disease-causing abnormalities in DNA and chromosomes

degeneracy of genetic code

some AA have more than 1 nucleotide codon specifying them during protein synthesis

no ambiguity

a codon will only encode 1 AA

codon

3 nucleotide sequence in mRNA, how message is read by ribosome

anti-codon

codon charged w/ a specific AA, eg. UAC = anticodon for AUG (Met, start codon)

start codon

AUG (Met)

stop codons

UAA, UAG, UGA

synonymous (silent) substitution

result of redundancy in genetic code, mutation codon often specifies same AA as the OG codon (Eg. transitions at 3rd position are likely silent), no change in AA usually expected to have no change in phenotype either

nonsynonymous substitution

2nd position changes = 100% risk of changing AA, 1st position changes = 95% risk of changing AA, missense mutations, nonsense mutations

missense mutations

substitutions that change one amino acid to another one, severity depends on where replacement happens, can either cause no effect or loss/gain of toxic effects

nonsense mutation

premature stop codon, nonsense-mediated decay -> protein gets destroyed

transition mutation

purine -> purine or vice versa

transversion mutation

purine -> pyr or vice versa

frameshift mutation

can indirectly lead to premature stop codon, sequence of coding NOT a multiple of 3 gets deleted = shift in reading frame -> in-frame premature stop codon, multiple of 3 gets deleted = no shift, often involves insertions/deletions, can also occur from some mutations that produce altered splicing (ie. intron retention)

missense mutation example

sickle cell disease;

the change: single nucleotide substitution in B-globin gene (HBB), A->T, changes codon GAG to GTG

the result: Glu is replaced w/ Val at position 6 on protein

the effect: altered HbS clumps together when deoxygenated causing RBCs to sickle

nonsense mutation example

Beta Thalassemia;

the change: single nucleotide substitution in B-globin gene (HBB), C->T, changes codon CAG to TAG

the result: Gln is replaced by a premature stop codon, so translation ends early

mutations that lead to a shift of frame

insertions/deletions at DNA level, can also occur from some mutations that produce altered splicing (ie. intron retention)

germ cell abnormality

constitutional, mutation present in all nucleated cells, present very early in development, eg. egg/sperm or soon after fertilization (zygote stage) has mutation that causes mutation in ALL cells

somatic abnormality

acquired, present only in certain cells/tissues of a person, Eg. lung cancer -> mutation only present in lung cells

structural abnormalities

arise thru chromosome breakage events that are incorrectly repaired or rearranged

structural abnormalities subtypes

deletion, inversion, ring chromosome, eccentric/dicentric chromosome, translocation

deletion

chromosome material is lost

inversion

chromosome material is switched around

ring chromosome

circular chromosome

single centromere structurally abnormal chromosomes

can by stably propagated thru successive rounds of mitosis

eccentric/dicentric chromosome

does not separate stably at mitosis and will eventually be lost

translocation

2 diff chromosomes have a single break and experience incorrect joining of the broken ends -> movement of chromosome material BTWN chromosomes

outcomes of structural abnormalities

outcomes depend on whether centromere is affected

centromere

spindle fibers attach here during separation

1 centromere

mitosis and meiosis occur, goes to next stage (chromosomal segregation in daughter cells)

2, or 0 centromeres

degraded in that stage, can't segregate

numerical abnormalities

changes in chromosome number that often arise thru errors in chromosome segregation

numerical abnormalities subtype

aneuploid

euploid

having complete sets of chromosomes (eg. n, 2n, 3n)

diploidy

2n, usual normal state in human somatic cells

aneuploid

deviations involving loss/gain of one or more chromosomes, arise thru nondisjunction and anaphase lag

aneuploid subtypes

trisomy, monosomy, polyploid

nondisjunction

paired chromosomes fail to separate

anaphase lag

lazy chromosome takes too long and one is left behindm telophase does not wait for it

cancer cells (aneuploidy)

usually show extreme aneuploidy w/ multiple chromosomal abnormalities

polyploid

many multiples of chromosomes, eg. 3n triploids and 4n tetraploids

translocation examples

philadelphia chromosome translocation btwn chromosomes 9 and 22 -> chronic myeloid leukemia

robertsonian translocation btwn chromosomes 14 and 21 -> familial down syndrome

duplication

segment of chromosome that is copied, that region is present in extra copies usually side-by-side, usually happens thru unequal crossing over or replication errors, increases gene dosage

duplication example

charcot-marie-tooth disease type 1A: caused by duplication on chromosome 17 containing PMP22 gene

bar eue phenotype in drosophilia )reduced, bar-shaped eyes) results from duplication on X chromosome

examples of deletion

williams syndrome: deletion on chromosome 7 that includes elastin gene

inversion example

common inversion of part of X chromosomes (involving F8 gene) causes about half of severe hemophilia A cases

pericentric inversion of chromosome 9 is a common variant that is usually harmless

diseases caused by nondisjunction

downs, turner syndrome, kleinfelter syndrome

how mutations result in disease

change in the sequence of gene product leads to either: loss of function (hypo/amorph) or gain of new toxic function (neomorph)

hypomorph

loss of function, mutant gene product is incapable of carrying out its normal task or have a significantly reduced ability to work

neomorph

gain of toxic function, mutant gene product may acquire altered function or occasionally a new function that is harmful in some way causing cells to die or behave inappropriately

gain of toxic function

common in cancer; may arise from chromosomal translocations -> chimeric genes (eg. philadelphia chromosome)

protein misfolding

point mutations -> change in protein structure -> accumulation -> damage/disease

poor genotype-phenotype correlations

modifier genes, environment

modifier genes

genes that modify other genes

modifier gene example

gene A = black eye color

gene B = blue eye color

gene Z = modifier gene that modifies gene A and causes different shades of black, regulates expression of gene A

modifier gene disease example

thalassemia

thalassemia

a and B globins must be in 1:1 ratio, decrease in a-globin causes B-globin to accumulate which leads to disease, modifier gene that tweaks B-globin causes less severe thalassemia (instead of 1:10 ratio it becomes 1:5 ratio -> less aggregation), people w/ the same mutation can have more/less severity based on modifier genes

environmental factors

expression of disease phenotype depends on environmental factors that may act at different levels: at a distance (radiation), direct exposure to harmful chemicals that we ingest, contact w/ microbes and toxins. important in triggering cancers

environmental factors example

identical twin study; identical twins have same exact genotype, but growing up in different locations/environments significantly changes their phenotypes

Turner syndrome mutation

sex chromosome monosomy (XO, 45X), lacking an X chromosome, the ONLY whole chromosome monosomy that is compatible with life in humans, 1/2500 live born females

Turner syndrome genetic mechanism

chromosomal nondisjunction and haploinsufficiency of specific genes

Turner syndrome clinical features

girls w/ short stature, primary ovarian failure (no menstruation), no secondary sex characteristic development, cubitus valgus (outward forearm angle), webbed neck, broad chest w/ wide spaced nipples, angulated nails, congenital heart abnormalities (coarctation of aorta -> premature death), lymphedema, horseshoe kidney (still functions, fused together), many have no identifiable features at birth, intellect is NOT affected

Turner syndrome dx clinical rule

female kid w/ short stature and not obtained puberty by age 15 -> screen for turner syndrome

Klinefelter syndrome mutation

sex chromosome trisomy (XXY), one extra X chromosome, 1/600 newborn

Klilnefelter syndrome genetic mechanism

chromosomal nondisjunction during cell division, followed by a gene dosage overload (overexpression) of genes that escape normal cellular silencing

Klinefelter syndrome clinical features

female features, disproportionately long arms/legs, testicular abnormality, tall, no male pattern baldness, breast development, wide hips, poor muscle tone, autoimmune disorder risk, osteoporosis, extra-gonadal tumors, DVT (clotting issues), mitral prolapse, lifespan NOT affected, VARIABLE intellectual disability, breast cancer is common, primary testicular failure (gynecomastia, infertility, small testes), testosterone and estrogen balance is twisted

Down syndrome mutation

trisomy 21, 1/700 live births

Down syndrome genetic mechanism

meiotic nondisjunction, dependent on age of mother (risk increases as age increases), cells get sticky and have trouble separating

Down syndrome clinical features

flat facial profile, small nose, epicanthal folds, brushfield spots (white spots on iris), short 5th fingers, wide gap btwn 1st and 2nd toes, single transverse palmar creases, neurologic problems (lower than avg IQ, alzheimer disease, low muscle tone/hypotonia, vision and hearing problems, congenital heart malformations - A/VSD), big tongue in small mouth (drooling, choking episodes, resp tract infection, incidence of leukemia is 11x more than general population, secretion issues affect fertility and immune system, live to 50s

Down syndrome leading cause of death

live to 50s, death usually caused by congenital heart malformations and resp tract infections

maternal age effect on down syndrome

21st autosome chromosome -> extra comes mostly from mother, by the time female child obtains puberty: 400k primary follicles, follicles all arrested in meiosis 1 from birth, after puberty follicles mature and become eggs -> are released during menstrual cycles, only 1 dominant follicle becomes egg in maturation, the longer an egg is arrested -> increased chance of downs (eggs stick together), 70% of cases occur at meiosis 1 in the mother

maternal age effect on downs example

maternal age <25 = 1/1600 live births

maternal age >42 = 1/40 live births