genetics 3

locus

specific section of chromosome

genotype

complete set of alleles at all loci in individuals

phenotype

detectable/visible effect of alleles

transmission genetics

mechanics of how genes are transmitted from parent to offspring

expression genetics

mechanism of how alleles of genes interact w/ e.o

somatic mutation

only affects individual; body cell after conception, not sperm/egg

gives rise to mosaicism- some mutated, some not

germline mutation

doesn’t affect individual, only passed down

homozygous

2 same alleles @ locus

heterozygous

2 diff alleles @ locus

hemizygous

only 1 copy of gene present

opposite deletion/imprinted region, x. chrom. genes in males

pleiotropy

gene responsible for several phenotypic traits (pku, sickle cell syndrome)

polygenic inheritance

multiple genes responsible for phenotype

complete dominance/recessive

phenotype of heterozygote matches 1 parental phenotype

Huntington’s disease complete dominance

CF considered comp. recessive, however hetero. prone to respiratory illness

incomplete dominance (non-dominance)

intermediate blend- both alleles affect phenotype

palomino horses show blended phenotype

co-dominance (non-dominance)

both alleles expressed simultaneously

ABO blood type; I^A, I^B co-dominant. I^A, I^B each dom. to i

haplo-sufficient (non-dominance)

mutant allele completely recessive

wildtype allele has sufficient biochem. activity

haplo-insufficient (non-dominance)

mutant allele dominant or incomplete dominant

single wildtype allele does not produce enough

mutant alleles could encode novel/altered biochem. product that could cause dom. expression

conditional mutation

mutant phenotype only expressed under certain conditions (Siamese cats)

classification of mutants

• morphological

• biochem.- auxotrophic mutants from prototrophic parents; step in biochem. pathway blocked (conditional)

• lethal- typically recessive + require both copies

• conditional- expresses mutant phenotype under certain conditions- temp. sensitive pigmentation of siamese cats, dark fur @ cooler temps.; diet dependent (PKU)

particular inheritance

individual alleles passed down

law of equal segregation

during gamete formation, alleles @ locus segregate

each gamete has equal probability of containing either allele

test cross

test the genotype of dominant phenotype parent by crossing w/homozygous recessive tester parent

(AAxaa= 4 Aa) (Aaxaa= 1:1 Aa:aa)

phenotypic rations

complete dominance- 3:1, 1:1

non-dominance- 1:2:1 (same as genotypic ratio)

lethal alleles- 2:1 (full recessive dies)

sex chromosomes

• x + Y used to be homologs, evolved to be heteromorphic but retained similar regions (psuedautosomal regions)

  • permit x + Y pair up

  • genes in this region show autosomal inheritance patterns

• loss of function in SRY region→ XY femals

• translocation of SRY→ x chromosome- xx males

• SHOX (bone regrowth) in region- xx, xy 2 functional copies

  • xxx, xyy taller, x shorter (turner syndrome)

• y chromosome microdeletions lead to male infertility

• microdeletions in long arm (Yq) most frequent (5-15%)

crossover

occurs in pachytene (phrophase I)

exchange between non-sister chromatids

2 loci must be sufficiently separated

orientation of chromosomes affect gamete product

• Orientation of chromosomes affect gemete product

  • Aa→ AB ab

  • Bb→ AB ab

increases genetic diversity

Meiosis I

reductional cell division→ 2 in cells

meiosis II

equational division→ 4 in cells

x-linked genes result in

hemizygous individuals

• w+ wild type, red eye dominant

• w- white eye recessive

• femals Xw+ Xw-, males Xw+Y, Xw-Y

test sex-linkage through

reciprocal crosses

• when diff results in F1 and F2 and male/female offspring have diff phenotypes, sex-linked explanation

• W+W+ female x W- male + W-W- female x W+ male

(phenotypes reversed relative to sex)

law of independent assortment

alignment during meiosis I is random, one allele doesn’t affect distribution of other alleles at other loci

dihybrid crosses

cross 2 pure breeding lines

P:RRYY x rryy

F1: RrYy x RrYy

F2: 9:3:3:1

product rule

both events occur together, multiply individual probability

sum rule

either event occurring, + probabilities

9:3:3:1 ratio

must have independent assortment, one allele @ each locus completely dominant, each 4 phenotypes unambiguous, no gene interaction/gene linkage

dihybrid test cross

RrYy x rryy= 1:1:1:1 ration

• # of segregation pairs= n

• # of genotype classes = 3^n

• # of phenotype classes = 2^n

further apart on chromosome = more crossover

recombination

process that results in gametes w/ combination of alleles not present in parent gametes

interchromosomal recombination

independent assortment b/w alleles w/ loci on diff chromosomes

intrachromosomal recombination

crossover b/w loci on same chromosome

parental gametes match

inpute

Recominant do not match

input

coupling (cis) configuration

both wildtype/mutant on 1 chromosome

AB

—

—

ab

repulsion (trans) configuration

one wild type + one mutant on 1 chromosome

Ab

—

—

aB

• if genes are linked, crossover occurs to produce recombinant gametes

unlinked genes

• independent assessment RF=0.5

• genes on completely diff chromosomes

• genes are far enough apart + crossover so numerous that alleles are distributed randomly

complete linkage

loci so close together that alleles always segregate together

• RF=0

partial linkage

loci far enough apart that crossovers occurs during some meioses

• RF= < 0.3

syntenic

genes on same chromosome, regardless of linkage

recombinant frequency (RF)

the # of recombinant gametes/ (# recombinat + # parental)

• can be used as measure of genetic distance (unit centimorgan)

  • 1 cM (1% RF) =10^6 bp

• best measured by testcross of dihybrid (AaBb x aabb)

  • AABB x aabb - coupling

    • parental AaBb, aabb

    • recombinat Aabb, aaBb

• AAbb x aaBB- repulsion

  • parental AaBb, aabb

  • recombinant AaBb, aabb

chromosome rearrangements

20% conceptions have chromosomal mutations

60% of spontaneous abortions

balanced mutations

no gain/loss of chrom. material

unbalanced mutations

gain/loss of chrom. material

serious health effects

gene balance

• metabolomic regulatory networks work best when enzymes/regulators are present in specific ratios

• ribosome is model for gene dosage balance

• unbalanced changes (deletions, duplications)

• balanced changes (inversion, reciprocal translocation, Robertsonian translocation)

mechanisms for chromosome rearrangements

1. errors in double-strand break repairs

• when ds break occur @ same location, NHEJ proteins fix breaks→ inaccurate, error prone, if multiple breaks then can join incorrect ends together

• HR (homologous recombination) repair pathway also exists (BRCA genes)→ accurate

2. errors in crossovers

• wrong pieces of DNA can be matched up when similar DNA sequence is @ multiple points

• extra/missing genes, inversion, translocations

translocations

2 breaks on diff chromosomes + incorrect rejoining

reciprocal translocation

2 chromosomes swap arms

Robertsonian translocation

all genes end upon 1 chromosome, other is so small it is lost

consequences of chromosome rearrangements

• breakpoints near gene can damage a gene + loss of function

• new genetic material @ breakpoint causes gene regulation problems

• gene dosage balance may change

• unbalanced changes→ loss of genetic material

  • hemizygous regions uncover recessive/imprinted alleles

• in balanced rearrangements, meiotic segregation→ unbalanced gametes

Cri-du-chat syndrome

deletion of part of short arm chrom. 5

single copy of CTNND2, int. disability

Charcot-Marie tooth (MT) disease

duplication (3 copies) of PMP22

gene dosage effect from 3 copies

1 copy of gene→ HNPP neuropathy

inversions

balanced, unlikely to cause health effects

paracentric (not included centromere) VS pericentric (includes centromere)

heterozygous inversion

can cause duplication/deletion of chrom. in gametes

reduced fertility

homozygous inversions

speciation

translocations inversions

balanced, unlikely to cause health effects

breakpoint effects

segment of a chromosome breaks off, flips 180 degrees, and reinserts itself. 

Ex:

• Philadelphia chromosome- breakpoint effects + CML leukemia

  • chrom 9 + 22 fusion→ BRC-ABL new gene

  • somatic in bone marrow stem cell

• adjacent segregation- duplication + deletion

• alternate segregation- balanced gametes

• adjacent- 2 rare- centromeres go together→ nondisjunction

epistasis

phenotype of one locus masks/prevents phenotypic expression of another

recessive epistasis

epistatic allele recessive (9:3:4)

dominant epistasis

epistatic allele dominant (12:3:1)

duplicate gene action

2 genes code for phenotype, (dup. dominant)

only recessive (aabb) results in diff. (15:1)

complementary gene action

loss of function on either (dup. recessive)

gene results in same phenotype (9:7)

brown gene in dogs

TRPI; dilutes eumelanin (black→brown)

tyrosinase-related protein 1 (B locus)

red gene

E locus- MCIR switches black/brown → red/yellow

melanocortin 1 receptor (human red hair/fair skin)

pheomelanin

penetrance

proportion of individuals w/ particular genotype that actually show phenotype (% of population)

expressivity

variability in mutant phenotypes observed in individuals w/ a particular phenotype

• complete (100%) vs incomplete penetrance (<100%)

• narrow (little variation) vs broad (lots of variation) expressivity

• due to random chance, environmental factors, mutations in other genes

• Neurofibromatosis type 1 has incomplete penetrance (50-80%) and broad expressivity (HBP, short stature, large head/pleiotropy)

genotype + environment + interaction=

phenotype

effects of environment on phenotype

• sex-limited (horns on male sheep, milk in female cows)

• sex-influenced (male pattern baldness dom. in males, recessive in females)

• age, temp., chemicals, diet

Congenital generalized hypertrichosis

• sex- influenced

• denser, more abundant hair, milder+patchier in females (hormonal + x-chrom inactivation)

androgenetic alopecia

medical genetics classifications

1. single gene/mendelian/monogenic

   • 1/200 births- CF, sickle cell, marfan, Huntington’s, heterochromatosis

2. multifactorial/complex/polygenic

   • combo of environment + multiple genes

   • heart disease, Alzheimer’s, arthritis, diabetes, cancer, obesity

   • fingerprints, skin/eye color

3. chromosomal

   • abnormalities in chromosome structure (missing, additional breaks, translocations)- down syndrome, trisomy

4. mitochondrial

polygenic

many genes affect one trait

multifactorial

many genes + environment/other factors

continuous

lack of distinct phenotype (height, ect.)

discontinuous

distinct phenotypes (blood type, male/female)

polygenic inheritance

additive effects of genes

threshold model

for discontinuous traits, a threshold exists where an individual is highly likely to have trait

• W/i local population - 89%; between local populations - 2%; B/W continental populations - 9%

clinal variation

existence of continuous gradient across a region/neighboring groups

• AIMS- ancestry informative markers

  • allele frequency vary more than average b/w populations

• Tyrosimase-enzyme→ synthesis of melanin

  • defective in albinism

aneuploidy

too many/too few individual chromosomes

• unbalanced

polyploidy

number change by whole chromone set

• x=level of ploidy

• diploid (n=x, 2n=2x), tetraploid (n=2x, 2n=4x), hexaploidy (n=3x. 2n=6x)

stable, fertile polyploids

even # of chrom. sets (or monoploid + gamete mitosis)

octoploid strawberries

sterile polyploids

odd # of chromosome sets

cavendish bananas, seedless watermelon (triploid)

aneuploidy results from

nondisjunction- failure of separation

unbalanced

rare, usually affects 1 chromosome

results in 2n+1, 2n-1 cells

can occur in mitosis, meiosis 1, meiosis 2

polyploidy examples

Turner syndrome 45, X monosomy

Klinefelter syndrome 47 XXY trisomy