Chromosomal Abnormalities / Genetics & Disease / Cancer Genetics

Single gene disorders examples

cystic fibrosis, albinism, sickle cell disease, galactosemia, etc (100% genetic)

familial aggregration

if disease has genetic component, then may cluster in families

higher the relative risk for disease

the stronger the genetic component

multifactoral diseases

genetics + environment…diabetes, schizophrenia, cancer, etc.

Chromosomal abnormalities

changes in # of chromosomes…missing or extra

OR rearrangements (# doesn’t change, PIECES change)…duplication, deletion, inversion, translocation

Aneuploidy

2n +- x chromosomes…gain or loss of 1 or more chromosome but not a complete set…can be monosomy, disomy, trisomy, tetrasomy, pentasomy, etc.

Euploidy

multiples of (n)…change in # of haploid chromosome sets…entire SET of chromosomes change, excess or lack of entire set of chromosomes…Diploidy (2n), polyploidy, triploidy, tetraploidy, pentaploidy

Causes of aneuploidy

random error during production of gametes called non-disjunction

Non-disjunction

paired homologs fail to ‘disjoin’ during segregation…can occur in both Anaphase 1 or 2 with different final results

Monosomy

Lack of 1 chromosome (2n-1)…NOT tolerated in humans b/c only 1 copy of gene (instead of 2)…haploinsufiency= inadequate function, exposes hidden defects…potential lethal recessive alleles

Y Chromosome

determines maleness, void of essential genes…older men losing Y chromosome = it’s okay!!

Syndromes associated with monosomy

Turner Syndrome…1 X…underdeveloped ovaries…females

Trisomy

Extra chromosome (2n+1)

X inactivation

genes in 1 X adapted to function as 1 copy…1 X is inactivated —> Barr Body (if females had 2 active Xs, then 2x genes than males…no)

Chromosomal Rearrangements

spontaneous or environmental DNA breaks occur constantly…sometimes not repaired = rearrangements —> Duplication, deletion, inversion, translocation

Deletions

missing region in chromosome…only tolerated when small…Ex. Cri-du-chat syndrome

Duplications

repeated region in chromosome…Ex. Charcot-Marie Tooth

Inversions

segment of chromosome turned 180 degrees…no loss of genetic material :)

pericentric

inverted segment contains centromere

paracentric

segment does not contain centromere

Risk of inversions

reduced fertility…non-viable offspring

Translocations

relocation of chromosome fragments…reciprocal & robertsonian

reciprocal translocation

exchange of genetic material between 2 chromosomes…if genetic info not lost = balanced translocation

Risk of translocation

EVEN IF BALANCED!!! break can disrupt important genes/create gene fusions…fertility issues, gametes with loss/duplication of genetic info —> non-viable offspring even if no loss of genetic info (Ex. two centromeres on 1 chromosome)

Robertsonian translocations

genetic exchange between acrocentric chromosomes (long arm & tiny arm)…loses genetic material but not important info

Familial down syndrome

caused by robertsonian translocation between 14 and 21…family passes down translocation…5% of down syndrome…

Non-familial down syndrome

caused by an extra copy of chromosome 21 due to nondisjunction during meiosis in mom…95% of Down syndrome

triplet expansion

multiple repeats of triplet nucleotide leading to genetic disorders…Ex. Huntington's disease

triplet expansion: anticipation

symptoms of genetic disorders appear at an earlier age and with increased severity in successive generations due to the increase in the number of triplet repeats.

How do we know diseases have genetic component?

relatives of affected individuals will have a higher probability of developing the disease than general population…aggregation & twin studies

Aggregation studies

relative risk= probability of disease in relatives/ general population…if it concentrates in family = genetic

concordance in twin studies

if both twins have disease (Ex. diabetes), they are said to be concordant for that disease…If MZ have a much higher concordance rate than DZ, it suggests that the trait has a strong genetic basis (more genes you share the more likely)…If concordance similar b/t MZ and DZ twins, likely influenced by environment

Twin studies

compare concordance in monozygous twins with dizygote twins

single trait diseases have what % concordance in MZ

100%…Ex. cystic fibrosis

common mutated genes that cause cancer

Tumor suppressor genes, proto-oncogenes, oncogenes

Tumor suppressor example

p53: DNA damage checkpoint

proto-oncogenes

normal genes, make proteins and contribute to cell growth/survival

oncogenes

mutated proto-oncogenes that drive cancer progression

Oncogene example

RAS oncogene…differs from RAS proto-oncogene by point mutation

what causes oncogenes

viruses, point mutations , gene amplifications, chromosomal translocations, DNA rearrangements (insertion, deletion, inversion), insertional mutagenesis

Loss of which genes promotes cancer

tumor suppressor genes

Gain of which genes promotes cancer

oncogenes

Multiple hit hypothesis

takes an accumulation of mutations (hits) over time to develop cancer…why cancer seen more in older people…if cancer shown early —> expected familial predisposition to cancer