Genetics

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Unless otherwise noted, the information on this genetics page is from Chapter 4 in the textbook (McCance & Huether, 2006). =GENETICS REVIEW=


 * || **DNA** || **RNA** ||
 * FUNCTION || Directs synthesis of body's proteins (by coding for amino acids) || site of protein synthesis ||
 * LOCATION || nucleus || leaves nucleus through pores and moves into cytoplasm ||
 * COMPOSITION || deoxyribose sugar, phosphate, nitrogenous base (adenine, thymine, cytosine, and guanine) || ribose sugar, phosphate, nitrogenous base (adenine, uracil, cytosine, guanine) ||
 * BONDS || A-T and C-G || A-U and C-G ||
 * STRUCTURE || double stranded helix || usually single stranded ||

DNA REPLICATION

 * consists of breaking the hydrogen bonds between the bases and leaving a single strand with unpaired bases. In order for replication to work, the bases have to bind their complementary base (A-U, G-C, etc). DNA polymerase travels along the single strand and adds the correct nucleotide to the free end of the strand. DNA polymerase also participates in DNA repair by proofreading and removing incorrect bases).
 * Replication occurs in the nucleus of the cell

Mutations
ex. radiation causes mutations by forming electrically charged ions that can produce chemcial reactions that damage DNA bases
 * Substitution: occurs when one base pair is substituted for another
 * Frameshift mutation: involves insertion or deletion of one or more base pairs to the DNA molecule;can significantly change the reading frame and alter the amino acid sequence
 * Mutagens: things that increase frequency of mutations
 * Mutational hot spot: areas very susceptible to mutations

__TRANSCRIPTION__

 * process by which RNA is synthesized from DNA template to yield mRNA
 * RNA polymerase binds to promoter site on the DNA, then pulls the DNA strand apart, allowing unattached DNA bases to be exposed;one of the strands becomes a template for mRNA
 * mRNA is complementary to the template strand (uracil is present instead of thymine)
 * termination sequence stops transcription
 * mRNA moves out of the nucleus through pores and into the cytoplasm.

Gene Splicing

 * before leaving the nucleus, many of the RNA sequences are moved by enzymes and the remaining sequences are spliced together to form the functional mRNA that will migrate into the cytoplasm
 * introns: excised sequences
 * exons: sequences left to code for proteins

__TRANSLATION__

 * occurs in the cytoplasm
 * process by which RNA directs the synthesis of polypeptides (which become proteins)
 * ribosomes attach to mRNA; tRNA brings codon to ribosome; peptide bonds join the amino acids together to make polypeptide chains, which yields protein molecule

__CHROMOSOMES__

 * gametes are sperm and egg cells; somatic cells are all the rest

A good visual for mitosis/cytokinesis can be found at http://www.maxanim.com/genetics/Mitosis/Mitosis.htm This site also has a decent meiosis refresher at http://www.maxanim.com/genetics/Stages%20of%20Meiosis/Stages%20of%20Meiosis.htm. They are both very short.
 * || Somatic Cells || Gametes ||
 * Chromosomes || 46 || 23 ||
 * Ploidy || diploid chromosomes; occur in 23 pairs || haploid; 1 of each pair ||
 * Replication || Mitosis/Cytokinesis || Meiosis ||

Terminology

 * There are 22 homologous autosomes in males and females. The 23rd pair is either an XX or XY pair.
 * __Karyotype__: ordered arrangement of chromosomes; achieved with different staining techniques. (The picture below is a spectral karyotype). Karyotypes are useful for identifying deletions and additions of chromosomes.
 * [[image:http://upload.wikimedia.org/wikipedia/commons/thumb/c/c6/Sky_spectral_karyotype.gif/300px-Sky_spectral_karyotype.gif width="300" height="238" align="center" link="http://en.wikipedia.org/wiki/Image:Sky_spectral_karyotype.gif"]]

This diagram was copied from http://en.wikipedia.org/wiki/Karyotype

Remember:it's generally better to have more than enough than not enough!!
 * __Euploid__: the normal number of chromosomes per cell (46 for humans)
 * __Polyploid:__ more than the two copies of each of the chromosomes (wikipedia.org/ploidy)
 * __Aneuploid__: abnormal number of chromosomes-either greater than or less than 23 chromosomes


 * Aneuploidy is usually the result of [|nondisjunction] which means that the chromosomes fail to separate normally during division; nondisjunction results in cells with too many or two few chromosomes
 * Genotype: genetic makeup of an individual
 * Phenotype- outward physical appearance, resulting from the genotype

Chromosomal Abnormalities

 * leading cause of miscarriage and retardation
 * large number of 1st trimester prenancies end in miscarriage due to chromosomal problem

Autosomal Abnormalities

 * Monosomies occur when there is one chromosome missing; trisomy means that there are three chromosomes-trisomy is usually a result of nondisjunction
 * Usually, monosomic pregnancies do not survive- monosomy X is an exception
 * [|Trisomy 13], [|Trisomy 18], and [|Trisomy 21] are most frequently seen trisomies in live births. Trisomy 16 is most frequently seen in miscarriages.
 * In a partial trisomy, only an extra part of a chromosome is present in each cell.
 * Trisomies may also occur in only some of the cells in the body
 * A [|mosaic] occurs when the body has 2 or more cell lines, each with a different karyotype. This occurs due to nonjunction during early mitosis in some, but not all, of the cells in an embryo.

Down's Syndrome- Trisomy 21 most cases are caused by nondisjunction in the mother's cell
 * risk factors increase with maternal age, probably because the mother's eggs are held in arrested development (prophase I) until they are expelled during ovulation

Sex Chromosome Abnormalities

 * Incidence is rather high (1:400 males, 1:650 females)
 * Except in the absence of X, some of these individuals will survive
 * A Single Y chromosome is enough to initiate gonad (testes) development


 * || Cause || Phenotype ||  ||
 * Trisomy X (X,X,X) || nondisjunction || female;sometimes sterile, irregular periods, mental retardation ||  ||
 * Turner Syndrome (45,X) || nondisjunction (loss of paternal X chromosome) || female, usually sterile, gonadal streaks rather than ovaries, increased susc. to cancer webbed neck, widely spaced nipples, coarc of the aorta, sparse body hair, cubitus valgus impaired spatial and math abilities many don't survive gestation-those who do often are mosaics (presence of some normal enhances fetal survival) ||  ||
 * Klinefelter (47, X,X,Y) || nondisjunction (freq increases with maternal age) || male, usually sterile,gynecomastia, small testes tall, mental retardation-degree of impairment increases with each addl X chromosome ||  ||
 * 47, XYY || nondisjunction of sperm cells || male, tall, lower IQ, few physical problems, but increase in behavioral problems ||  ||

Structural Abnormalities
__Deletions__- caused by broken chromosomes and lost DNA; deletions can affect only a nucleotide or a large part of a chromosome Ex. Cri du Chat is caused by a deletion of a small part of the arm of Chromosome 5 -characteristics of child: low birth weight, severe MR, microcephaly, heart defects, characteristic (cat like) cry

__Duplications__- usually have less severe consequeces that deletions

__Inversion__- this occurs when the chromosome breaks and one of the broken pieces is reinserted, although in an inverted order -this can eventually lead to duplication or deletion of material in the chromosome; the following has a very short (<1min explanation of inversion); hit the full screen button when it pops up: http://www.maxanim.com/genetics/Inversion/Inversion.swf

__Translocations__ occur when the chromosome is rearranged by the interchange between nonhomologous chromatids http://en.wikipedia.org/wiki/Translocation



Wikipedia reports that AML, CML, a form of infertility, and a small percentage of Down's Syndrome are caused by translocations (wikipedia.org/translocation)

__Fragile Sites__- for unknown reasons, some part of the chromosomes have weak spots, which can easily break or gap;usually these areas don't cause disease; an exception is on the long arm of the X chromosome, which is associated with Fragile X Syndrome Fragile X- second most common genetic cause of MR and the most common cause of autism (fragilex.org) . The following explanation is taken directly from http://www.fragilex.org/html/molecular.htm. People who do not have fragile X syndrome, make FMRP (fragile X mental retardation protein) in some of their cells. Those cells that do make FMRP are regulated as to when they make it, so that it is present when needed in the places where it is needed. A person with fragile X syndrome has a mutation in the FMR1 (fragile X mental retardation 1) gene in the DNA that makes up the X chromosome. That mutation causes the cell to methylate a regulatory region of the FMR1 gene. The methylation turns off the FMR1 gene. Since the gene is turned off, the person doesn't make FMRP. That lack of a specific protein triggers fragile X syndrome.

This is an example of a disorder that affects males (usually) more seriously than females. Because females carry 2 X chromosomes, they have two genes directing production of FMRP-even with one mutated section, females may have "enough" of the FMRP to protect them from some of the consequences of the disorder.

A few more genetic terms: __Mendelian traits__ traits caused by single genes Genes are located on a particular spot of a chromosome called a __locus.__ The different forms that the gene can take are called __alleles__ A locus that has 2 or forms of expression (alleles) that appear with frequency in the population is called __polymorphic homozygous-__ 2 identical genes (ex. AA, bb, CC) __heterozygous__-genes are not identical (ex. Aa, Bb, Cc) __dominant-__the allele whose expression can be seen __recessive__-the allete whose expression is hidden __carrier__- person who has the disease but is phenotypically normal __codominant__- occurs when both alleles are expressed;common example is the ABO blood group system (ex. AB blood type) __pedigree-__an organized summary of familial relationships and expression of genetic disease __proband__-first individual who is affected by disease/condition

Principles of Genetic Transmission

 * Autosomal Dominant Inheritance**

Both of the parents in this punnett are affected
 * diseases caused this way are rare
 * || D || d ||
 * D || DD homozygous affected || Dd heterozygous affected ||
 * d || Dd heterozygous affected || dd homozygous normal ||

1. Males and females are equally likely to pass the trait to a child. 2. If a child is affected, so must be one of the parents. Barring a mutuation, if neither parent has the trait, none of the children will have the trait. 3. Heterozygous parents will pass the trait to half of their children. 4. An example of an autosomal dominant disease is achondroplasia.

__Recurrence risk__- probability that subsequent children will also have the disease __Occurrence Risks__- probability that a child will have a specific disease (this is before the couple have had children)

__Penetrance__- extent to which a gene will be expressed (how much of the phenotype is expressed) -a highly penetrant gene will express itself regardless of the environment, whereas a less penetrant gene may reveal itself to a small (or lesser) degree (wikipedia.org/penetrance) -the penetrance of some disorders are age related: Huntington's disease is a progressive neuro disorder that is usually not expressed until after 40yrs of age; other examples of age related penetrant disease include: hemochromatosis, polycystic kidney disease and familial breast CA

__Expressivity-__ also refers to the extent to how "much" a gene is expressed; most diseases exhibit variable expressivity -environmental factors, mutations, and nearby genes that can modify expression of the gene can affect expression

__Genomic Imprinting__- phenotype may differ according to from whom the gene is inherited -may have different expression according to whether inherited from mother or father


 * Autosomal Recessive Inheritance**


 * || D || d ||
 * D || DD homozygous, normal || Dd heterozygous, carrier ||
 * d || Dd heterozygous, carrier || dd homozygous, affected ||

1) males and females are equally affected 2) consanguity often present -this is marriage between relatives -offspring of marriage between 1st cousins have double the risk for genetic disease 3) disease is seen in siblings, but not in the parents 4) 1/4 of offspring affected 5) recurrence risk for offspring of carrier parents is 25% 6) 2 parents with a recessive disease will only have affected children (100% will have disease)
 * most common lethal recessive disease in white children is cystic fibrosis
 * gene therapy link
 * **other disorders: PKU, sickle cell anemia, Tay Sachs, hemochromatosis, galactosemia**
 * **other disorders: PKU, sickle cell anemia, Tay Sachs, hemochromatosis, galactosemia**

Sex linked diseases are caused by genes on sex chromosomes -males should have no Barr bodies (they only have 1 X); the number of Barr bodies is one less than the number of X chromosomes (XXX would have 2 Barr bodies) -this might explain why males and females have equal amounts of gene products coded by the X chromosome -new research suggests that X inactivation is incomplete and that some expression may still occur from the inactive chromosome (wikipedia.org/Lyonhypothesis) Sex limited traits occur in only one of the sexes. Sex influenced traits occur more often in one sex than the other.
 * most are found on the X chromosome
 * X linked dominant disease is rare
 * if a male has a disease affected his X chromosome, he is called hemizygous
 * males who inherit an X with a disease will be affected because the Y chromosome doesn't carry a normal allele to counter the effects
 * Lyon hyothesis states that in cells with more than one X chromosome (as in females), one of the X's will be inactivated; this inactivation forms Barr bodies which can be seen during interphase


 * X linked Recessive Disease**

mother is a carrier, father is normal (below)

1) Trait is seen more often in males 2) There is no father to son transmission because a father will only give a son a Y chromosome. 3) The trait may appear to skip generations because it may be transmitted through several carrier females**.**
 * || XH || Xh ||
 * XH || XHXH norma femalel || XHXh carrier female ||
 * Y || XHY normal male || XhY affected male ||


 * || XH || XH ||
 * Xh || XHXh carrier female || XHXh carrier female ||
 * Y || XHY normal male || XHY normal male ||

in this instance, a normal female is crossed with an affected male half of the children will be carriers

a carrier female crosses with an affected male 25% of the children will be carriers, 50% will be affected
 * || XH || Xh ||
 * Xh || XHXh carrier female || XhXh affected female ||
 * Y || XHY normal male || XhY affected male ||

Most common X linked recessive disease is Duchenne muscular dystrophy, which is a progressive muscular disorder affecting the heart, respiratory muscles, and other muscles. Death is by cardiac and/or respiratory failure, usually by age 20.

More genetic terms: Recombination is the exchange of genetic information, resulting in a new combination of alleles. It's the result of independent assortment and crossing over that occurs during meiosis http://www.mhhe.com/biosci/esp/2001_gbio/folder_structure/ge/m1/s6/ Crossing over occurs when the arms of homologous chromosomes "cross over" and exchange genetic info., resulting in a new combination of alleles.

The following refers to information from Chapter 5 of the text (McCance & Huether, 2006) __Incidence Rate__ is the number of new cases of a disease during a specific period divided by a specified population __Prevalence Rate__ is the number of people living with a disease divided by a certain population; prevalence varies among different populations __Relative Risk__ is how much a certain risk factor (ex. lead exposure) influences a certain outcome (ex. mental retardation). http://www.mindspring.com/~hlthdata/ex-rr1.html

__Multifactorial Inheritance__-interaction of genetics and environment that cause variation in disease expression 1) Recurrence risks increase if more than one family member is affected. This doesn't mean the family's risk has actually increased; it means that a more accurate view of their true risk is available. 2) If the expression of the disease is severe in the proband (the first person to exhibit the disease), the recurrence risk is greater. 3) If the proband is the less usually affected gender, the recurrence risk is higher. 4) The more distant the affected relative, the less risk of recurrence. 5) "If prevalence of the disease in a population is f, the risk for offspring/siblings of probands is the square root of f" (p. , McCance & Huether, 2006).

__Twin studies__:

__Adoption Studies__ See Table 5-3: very interesting table showing concordance rates in twins for certain diseases
 * Identical twins are called monozygotic. They are genetically identical so any differences between them should be caused by environmental factors.
 * Fraternal twins are called dizygotic. They are as genetically alike as any siblings.
 * A concordant trait is a trait shared by both of the twins.
 * A disconcordant trait is one that is not shared by both of the twins.
 * are used to estimate genetic contributions to a multifactorial trait.
 * when interpreting results of adoption studies, prenatal environment, age at adoption, and preexisting similarities between adoptees and adoptive parents must be considered

Diseases such as CHD, diabetes, obesity, alcoholism, some psychiatric disorders and cancers ar multifactoral- genetic, environmental and lifestyle all take part in development and severity of these diseases

To Keep in Mind and to teach our patients:
 * Just because there is a genetic component to a disease, it does not mean the course cannot be altered!!
 * Identification of a "genetic lesion" can lead to prevention and more effective treatment

Interesting rare genetic skin disorder: I want to share a very unique genetic disorder that effects the skin named Harlequin Ichthyyosis. This to me brings together both the remarkable cellular functions together with genetics. There is an episode on this evening on TLC called "My skin could kill me." For more information go to: http://www.mymultiplesclerosis.co.uk/misc/harlequin.html.

References

Additional Online Resources For Health Care Providers

International Society of Nurses in Genetics (Information on genetics education, practice and research) [|www.isong.org]

American College of Medical Genetics Professionals (Provides information of genetic advances applied to heathcare) [|www.acmg.net]

National Human Genome Project (Provides information on the Human Genome Project and its application to society) [|www.ornl.gov/sci/techresources/Human_Genome/project/about.shtml]

National Coalition for Health Professional Education in Genetics (Provides recommendations for genetics core competencies and education for healthcare professionals) [|www.nchpeg.org]

Genetic Alliance (Provides information to consumer and professionals) [|www.geneticalliance.org]

National Cancer Institute (Provides information on cancer and genetics) [|www.cancer.gov/cancerinfo/prevention-genetics-causes]

__**Hey...Found something interesting....Ever heard of a Advanced Practice Nurse Geneticist? This is copied from http://nursing.about.com/gi/dynamic/offsite.htm?zi=1/XJ&sdn=nursing&zu=http%3A%2F%2Fwww.ispub.com%2Fostia%2Findex.php%3FxmlFilePath%3Djournals%2Fijanp%2Ffront.xml**__

=What Do Genetics Nurses Do?= All nurses have a role in the delivery of genetics services and the management of genetic information. Nurses require genetic knowledge to identify, refer, support, and care for persons affected by or at risk for genetic conditions (10). “Genetic nursing is a holistic practice that includes assessing, planning, implementing, and evaluating the physical, spiritual, ethical, and psychoslcial aspects of patients and families who have genetic concerns” (14, p.246). Genetics nurses practice in many different environments. Genetic nursing practice includes but is not limited to the following activities: client and family assessment to identify genetic risk factors and intervention, information, service, and referral needs, take a detailed family history and construct a pedigree, analyze the assessment data, provide genetic education, and develop and carry out a plan of care to address genetic concerns (10). In addition, APNs in genetics provide genetic counseling, order and interpret genetic tests if within their scope of practice, and provide surveillance and management of persons affected by or at risk for genetic conditions (9). Figure 5 provides an overview of genetic nursing activities. In oncology for example, areas of responsibility begin with risk assessments for cancer in patients and family members. This assessment includes a detailed family history, construction of a pedigree, and assessment of hereditary, environmental and lifestyle cancer risk factors (12). Once these risk factors are determined, the information is interpreted to the patient. Recommendations for cancer prevention and early detection can be tailored to the specific risks identified. If genetic testing for a cancer susceptibility gene is appropriate, the individual/family should be informed about the risks and benefits associated with the test, and the potential risks and benefits associated with the screening and prevention measures. The nurse also needs to explore possible psychosocial responses to the potential outcomes of a genetic test. This education may be done individually or with several family members. If testing is pursued, results are disclosed in person. At that point a tailored plan for prevention and early detection is written and given to the family or individual. Long-term follow-up includes assessment of adjustment to the test results and compliance and follow-through with the plan for cancer prevention and early detection.
 * Figure 5: What Do Genetic Nurses Do?**
 * Take detailed family histories and construct pedigrees
 * Assess hereditary & nonhereditary risk factors
 * Interpret the pedigree & identify genetic conditions or genetic predisposition to disease
 * Provide genetic information to individuals/ families
 * Provide genetic counseling (APNG)
 * Interpret genetic tests & laboratory data (some APNs can order genetic tests)
 * Manage and care for patients & families at risk for or affected by genetic diseases or diseases with a genetic componen

In-depth credentialing is required...check out the website if interested...