T3 mendelian & non-mendelian inheritance

mendel’s laws of inheritance

1. law of dominance & uniformity

2. law of segregation

3. law of independent assortment

law of dominance & uniformity 

if atleast 1 dominant allele is present → dominant trait will appear

law of segregation

during gamete formation, 2 alleles for each gene separate randomly → each gamete receive only 1 allele from each gene

law of independent assortment

genes for different traits are passed on independently of one another

human karyotype

46 chromosomes → 23 pairs

SRY gene

sex-determining region on Y → controls male sex development

pseudoautosomal regions (PAR) - location

tips of both X and Y chromosomes

pseudoautosomal regions (PAR) - function

allows pairing & exchange of genetic material (crossing over) during meiosis

sex-limited traits

expressed in only 1 gender BUT genes are presented in both gender

sex-limited traits - controlled by…

autosomal genes

sex-limited traits - expression depends on…

sex hormones 

sex-influenced traits

appear in both genders BUT expression differs → dominant in one sex, recessive in another

typical mendelian inheritance

autosomal dominant, autosomal recessive, x-linked dominant, x-linked recessive, Y-linked

autosomal dominant - pattern

appears in every generation, both sexes affected equally, male-to-male transmission can occur 

autosomal dominant - diseases

polydactyly & familial hypercholesterolemia

polydactyly

extra fingers / toes

familial hypercholesterolemia - heterozygotes

very high LDL, tendon xanthomas, premature coronary artery disease

familial hypercholesterolemia - homozygotes

no normal LDL receptors, severe hypercholesterolemia, early coronary disease 

autosomal recessive - pattern

often skip generations, both sexes affected equally

autosomal recessive - diseases

hypotrichosis & sickle cell

hypotrichosis

lack of hair growth

sickle cell disease

point mutation in beta-globin gene → glutamine becomes valine at position 6

HbS/HbS

sickle cell anemia disease

HbA/HbS

sickle cell trait → heterozygous condition

x-linked dominant - pattern

does not skip generations, affected males must have affected mother, affected father must have all daughters affected

x-linked dominant - diseases

vitamin D-resistant rickets

x-linked recessive - pattern

mostly males affected (requires only 1 X), skip generations via female carriers, no male-to-male transmission

x-linked recessive - diseases

hemophilia in queen victoria family & duchenne muscular dystrophy (DMD)

duchenne muscular dystrophy (DMD)

severe muscle weakness in early childhood

Y-linked (holandric) - pattern

trait appears only in males, affected father have all sons affected, father-to-son

Y-linked (holandric) - diseases

hairy ear rims & retinitis pigmentosa

retinitis pigmentosa

night blindness → progress to complete blindness

XY females with gonadal dysgenesis

SRY mutation → Y chromosomes fail to initiate testis development → remain as streak gonads (non functional connective tissues)

atypical mendelian inheritance

genetic anticipation, pseudoautosomal inheritance, pseudodominant inheritance, mosaicism, digenic inheritance, uniparental disomy, imprinting disorders

genetic anticipation

signs and symptoms appear at an earlier age → become mores severe in each successive generation

genetic anticipation - cause by…

mutation of trinucleotide repeat expansion (TNRE) → short DNA sequence repeat many times

genetic anticipation - as generation increase

number of repeats increases → earlier onset → more severe symptoms

genetic anticipation - examples

huntington disease & fragile X syndrome

huntington disease - repeat sequnce

CAG

hungtington disease - symptoms

progressive chorea and dementia due to HTT gene affected

fragile X syndrome - repeat sequence

CGG

fragile X syndrome - symptoms

learning disability, cognitive impairment due to mutation in FMR1 gene

pseudoautosomal inheritance

homologous regions on X and Y chromosomes undergoes recombination during meiosis → makes inheritance pattern looks autosomal (even though genes are on sex chromosomes)

pseudoautosomal inheritance - examples

leri-weill syndrome

leri-weill syndrome - cause

mutation or deletion of SHOX gene located on PAR1 region of X and Y chromosomes 

leri-weill syndrome - symptoms

short forearms & short stature → recombination frequency higher in men than women

pseudodominant inheritance

recessive condition appears to follow a dominant pattern → homozygous recessive (affected) mates with heterozygous (carrier)

pseudodominant inheritance - example

gilbert syndrome

gilbert syndrome - cause

missense mutation or promoter change in UGT1A1 gene (encodes bilirubin-UGT enzyme)

gilbert syndrome - symptoms

mild hyperbilirubinemia (elevated unconjugated bilirubin)

mosaicism

genetic abnormality arise during mitosis (after fertilization) → results in 2 or more genetically different cell lines within one person

mosaicism - types

somatic & germline

somatic mosaicism

mutation occurs in body (somatcic) cells → no transmission to offspring unless germ cells are affected

somatic mosaicism - examples

neurofibromatosis type I (NF1), patchy skin color, cafe-au-lait spots, eye color difference

germline mosaicism

mutation occurs in germ cells → parent appears normal but can pass mutations to offspring

mixed mosaicism

mutation affects both somatic and germline cells → parent can show mild symptoms and pass on condition to offspring

germline mosaicism - examples

tuberous sclerosis

uniparental disomy

both copies of a chromosome come from 1 parent instead of one from each

uniparental disomy - types

heterodisomy & isodisomy

heterodisomy

2 different homologous chromosomes from 1 parent → error in meiosis I

isodisomy

2 identical copies of the same chromosome from1 parent → error in meiosis II

uniparental disomy - mechanism

trisomy rescue: zygote has 3 copies of a chromosome → one chromosome is lost → both remaining copies are from 1 parent = UPD

uniparental disomy - consequences

usually no effect but can cause disorders when imprinted genes are involved 

uniparental disomy - example

autosomal recessive non-syndromic deafness

autosomal recessive non-syndromic deafness - symptoms

alter connexin proteins → change structure of gap junction channel → affect function or survival of cells that are needed for hearing

autosomal recessive non-syndromic deafness - causes

mutation in GJB2 gene → connexin 26 protein & GJB6 gene → connexin 30 protein, both on chromosome 13

imprinting disorders

only one allele (mom or dad) is expressed while the other is silenced (imprinted)

imprinting disorders - examples

prader-willi syndrome & angelman syndrome

prader-willi syndrome

loss of paternal contribution

angelman syndrome

loss of maternal contribution

non-mendelian inheritance

multifactorial traits & mitochondrial inheritance

multifactorial traits

many genes + environment act together to determine a trait or disease

multifactorial disorders - characteristics

occurs in isolation, risk in relatives, proband only affected member, environmental influence, gender difference, pedigree analysis cannot confirm, ethnic variation

purely genetic - concordance of MZ twins

100%

multifactorial - concordance of MZ twins

high but less than 100%

multifactorail traits - family correlation

closer relatives show stronger resemblance (genetic effect)

multifactorial disorders - example

coronary artery disease

coronary artery disease - pattern

runs in families (not mendelian), more common in men, high risk in african americans

continuous multifactorial traits - characteristics

continuosly graded distribution, no clear boundaries between normal & abnormal, controlled by many genes + environment

discontinuous multifactorial traits - characteristics

either present or absent, depend on underlying continuous liability → disease appear only when liability crosses threshold

liability

total of genetic risk + environmental factors

discontinuous multifactorial trait - example

cleft lip & palate

cleft lip & palate - mechanism

parents can be unaffected (below threshold), each parent carries some underactive genes for lip/palate formation → together exceed threshold in child

discontinuous multifacotrial - further above threshold…

more severe the defect

general population - liability curve

further to the left (lower liability)

first degree relatives - liability curve

further to the right (higher liability)

mitochondrial inheritance

contain mtDNA separated from nuclear DNA → transmission of genetic material from mother 

mitochondrial chromosomes - characteristics

self-replicating, codon usage is different, no introns, both DNA strands are transcribes & translated 

mitochondrial inheritance - mother affected

all children affected

mitochondrial inheritance - father affected

no children affected

mitochondrial disorders - example

leber hereditary optic neuropathy (LHON)

leber hereditary optic neuropathy (LHON) - symptoms

bilateral central vision loss

leber hereditary optic neuropathy (LHON) - cause

point mutations in mtDNA → mitochondrial dysfunction → death of optic nerve cells

progressive external ophthalmoplegia - cause

mtDNA deletions → mutations of nuclear gene that encodes polymerase gamma → mtDNA replication (autosomal dominant)

progressive external ophthalmoplegia - symptoms

weakness of external eye muscle