions of genes on chromosomes has been one of the most important endeavors in human genetics For most genetic diseases it is not possible to test directly for the disease causing mutation, often by sequencing the germline DNA in family members As the cost of sequencing the whole human genome has declined it is now common to search for disease causing mutations in an individual or family by evaluating their entire germline DNA sequence Currently the genetic causes of about 4700 Mendelian conditions have been determined, enabling genetic testing, more accurate diagnosis and in some cases more effective treatment of the disease 24 Precision or personalized medicine Each persons unique genetic and environmental risk factors are taken into account in the diagnosis and management of diseases It is becoming increasingly common to diagnose disease by searching for disease causing variance in the persons entire DNA sequence Perhaps the area in which genetics is contributing most significantly is the guidance of therapeutic drug prescription – Out of 1200 drugs approved by the FDA 15% have recommendations for genetic testing to guide administration and dosing – Variance in the CYP2D6 gene (encodes a cytochrome P 450 enzyme) influences the metabolism of more than 25% of all prescribed drugs – Testing of the CYP2D6 can reduce trial and error for estimating appropriate drug levels 25