Chapter 4 - genes and genetic diseases

Deoxyribonucleic Acid (DNA)

• Chromosome contain genes

• Genes are the basic unit of inheritance and are composed of DNA

• Double helix structure

What does DNA subunit or nucleotide contain?

• one pentose sugar (deoxyribose)

• One phosphate group

• One nitrogenous base

Nitrogenous base - in DNA

• cytosine (C)

• Thymine (T)

• Adenine (A)

• Guanine (G)

DNA as the genetic code

• DNA provides the code for all body proteins

• Proteins composed of one or more polypeptides

Replication

• DNA strand is untwisted and unzipped

• DNA polymerase pairs the complementary bases

  • Adenine-thymine

  • Cytosine-guanine

• DNA polymerase adds new nucleotides and “proofs” the new protein

  • if not correct, the incorrect nucleotide is excised and replaced

DNA polymerase functions to

add the correct nucleotides to a DNA strand

Mutation

• any inherited alteration of genetic material

frameshift mutation

• involves the insertion or deletion of one or more base pairs to the DNA molecules

mutagens

• agents, such as radiation and chemicals, that increase the frequency of mutations

Base pair substitution or missense mutation

• one base pair is substituted for another - may result in changes in amino acid sequence

• May or may not cause disease or problems

Where is DNA formed?

• nucleus

Where is protein formed?

• cytoplasm

Transcription and translation - from genes to protein

• DNA code is transported from the nucleus to the cytoplasm and protein is subsequently formed

  • Mediated by RNA (ribonucleic acid)

What are the 4 bases of RNA?

• uracil

• Adenine

• Cytosine

• Guanine

• G+c

• A+u

• Single strand

Transcription

• RNA is synthesized from the DNA template via RNA polymerase

• the process of copying a segment of DNA into RNA

• DNA specifies a sequence of mRNA

• Transcription contours until the termination sequence is reached

• MRNA then moves out of the nucleus and into the cytoplasm

• Gene splicing occurs

  • Introns and exons

What does RNA polymerase bind to?

• promoter site on DNA

translation

• 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)

What is ribosome the site for?

• protein synthesis in the cell

Somatic cell

• Any body cell that is not a gamete, containing a full set of chromosomes.

• Contain 46 chromosome (23 pairs)

• One member from mother + one member from father = 1 pair

• Diploid cells - from mitosis

Gametes

• sperm and egg cells

• Contain 23 chromosomes

• Haploid cell

  • One member from a chromosome pair

  • From meiosis

Meiosis

formation of haploid cells from diploid cells

Autosomes

• first 22 of the 23 pairs of chromosomes in males and females

• 2 members are virtually identical and are thus said to be homologous

Sex chromosomes

• male up the remaking pair of chromsomes

Homologous pair

• XX

• Female

Non homologous pair

• XY

• Males

Karyotype

• the length and centromere location determine the ordered display of chromosomes

Chromosomal aberrations

• deviation in the normal structure or number of chromosomes within a cell

Euploid cells

• have a multiple of the normal number of chromosomes

• Haploid and diploid cells are Euploid forms

Polyploid cells

• an Euploid cell has more than the diploid number of chromosomes, such as triploid or tetraploid cells.

Triploidy

• is a zygote that has three copies of each chromosome resulting in a total of 69 chromosomes.

• Fetuses do not survive or are stillborn or spontaneously aborted

tetraploidy

• has four copies of each chromosome - 92 total chromosome

• Do not survive or are stillborn or spontaneously aborted

Aneuploidy

• somatic cells that does not contain a multiple of 23 chromosomes

Trisomy (trisomic)

• cell contains 3 copies of one chromosome

• Infants can survive with trisomy of certain chromosomes

Monosomy

• is the presence of only one copy of any chromosome

• Often fatal

Aneuploidy of sex chromosomes

• usually presents less serious consequences than Autosomes

• Y chromosome usually causes no problems since it contains little genetic material

• For the X chromosome, inactivation of extra chromosomes largely diminishes their effect

nondisjunction

• usually the cause of aneuploidy

• The failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis

Autosomal aneuploidy

• trisomy

• Partial trisomy

• Chromosomal mosaics

Trisomy

• A type of aneuploidy involving three copies of a chromosome instead of the usual two, often leading to developmental disorders.

• Chromosomes 13, 18 and 21 can survive

partial trisomy

• only an extra portion of a chromosome is present in each cell

• resulting in duplication of some genes while the rest remain in the normal diploid state.

• Not as severe as trisomies

Chromosomal mosacis

• are trisomies that occur in only some cells of the body

• Body has 2 or more different cell lines - each of which has a different karyotype

Down Syndrome - autosomal aneuoploidy

• trisomy of chromosome 21 (extra chromosome)

• Occurs 1 in 800 live births

Manifestations of Down syndrome

• mental challenges

• Low nasal bridge

• Epicanthal folds

• Protruding tongue

• Flat, low - set ears

• Short stature

• Poor muscle tone

• Has an increased risk of congenital heart disease, respiratory infections and leukemia

Sex chromosome aneuploidy

• trisomy X most common sex chromosome aneuploidy

• Turner syndrome

• Klinefelter syndrome

Trisomy X

• females have 3 X chromosomes

• Occur 1 in 1000 female births

Symptoms of trisomy X

• sterility

• Menstrual irregularity

• Cognitive deficits

• Symptoms worsen with each additional X chromosome

Turner syndrome

• female have only one X chromosome

• Denoted as karyotype 45,X.

• Occurs 1 in 2500 female births

• Teenagers receive estrogen

Turner syndrome Characteristics

• 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

Klinefelter Syndrome

• individuals with at least one Y and two X chromosomes

• Some individuals can be XXXY and XXXXY

• Have male appearance - increase with each X

• Disorder risk increases with the mothers age

• Occurs in males at brith

Klinefelter Characteristics

• male appearances

• Female like breasts (gynecomastia)

• Small testes

• Sparse body hair

• 1 in 1000 male births

Abnormalities of chromosomal structure

• chromosomal breakage

• Deleteion

• Duplication

• Inversion

• Translocation

• Fragile sites

• are structural changes in chromosomes that can lead to genetic disorders by altering gene function.

Chromosome Breakage

• if 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 virsuses

Deletion - abnormality of chromosome structure

• chromosome breakage or loss of DNA

• Ex - Cri du chat syndrome - “cry of the cat”

  • Low birth weight, mentally challenged and microcephaly

duplications - abnormalities of chromosomes structure

• excess genetic material

• Usually have less consequences

Inversion - abnormality of chromosome structure

• chromosomal rearrangement in which a chromosome segment is inverted

• Usually affects offspring

• Ex. ABCDEFG becomes ABEDCFG

Translocation - abnormality of chromosomal structure

• the interchange of genetic material between non homologous chromosomes

• 2 types

  • Robertsonian

  • Reciprocal

Robertsonian Translocation

• long arms of two non homologous chromosomes fuse at the centromere, forming a single chromosome - common in Down syndrome

Reciprocal Translocation

• breaks take place in two different chromosomes and the material is exchanged

Fragile Sites

• chromosomes develop breaks and gaps when the cells are cultured in a folate - deficient medium

• Most have no apparent relationship to disease

Fragile X Syndrome

• site is on the long arms of the X chromosome

• Has an elevated number of repeated DNA sequences

• Associated with being mentally challenged

• Second in occurrence to Down syndrome

Elements of formal genetics

• genetic inheritance

• Mendelian traits

• Locus

• Allele

• Polymorphism or polymorphic

• Genotype

• Phenotype

• Carrier

• Dominance and recessive

Genetic inheritance

• mechanisms by which an individual’s set of paired chromosomes produced traits

• Explains the patterns of inheritance for traits and diseases that appear in families

Mendelian traits

• are inherited traits primarily attributed to single genes

Locus

• location occupied by a gene on a chromosome

Allele

• one of several different forms of gene at a locus

• A form of a gene

• One member of a gene from the mother - one from the father

• Either heterozygous or homozygous

• Can be codminant - both alleles are expressed

• Ex. A gene for for eye color is a gene, different versions would be an allele for brown eyes, and a allele for green eyes

Homozygous

genes are identical

heterozygous

Genes are different

Polymorphism or polymorphic (mean the same thing)

• is a locus that has 2 or more alleles that occur with appreciable frequency

Genotype

• is the composition of genes at a given locus

Phenotype

• is the outward appearance of an indivuals

• Results from genotype and the environment

genotype & phenotype example

• infant with phenylketonuria (PKU) has the PKU genotype

  • if left untreated, the infant will have cognitive impairments which is the PKU phenotype

  • If treated, the infant will still have the PKU genotype but can have a normal phenotype

Dominance and recessiveness

• if two alleles are found together, then the allele that is observable is dominant and the one whose effects are hidden it recessive

• Dominant allele = capital letter

• Recessive allele = lowercase letter

Carrier

• has a disease allele but is phenotypically normal

• Can pass disease to offspring

Mode of inheritance

• is inherited pattern through the generations of a family

Mendez’s two laws

• principle of segregation

• Principle of independent assortment

Principle of segregation

• homologous genes separate from one another

• Each 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

Chromosome theory of inheritance

• chromosomes follow Mendel’s two laws

4 major types of genetic diseases

• autosomal dominant

• Autosomal recessive

• X-linked dominant

• X-linked recessive

Pedigree

• is the tool used to study specific genetic disorders within families

• Begins with proband

Proband

• the individual in a pedigree whose affected status is being studied. It serves as the starting point for tracing the inheritance of a genetic condition.

• Propsitus - male

• Propsita - female

Autosomal dominant inheritance

• the union of a normal parent with an affected heterozygous parent usually produces the affected offspring

Characteristics of autosomal dominant inheritance

• condition is expressed equally in males and females

  • Both just as likely to pass gene to his or her offspring

• ½ children of an affected heterozygous parent will express the condition

• No generational skipping

recurrence risk - autosomal dominant inheritance

• probability that a family member will have a genetic diseases

• One parent with autosomal dominant disease other normal

  • Each birth is an independent event 50% chance with each birth

New mutation

• no history of an autosomal dominant condition is present but the child develops the mutation

• Not from parent

Germline mosaicism

• 2 or more offspring have an autosomal dominat disease when the family has no history of the disease

• Parent carries the mutation in his or her germline but does not actually express the autosomal dominant disease but transmits it to his or her offspring

Penetrance

• is the percentage of individuals with a specific genotype who also express the expected phenotype

Incomplete penetrance

• individual who has the gene for a disease but does not express the diseases

  • Ex - retinoblastoma (eye tumor in children)

Age-dependent penetrance

• does not express a disease until a certain age is reached

  • Ex. Huntington disease

Expressivity

• is a variation in a phenotype associated with a particular genotype

• Can be caused by modifier genes, environmental factors and mutations

  • Ex. Von recklinghausen disease

Von recklinghausen disease

• autosomal dominant

• Expressivity varies from brown spots on the skin to malignant tumors, scoliosis, gliomas and neuromas

Autosomal recessive inheritance

• abnormal allele is recessive and the person must be homozygous to express the disease

• Rare but many individuals are carriers

• Trait usually appears in the children, not in the parents

Cyctsic fibrosis - example of autosomal recessive inheritance

• gene forms chloride channels with defective transport, which leads to salt imbalance that results in abnormally thick, dehydrated mucus

  • Lungs and pancreas are affected

  • Person does not survive past 40 years of age

Characteristics - autosomal recessive inheritance

• condition is expressed equally in males and females

• Is observed in siblings but not in parents

• Approximately one - quarter of offspring will be affected

• Consanguinity may be present

Consanguinity

• Inbreeding

• Boinking a relative

• Dramatically increases the recurrence risk of recessive disorder

Recurrence risk - autosomal recessive inheritance

• when both parents are heterozygous carriers of an autosomal recessive disease

• Occurrence and recurrence risk for each child are 25%

• ¼ of the offspring are normal

• ½ are carriers

• Carrier detection tests are available

X-linked inheritance

• a disorder that involves x and Y chromosomes

• Y-linked disorders are uncommon because the Y chromosome contains relatively few genes

X-linked inheritance - female

• have 2 X chromosomes

• Can be homozygous or heterozygous for the disease

  • Homozygous for normal

X - linked inheritance - males

• have one X chromosomes

• Always hemizygous

• If inherits an X recessive gene then he will express the disease because no normal allele is present to counteract the diseased allele

X-inactivation

• process by which one X chromosome in the somatic cells of females is permanently inactivated

• Barr bodies

• Occurs early in embryonic development

• X-inactive specific transcript (XIST) gene which causes x-inactivation uses methylation

Barr Bodies

• inactivated X chromosomes

• Females have 1 inactive X chromosome

• Males have no inactive X chromomes

• One less than the number of X in the chromosome cell

  • Ex - female XX = 1 inactive

    • Male XY = 0 inactive