genes & genetic disease

Genes & Genetic DiseaseTouro University NevadaPatricia Strobehn, MSN, APRN, FNP-BCAssistant Professor, School of Nursing

History of Genetics• Gregor Mendel was the founder of Modern Genetics• Discovered that chromosomes contain genes• Humans have between 20,000-25,000 genes• 1/3 of inpatient pediatric patients are children with genetic

disease

DNA Overview• Double Helix is made of 4 nitrogenous bases – A,C,G,T• Adenine, Cystosine, Guanine, Thymine• Each DNA sub-unit is called a nucleotide• DNA provides a code for the body’s proteins• These Proteins form polypeptides• Polypeptides are made out of the 20 possible amino acids• The sequence of three bases are called Codons• DNA is formed and replicated in the cell nucleus

Replication

• The DNA strand is untwisted and unzipped, the single strand acts a template for replication.• DNA must be able to replicate itself accurately during cell

division or mutations can occur. • DNA polymerase pairs the complimentary bases together• Accurate replication is the consistent pairing of A,C,G,T• Complementary base pairing is the key to accurate

replication.• Alterations in DNA sequencing can lead to disease

Replication

Replication Q & A

Which information is correct regarding DNA polymerase?

DNA polymerase functions to:

1. Signal the end of a gene.

2. Pull apart a portion of a DNA strand.

3. Add the correct nucleotides to a DNA strand.

4. Provide a template for the sequence of mRNA nucleotides.

Gene Mutation• A mutation is an inherited alteration of genetic material.• Usually a result of inaccurate replication• Common types of Gene Mutations include:

Base Pair SubstitutionFrame-shift Mutation

• Mutagens also alter DNA• https://www.youtube.com/watch?v=eDbK0cxKKsk

https://www.youtube.com/watch?v=eDbK0cxKKsk

https://www.youtube.com/watch?v=eDbK0cxKKsk

Transcription

• Transcription is the process by which RNA is synthesized from a DNA template.• RNA is synthesized from the DNA template via RNA

polymerase.• RNA polymerase binds to the promoter site on DNA.

• DNA specifies a sequence of mRNA.• Transcription continues until the termination sequence is

reached.• mRNA then moves out of the nucleus and into the

cytoplasm.• Gene splicing occurs.• Introns and extrons

Transcription

Translation

• Is the process by which RNA directs the synthesis of a polypeptide via the interaction with transfer RNA (tRNA).• tRNA contains a sequence of nucleotides (anticodon)

complementary to the triad of nucleotides on the mRNA strand (codon).• Ribosome is the site of protein synthesis.• Ribosome helps mRNA and tRNA make polypeptides.• When ribosome arrives at a termination signal on the

mRNA sequence, translation and polypeptide formation cease.

Translation Q & A

At what site does protein synthesis occur?

The site of protein synthesis is the: 1. Codon

2. Intron

3. Ribosome

4. Anticodon

Chromosomes

• Somatic cells• Contain 46 chromosomes (23 pairs)• One member from the mother; one from the father• Diploid cells

• Gametes• Sperm and egg cells• Contain 23 chromosomes• Haploid cells • One member of each chromosome pair

• Meiosis• Formation of haploid cells from diploid cells

Chromosomes• Autosomes• Are the first 22 of the 23 pairs of chromosomes in males and

females.• The two members are virtually identical and are thus said to be

homologous.• Sex chromosomes• Make up the remaining pair of chromosomes.• In females, it is a homologous pair (XX).• In males, it is a nonhomologous pair (XY).

• Karyotype• The length and centromere location determine the ordered

display of chromosomes.

Chromosomal Abnormalities• Effects may or may not have serious consequences.• Chromosome breakage• If a chromosome break occurs, then the break is usually repaired

with no damage.• Breaks can stay or can heal in a way that alters the structure of

the chromosome.• Can occur spontaneously.• Agents of chromosome breakage include Ionizing radiation,

chemicals, and viruses.

Chromosomal Abnormalities

• Deletions• Chromosome breakage or loss of DNA• Example: Cri du chat syndrome or “cry of the cat”• Low birth weight, mentally challenged, and microcephaly

• Duplications• Excess genetic material• Usually have less serious consequences

• Inversion• Chromosomal rearrangement in which a chromosome

segment is inverted: ABCDEFG becomes ABEDCFG• Usually affects offspring

Chromosomal Abnormalities

• Translocation• Is the interchange of genetic material between

nonhomologous chromosomes.• Types of translocation• Robertsonian: Long arms of two nonhomologous

chromosomes fuse at the centromere, forming a single chromosome; is common in Downs syndrome.

• Reciprocal: Breaks take place in two different chromosomes, and the material is exchanged

• Fragile Sites• Chromosomes develop breaks and gaps

Genetic Transmission• Humans are diploid organisms• Chromosomal pairs are made from both Paternal and

Maternal DNA – XX XY• Homozygous pairs- Identical genes• Heterozygous pairs – Non- identical genes• Genotype - The composition of genes at a specific location• Phenotype - The outward appearance of an individual is a

result of both: the persons genotype and the environment.• Dominant - The allele whose effects are observable• Recessive – The allele whose effects are hidden• Carrier – is an individual who has a disease-causing allele but

is phenotypically normal.

Autosomal Inheritance

Dominant

• Rare: Observed in less than 1:500• Does not skip

generations• One parent has the

Phenotype • Ex: Achondroplasia

Recessive

• Carriers are typically phenotypically normal• Can skip generations• Requires a homozygous

recessive allele to actually be expressed• EX. Cystic Fibrosis

X- Linked Inheritance • Y chromosome only contains a few dozen genes. • Most of the sex-linked traits are located on the X-

Chromosome• X-linked recessive diseases are much more common• Females receive two long x-linked chromosomes and Males

receive one long x-linked chromosome and one short y.• Males are more frequently affected

Multifactorial Inheritance• Multifactorial Trait -Traits or disease in which variation is

thought to be caused by the combined effects of multiple genes.

• Ex: Height: Phenotype is determined by genotype. >100 genes have been identified to contribute to height.

• Ex: Blood Pressure: Phenotype is determined by genotype and other environmental factors such as diet, exercise and stress.

• Twin Studies vs Adoption Studies

Multifactorial Disorders

• Coronary Heart Disease• Accounts for 25% of all deaths in the U.S.• Caused by Atherosclerosis• Risk Factors: obesity, smoking, HTN, elevated cholesterol levels

and a family history• An individual with a positive family history is 2-7x more likely to

have heart disease• Risk increases with more affected family members • Risk increases to 13x more likely if two first-degree relatives were

affected by CHD before the age of 55• Women do develop at a later age than men


• Familial Hypercholesterolemia (FH)• LDL Receptor gene was discovered in 1894• FH is caused by a reduced number of functional LDL receptors• Autosomal Dominant FH accounts for 5% of Myocardial

Infarctions in individuals <60 years old. • Heterozygotes: 1:500 individuals have cholesterol levels that are

usually twice the normal range.• Homozygotes: 1:1,000,000 have cholesterol levels that range

from 600-1,200. Most experience MI’s before age 20. • Individuals develop Xanthomas (fatty deposits) due to excess

levels of circulating cholesterol.


• Breast Cancer• Affects 12% of women by age 85 years old• Risk doubles with one affected first-degree relative• Autosomal Dominant individuals account for 5% of all breast CA• BRCA1 and BRCA2 female carriers have a 50-80% overall lifetime risk• BRCA2 male carriers have a 6% overall lifetime risk (100x other men)

• Colorectal Cancer• Second leading cause of Cancer in the U.S. • 1:20 Americans will be affected• Risk is 2-3x more with one affected first-degree relative


• Diabetes Mellitus• Siblings of those with DM have a higher rate of susceptibility• TCF7L2 gene has the most significance in regards to Type 2• Most common risk factors for Type 2 are family history and

obesity

• Obesity• Strong evidence exists for both heredity and environmental risk

factors• Four adoption studies showed that body weights of adopted

individuals correlated significantly with their natural parent’s body weights and not with their adoptive parent’s body weights.


• Alzheimer Disease• Risk doubles in those who have an affected first-degree relative• Most cases do not appear to be caused by any single-loci• Early onset occurs before age 65• Early onset attributed to mutations in amyloid-beta precursor protein

(APP), presenilin 1 (PS1) and presenilin 2 (PS2)• Common late onset occurs after age 65• Later onset attributed to allelic variation of apolipoprotein E (APOE)• Europeans and Japanese are at other risk than other populations


• Alcoholism• 10% of adult Males are affected• 3-5% of Females are affected• Risk of developing alcoholism of those with one affected parent is 3-5x

higher than those whose parents are unaffected• Monozygotic twin studies have a concordance rate >60% • Adoptive studies show that the offspring of an alcoholic parent, even

when raised by non-alcoholic parents have 4x the chance of developing alcoholism

• Those with the ALDHY2 gene are much less likely to become alcoholics due to unpleasant effects – considered the “protective” allele.


• Schizophrenia• Risk of Schizophrenia if one parent is affected is 8-10%• Monozygotic twin studies have a concordance rate of 47%

• Bipolar Disorder• Risk of Bipolar disorder if one parent is affected is 5-10%• Monozygotic twins have a concordance rate of 79%• Some loci have been identified due to pharmaceutical research• Examples include monoamine oxidase A (MAOA), the serotonin

transporter (5HTT) and catechol-O-methytransferase (COMT)

Genetic Testing

Carrier Screening• Identifies heterozygous

carriers for recessive diseases.

• People use to help make reproductive decisions

• Cystic fibrosis, sickle-cell disease, Tay-Sachs disease

• Carrier Screening has reduced the prevalence of some of these diseases over the past two decades.

Prenatal Diagnosis• Amniocentesis at 16 weeks• Chorionic villus sampling

(CVS) at 10-12 weeks • Pre-implantation genetic

diagnosis (PGD) is carried out on early embryos prior to implantation

• Analysis of Fetal DNA in maternal circulation available as early as 6 weeks.

• Newborn Screening: PKU

Autosomal Aneuploidy

• Down syndrome• Is the best-known example of aneuploidy.• Trisomy 21

• Occurs 1 in 800 live births.• Manifestations: Mental challenges; low nasal bridge;

epicanthal folds; protruding tongue; flat, low-set ears; and poor muscle tone.• Risk increases with maternal age. • Has an increased risk of congenital heart disease,

respiratory infections, and leukemia.

Down Syndrome

Sex Chromosome Aneuploidy

• Turner syndrome• Females have only one X chromosome• Denoted as karyotype 45,X.• Characteristics include:• Absence of ovaries (sterile)• Short stature • Webbing of the neck• Widely spaced nipples • High number of aborted fetuses• X chromosome that is usually inherited from the

mother• Occurs 1 in 2500 female births.• Teenagers receive estrogen.

Turner Syndrome

Sex Chromosome Aneuploidy

• Klinefelter syndrome• Individuals with at least one Y and two X chromosomes.• Characteristics include:• Male appearance• Femalelike breasts (gynecomastia)• Small testes• Sparse body hair• 1 in 1000 male births

• Some individuals can be XXXY and XXXXY; will have male appearance; abnormalities will increase with each X; can also have an extra Y chromosome.

• Disorder increases with the mother’s age.

Klinefelter Syndrome

Need to know!!!• How to describe the genetic abnormalities and resulting

clinical abnormalities associated with the following diseases: Down syndrome, Turner syndrome, Klinefelter syndrome, cri du chat syndrome, Huntington disease, cystic fibrosis, neurofibromatosis, hemophilia, and Duchenne muscular dystrophy

• The difference between a genotype and phenotype• How to describe the following elements of inheritance:

autosomal, sex-linked, carrier, dominant, and recessive.• Know the cause and possible outcomes for the following

mutations: base-pair substitution, frameshift substitution, spontaneous mutation, and mutational hotspots.

Need to know!!!• How to Identify and describe the familial tendencies and

contributing environmental factors in the following diseases: coronary artery disease (CAD), hypercholesterolemia, hypertension, colorectal cancer, diabetes, breast cancer, and obesity.

• How to Identify and describe the following complex multifactorial diseases: Alzheimer disease, alcoholism, schizophrenia, and bipolar disorder.

Questions

genes & genetic disease

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