GCD 4143 exam 1

genetics

the study of inheritance of individual genes/alleles; study of variation in humans

genomics

study of inheritance of all genes/alleles of a person

genetics without genomics example

pedigree analysis

genomics without genetics example

ancestry, pharmacogenetics

minor allele

less frequent allele

major allele

more frequent allele

derived allele

newer allele in evolutionary time created by mutation

ancestral allele

older allele in evolutionary time prior to a mutation

polymorphism

variant for which the minor allele frequency is at least 1%

how many chromosomes in a typical human?

22 autosomes + xx/xy

genome composition (%)

Repeated sequences: 50%

Transposons: just under 50%
- Sines: 20%
-Lines: 20%
- retroviral-like elements: 10%

Unique sequences: 50%

Genes: 25%
- protein-coding regions: 1%
- non-coding non-repetitive DNA: 25%

genome composition (\#)

total bp: 3 million

protein coding: 20,000

non-coding: 22,000

pseudogenes: 15,000

transcripts: 200,000

law of uniformity

after crossing 2 homozygotes of different alleles, all progeny of the first generation are identical and heterozygous

law of segregation

the two alleles at a single locus are never found in the same gamete but segregate and pass to different gametes

law of independence

each pair of alleles acts independently during segregation into the gametes

Alkaptonuria

AR homagentistic acid dioxygenase deficiency;
Arthritis and urine turns black when exposed to air, dark skin

genotype frequency

fraction of each genotype among individuals in the population

allele frequency

the fraction of all chromosomes in the population that carry that allele

short tandem repeat polymorphism (STRP)

a stretch of 2-4 repeated nucleotides (ex GTGTGTGTGTGT)

human genome project

- determined haploid human dna sequence
-identified sequence location of expressed rna
- identified sequence variation

eugenics

the "science" of improving the human race by eliminating disease and increasing intelligence, strength, etc

why did eugenics come about?

1800s: concerns about degeneration of british upper class by mixing with lower class people

positive eugenics

promote good alleles

negative eugenics

reduce/eliminate bad alleles

eugenics in usa

positive programs: promote marriage between "fit" individuals

negative programs: forbid inter-racial marriage, forced sterilization, immigration limitation

us sterilization laws

1920s: colony for disabled and undesired (prostitutes, orphans, feminists, etc)

containment zones to separate out genetically "inferior" individuals

Buck v Bell 1927 supported that compulsory sterilization was permissible

eugenics in mn

mn eugenics society founded by dr. charles dight

institutionalization, sterilization, "racial hygene"

lebensunwertes leben

"life unworthy of living"

"racial hygene", often for jews as well as gypsies, soviet, polish

autosomal recessive

two copies of an abnormal gene must be present in order for the disease or trait to develop

autosomal dominant

one copy of an abnormal gene must be present in order for the disease or trait to develop

Y-linked traits

only affect males, and affect all sons of an affected male.

x-linked traits

traits carried on the X chromosome, the recessive trait shows up more commonly in males due to them only having one X

co-dominant

in a diploid organism, two different alleles of a gene that are both expressed in a heterozygous individual

penetrance

the probability that a mutant allele will cause disease

reduced penetrance

not all individuals with the disease genotype get the disease

age-dependent disease onset

can create illusion of penetrance if individuals aren't old enough to develop the disease

expressivity

severity of expression of the phenotype

what phenomoena complicate the idea of a single gene disease?

reduced penetrance and variable expressivity

proband

the person from whom the pedigree is initiated

Cystic Fibrosis inheritance

ar

cystic fibrosis manifestations

abnormal mucous secretions with increased salt in the sweat

chronic obstructive lung disease, pancreatic insufficiency, biliary obstruction and fibrosis, infertility

pleiotropy

a single mutation an cause multiple symptoms

cystic fibrosis transmembrane conductance regulator (CFTR)

cAMP-regulated chloride ion channel with 5 domains:

-2 membrane-spanning domains
-2 hydrophilic regions with atp-binding domains
-1 highly charged cytoplasmic region with many phosphorylation sequences

result of CFTR defects

reduced fluid secretion --\> increased mucal protein --\> thick mucous

loss of function alleles

prevent protein production or lead to a nonfunctional protein (most AR disorders)

incomplete dominance/semidominance

carriers have slight sub-disease characteristics

HWE assumptions

1. No Selection
2. No Mutation
3. No Migration
4. No Chance Events (drift)
5. Individuals choose mates at random

compound heterozygotes

two disease alleles with different mutations

consanguinity

inbreeding; leads to decreased compound heterozygotes

causes of ad diseases

gain of function (GOF) mutation

null mutation (haploinsufficiency at the locus)

dominant negative mutation (inactivation of normal product by mutant)

somatic mutation of normal allele

alpha-1-antitrypsin (P1/SERPINA1)

inhibits elastase which breaks down elastin

mutation destroys recognition of elastase and switches to inhibit thrombin (GoF)

results in bleeding disorder

osteogenesis imperfecta (OI)

collagen disorder --\> brittle bones; can be AD or AR; result of haploinsufficiency (I) or dom neg (II)

OI genes and muts

COL1A1 and COL1A2

type I null mutations results in decrease of type I procollagen due to there being half the amount of proalpha1 chains

type II pt mutations results in multiple skeletal problems

germline/gonadal mosaicism

parent carries mutations in their germ line but does not express the disease phenotype

mosaicism

postzygotic mutation that results in two or more cell lines that are distinct

achondroplasia (AD)

dwarfism; 90% of cases are from new muts in the fibroblast growth factor receptor 3 (FGFR3)

homozygous is much more severe than het

FGFR3

function: limit osteogenesis

mutation leads to activation of receptor

other FGFR3 diseases

thanatrophoric dysplasia (TD) and hypochondroplasia (HCH)

AD polycystic kidney disease (ADPKD)

fluid filled kidney cysts

hypertension, hematuria, ab pain, renal failure

normal polycystin 1 and 2

1. PC1 and 2 heterodimerize
2. PC1 activates g-protein signaling pathway -\> modulating voltage-gated Ca++ and K+ channels

PC2: Ca++ permeable cation channels

3. PC1 and 2 mediate transduction of extracellular mechanical stimulus through the cilia into Ca++ signaling repsonse inside kidney epithelial cells

2 hit hypothesis ADPKD

inherit one mutation -\> each cyst develops a second mutation

ADPKD treatment

low sodium intake

antihypertensive therapies

kidney transplant

treatment of polycystic liver disease

Marfan syndrome inheritance pattern

AD

marfan syndrome

tall stature, excessive length of upper and lower extremeties, mild pectus excavatum, myopia, joint hypermobility,, HEART PROBLEMS

marfan syndrome gene

fibrillin (FBN1)

fibrillin \= major component of extracellular microfibrils and has widespread distribution in both elastic and nonelastic connective tissue throughout the body

muts are dom neg

fbn1 function

binds tumor growth factor beta (TGFB)

insufficient binding leads to overactivation of pathways sensitive to TGFB --\> phosphorylation of smad proteins --\> pathogenesis

down syndrome (trisomy 21)

mental deficiencies, simian crease, slanted eyes, flattened face, short stature

edward syndrome (trisomy 18)

mental and physicial deficiencies, facial abnormalities, extreme muscle tone, early death

patau syndrome (trisomy 13)

mental and physicial deficiencies, defects in organs, large triangular nose, early death

aneuploidy

loss or gain of whole chromosomes

x aneuploidies

turner syndrome (X0)

Trisomy X (XXX)

Tetrasomy X (XXXX)

Klinefelter's syndrome (XXY)

how many barr bodies develop?

Total x chromosomes - 1

inactivation of x chromosome steps

1. count chromosomes
2. choose random x to inactivate
3. assemble inactivation factors
4. spread along x
5. establish inactive state

x chromosome inactivation manifestation

underacetylated histones, methylated cpg islands, delayed dna replication

x inactivation center

cis-acting locus required for x inactivation

contains xist

x inactivation specific transcript (xist)

constitutively expressed from the inactive x chromosome

encodes rna that is not translated

rna is spliced and poly-adenylated but does not leave the nucleus

coats only the x chromosome that is expressing xist

both necessary and sufficient for x inactivation

x-inactivation controlling element (XCE)

allows for stable xist rna; influences which x is inactivated

tsix

modulator of xist activity

spliced and polyadenylated; associated with future x chromosome

if deleted, x chrom without tsix is inactivated

what % of x-linked genes remain active on inactivated x-chromosome?

15%

how does xist spread?

xist binds to distal sites that are spatially close to the newly transcribed xist rna.

xist modified chromatin structure at these regions and spreads from there.

regions that excape XCI can loop out and remain active while still permitting spatial spread of xist

ectodysplasin a (EDA)

protein made by ectodermal dysplasia a (EDA) locus on x chromosome

defects lead to x-linked hyphidrotic ectodermal dysplasia

x-linked hypohidrotic ectodermal dysplasia (XLHED)

hypotrichosis

absent eyebrows

prominent forehead, broad nose, thick lips

hypohydrosis

hypodontia/oligodontia

can have somatic mosaicism

example of xci in cats

torties, calicos

horner's laws of color blindness

\**** not correct \****

1. no female is color blind

2. color blind fathers have color-normal daughters

3. color blind sons always descend from color normal mothers

4. if a color blind father has a color blind son, it is an exception

5. sons of daughters whose fathers are color blind have highest risk of being color blind

what color blindness is x-linked?

deuteranopic (red-green) and protanopic (red-green)

tritanopic is on chr 7

segregation of a hypothetical y-linked trait

transmission is male to male only; all males from affected males are affected

sex-determining region y (SRY)

encodes TF

LoF --\> XY offspring that appear female

translocation --\> XX offspring that appear male

eukaryotic initiation factor 2 subunit 3 (Eif2s3y) or eukaryotic translation initiation factor 1a, y-linked (EIF1AY)

eif2s3y \= mouse spermatogonial proliferation gene

eif1ay \= human; unknown function but excapes xci

growth control y (GCY)

variation often leads to short stature

pseudoautosomal region

small region on the ends of X and Y chromosomes that contain homologous gene sequences; x and y pair here

Leri-Weill dyschondrostenosis

null mutations in SHOX (short stature homeobox) lead to short stature and forearms in typically women

result of haploinsufficiency

langer mesomelic dysplasia

missense mutations in SHOX lead to a more severe form of leri-weill dyschondrostenosis

mitochondrial biology

mt chromosome is part of human genome outside of nucleus; many mt genes have moved to nuclear chromosomes

mitochondrial inheritance

strictly maternal

why do mitochondrial mutations accumulate?

there is little dna repair

mitochondrial genome vs nuclear genome

mt:
- 100s-1000s of copies of the genome
- varying proportion of mutant mtdna molecules
- strictly maternal inheritance
- no introns (mammals)
- one circular dna chromosome, 1-100k copies
- 37 genes
- very little repetitive dna
- continuous transcription of multiple genes
- no recombination

nuclear:
- 2 copies of genome
- 0, 1, or 2 mutant alleles
- paternal and maternal inheritance
- introns and exons
- 23/24 different chromosomes with 46 total
- 25000-30000 genes
- lots of repetitive dna
- individual gene transcription
- recombination occurs

mitochondrial functions

1. produce atp through oxidative phosphorylation
2. initiation of apoptosis
3. generation of reactive oxygen species (ROS)

important genes in mtdna

polypeptides, rRNA, tRNA

nuclear vs mt codon usage

to summarize:

1. nuclear and mt have varying stop codons, but still share some of the same codons

2. very few amino acid codons vary between mt and nuclear dna

what % of mitochondrial proteins are encoded by nuclear DNA? why is that significant?

95%; nuclear gene defects can cause multiple oxphos issues