BU HC 752 Bio of Disease Fall 2011-Week 2.3 and 2.4

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Genomic Replication and Inheritence Congenital and Hereditary Diseases

Cell Cycle

an orderly process during which a parent cell divides into genetically identical daughter cells.

2 parts: interphase and cell division

2 main parts of cell cycle

-Interphase: Most of cell cycle spent here; divided into 3 stages
G1: before DNA synthesis
S: DNA synthesis
G2: after DNA synthesis

-Cell division: mitosis and cytokinesis

Mitosis

is the phase of the cell cycle phase when chromosomal duplication and cell division result in 2 daughter cells receiving exactly the same # and kinds of chromosomes as a parent cell (dipoid->diploid)
-the physiological process of growth, repair, and immune response require cells to undergo mitosis and multiply.

Meiosis

is a process of chromosomal reduction and cell division that ultimatly results in the formation of 4 genetically different daughrer cells, each with half as many chromosomes as the parent cell (diploid->haploid)
-involves 2 divisions: meiosis I and meiosis II
-takes place to form gametes, the haploid sperm and egg

Fertilization

the fusion of the chromosomal content of the haploid sperm and egg to form a diploid embryo (zygote-cell resulting from the union of egg and sperm)

Mitosis Process

Duplication:
-occurs during interphase when the DNA making up the entire genome replicates with enzyme unzipping each of the 2 parental strands, new nucleotides move in to compliment each parental strand and join together to make a new DNA strand. Each parent serves as a template for a new strand. 2 sister chromatids held together at centromere completing reproduction of genetic info to be transmitted to next generation of cells.

Division: nuclear contents divide and sister chromatids divide to become 2 individual chromosomes, one for each daughter cell. Each daughter cell gets a complete set of chromosomes and is diploid (2n), then cytokinesis occurs with the division of the parents cytoplasm

Meiosis I process

homologous chromosomes (one from each parent) pair together in synapsis.
-non-sister chromatids often exchange material (aka crossing over or recombination)
-next, homologous chromosomes of each pair separate, each daughter cell receiving one member of each pair
-reduces the # of chromosomes to half so each daughter cell haploid (1n)
-random distribution (aka independent assortment) of maternal and paternal homologous chromosomes to the daughter cells

Meiosis II process

-Chromosomes in haploid number, but still duplicate so now division of each cell now separates the sister chromatids into 2 daughter cells that are haploid (1n)

Genetic Diversity

3 processes:
-crossing over exchange of genetic material during meiosis I results in recombination
-independent assortment during meiosis I with random distribution of homologous parental chromosomes into daughter cells
-fertilization when one egg, containing 223 possible combos of maternal chromosomes and one sperm containing 223 possible combos of paternal, unite to form a zygote

Locus

physical location of gene or other DNA sequence on a chromosome

Allele

is one of two or more alternate forms of a gene ar a given locus, occur in pairs with one from mother and one from the father
-represented by a letter and be dominant (T) or recessive (t)

homozygous

an individual has 2 identical genes (2 of the same alleles) at a given locus (TT or tt)

heterozygous

an individual has 2 different genes (2 dif alleles) at a given locus (Tt)

Autosomal traits

A single gene trait that is determined by the alleles ar a single locus. Genotype for a single gene trait on an autosomal chromosome can be:

-homozygous dominant: 2 dominant alleles (TT)
-homozygous recessive: 2 recessive alleles (tt)
-heterozygous: 1 dominant and 1 recessive (Tt)

Dominant Gene

masks the expression of a recessive gene and is expressed whether in homo or heterozygous state

Recessive Gene

only expressed in the homozygous state

Punnet Square

probability of offspring inheriting a particular combination of alleles, and thus a particular phenotype for a trait determined by those alleles can be determined using this

Sex-linked traits

x-link inherited: allele is carried on x chromosome
y-link inherited: allele is carried on y chromosome

Most sex linked traits are x-linked with exception of gene that actually determines sex (SRY) on Y.

Sex-determining region of Y (SRY) gene

gene that determines sex, located on the Y chromsome
Due to this gene encoding a transcription factor that intitiates a series of gene activations leading to formation of testes from embryonic cells of urogenital ridge
-absence of this gene, ovaries begin to develop in same area around 11 weeks

Urogenital Ridge

male and female gonads derive embryologically from this structure

Hereditary or Genetic Disease

a disease resulting from an abnormality in an individual's genome due to a defect in either a chromosome or an individual gene
-most hereditary diseases are transmitted on autosomal chromosomes

Congenital Disease and Congenital Defect

refers to any abnormality present at birth, even though the problem may not be detected until sometime after birth

2-3% of all newborns have this and an additional 2-3% are not recognized at birth

Etiologies of Congenital Diseases

broadly classified as genetic, environmental, or a combination of the two

Teratogens

non-genetic, environmental agents that can cause intrauterine injury leading to the development of congenital disease. Include drugs, chemicals, radiation, and pathogens. ex. DES or radiation

-embryo most vulnerable between 3rd and 8th week when organ systems forming

Nondisjunction

failure of homologous chromosomes to separate in first or second meiosis division during the formation of the germ cells
-can involve autosomal or sex chromosomes, and result in abnormal distribution of chromosomes amongst germ cells so one extra or one lacking ex. monosomy and trisomy

Monosomy

the absense of one chromosome of a homologous pair in a cell

Trisomy

the presence of an extra chromosome in a cell

Nondisjunction in autosomal chromosomes

rarely seen as absence of an autochromosomal chromosome generally results in the loss of genes required for development and, as a result, the embryo is aborted ex. Down Syndrome most common

Down Syndrome

most common autosomal trisomy, 3 copies of chromosome 21
-nondisjunction in oogenesis (egg formation) account for 95% of the cases, frequency increases with age of mother
-characterized by congenital cardiac malformation, defects in other organ systems, developmental disabilities, increased incidence of leukemia and accelerated aging, Gart gene for mental retardation

Nondisjunction in sex chromosomes

Consequences:
extra Y: no significant effect
absent Y: body configuration is female
extra X in female: little effect, one x inactivated
extra X in male: adverse effects on male development

Variations in normal number of sex chromosomes often associated with reduced intelligence.

Turners Syndrome

(X) Women, short of stature, broad neck and chest, mental retardation, underdeveloped sex organs, absence of breasts and usually sterile

Triple X Syndrome

(XXX) Somewhat common with usually normal sexual development. Fertility and intelligence may be normal or decreased.

Klinefelter's Syndrome

(XXY) Men can have underdeveloped sex organs, have breasts, large hands, long arms and legs, can have normal or some degree of mental retardation. Can go unrecognized. Infertility is most common feature and its estimated 2% of infertile men have this syndrome.

Jacob's Syndrome

(XYY) Men usually tall with some decrease in fertility and intelligence

Barr bodies

are inactive, condensed x-chromosomes that appear at the edge of cells

Androgen Insensitivity Syndrome (AIS)

aka testicular feminization syndrome, a genetic condition in which an XY male zygote can develop a phenotypical female adult, or varying degrees of sexual ambiguity
-it is a failure of androgen (testosterone) receptors to function, resulting in failure of male reproductive tract to develop

Changes in chromosome structure

-deletions: when chromosome breaks during meiosis and broken piece is lost
-translocations: movement of chromosome segments from one chromosome to another non-homologous chromosome
-duplications: presence of chromosome segment more than once in same chromosome
-inversions: occur when segment of chromosome is inverted 180 degrees

Philadelphia chromosome

translocation 9;22 best-known neoplasm-associated chromosomal abnormality associated with chronic myelogenous leukemia (CML)

Autosomal dominant diseases

are expressed in the heterozygous state so if either parent carries an abnormal gene there is a
-1:2 chance offspring will receive disease and be affected by disease.
-Male and female are equally affected

Autosomal recessive diseases

are only expressed in homozygous individuals
-both parents must carry the abnormal gene
-then there is a 1 in 4 chance of infant receiving both genes and being affected by the disease
-Also, a 1 in 2 chance of child being heterozygous for gene, in which case they could be unaffected, but act as a carrier of the disease
-male and female equally affected
ex. Cystic Fibrosis

Cystic Fibrosis

autosomal recessive single gene disease, most common lethal genetic disorder in the US
-gene responsible is cystic fibrosis transmembrane conductance regulator (CFTR) that regulates transport of chloride ions across plasma membrane
-severity of CF symptoms is partly based on the location and type of CF gene mutation a person has with most common being cystic fibrosis delta F508 mutation, a deletion of 3 base pairs in the coding sequence for this gene

X-linked hereditary disease

usually affect males as they have a single x chromosome that carries the mutation, and thus a recessive allele will be expressed. In females, the effect of the mutation may be masked by the second healthy copy of the X chromosome so they are only carriers of the disease. Most are recessive. ex. muscular dystrophy

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