ova and spermatocytes

HAPLOID

all cells that are not gametes

DIPLOID

substituting a pyrimidine for a pyrimidine

substituting a purine for a purine

definition: variation within populations

types: single nucleotide polymorphisms (SNPs)

insertion/deletion polymorphisms (VNTR)--microsatellites and minisatellites

substitution of one or the other of 2 bases at 1 location

biallelic

occurs every 1000bp

(does not change the functionality of protein; does not cause disease per say)

affected individuals in all generations

males and females equally affected

(Aa) = affected

(aa) = affected

common to have only 1 generation affected

equal # of males/females affected

all children of 2 affected parents will be affected (aa x aa)

X.h. X is a carrier

X.h X.h = affected

may skip generations

more affected MALES than females

ALL sons of affected mother are infected

fathers NEVER transmit to sons

2 unaffected parents can have an affected child

successive generations

more FEMALES than males affected

ALL daughters of affected males are affected

both sons and daughters of affected heterozygous female may be affected

X.A X.a = affected

X.a Y = not affected

• disorders that run in a family but do not show patterns of unifactorial inheritance
• mult. genes involved in expression of trait
• genes do not act in dominant/recessive manner
• genes act in concert
• ENVIRONMENTAL factors interact with genotype to produce final phenotype

cafe au lait spots

axillary and inguinal freckling

lisch nodules

AUTOSOMAL DOMINANT

extreme pleiotropy

loss-of-function mutation

tumor suppressor gene

De novo mutations

   [image] 

MUTATION IN FGF RECEPTOR (FGFR3)

Rhizomelic short stature

megalencephaly

spinal cord compression

AUTOSOMAL DOMINANT

gain-of-function mutations

De novo mutations (unaffected parents)

advanced paternal age

INCOMPLETE DOMINANCE

[image]

progressive pulmonary disease

exocrine pancreatic insufficiency

elevated sweat chloride concentration

AUTOSOMAL RECESSIVE

tissue-specific expression of mutations

variable expression

environmental modifiers

[image]

bleeding diathesis

hemarthroses

hematomas

X-LINKED RECESSIVE

variable expression

defect in clotting factor 8 or 9

males more affected than females

[image]

neurodevelopmental regression

repetitive stereotypic hand movements

X-LINKED DOMINANT

loss-of-function mutation

incomplete penetrance

[image]

movement abnormalities

cognitive abnormalities

psychiatric abnormalities

AUTOSOMAL DOMINANT

unstable repeat expansion

novel property mutation

anticipation

incomplete penetrance (can skip generation)

variable expression

[image]

myotonia

muscular dystrophy

cataracts

hypogonadism

AUTOSOMAL DOMINANT

unstable repeat expansion

gain-of-funtion

anticipation

incomplete penetrance

variable expression

pleiotropy

[image]

circular DNA

37 genes total: 13 encode for protein subunits of an oxidative phosphorylation complex

mutations in mtDNA maternally inherited

mtDNA is maternally inherited

100% occurence in siblings

symptoms vary (variable expression)

occurs in successive generations

involvement of 3 or more organ systems

common cause of inherited maternal vision failure

due to 1 of 3 homoplastic pt mutations in NADH dehydrogenase component of complex I

additional environmental or genetic factors involved

[image]

progressive neurodegenerative disorder

common features include: encephalomyopathy, lactic acidosis, and stroke-like episodes and migraines

80% of patients have a heteroplasmic A-to-G pt mutation in tRNA-leucine

myopathy

dementia

myoclonic seizures

ataxia

deafness

mutations in the tRNA-lysine gene

[image]

primarily impacts nervous system: sensory neuropathy, muscle weakness, ataxia, vision loss, learning disabilities in children; dementia in older adults

mutations in the mtDNA encoding for the ATP6 subunit

chromosome where p arm = q arm in length

(chromosomes 1, 2, and 3)

p arm almost non-existant (contains redundant genomic info)

chromosomes: 13, 14, 15, 21, 22*

autosomal or sex chromosomes

--gain or loss of a chromosome

monosomy

trisomy

tetrasomy

failure to split DNA correctly: 1 egg may get no chromosomes while other gets both

--more likely to occur during oogenesis than spermatogenesis

--increases with maternal age

95% of cases involve trisomy 21

others involve mosaicism and Robertsonian translocations

--increases with maternal age

--distinct dysmorphic facial features, mental retardation and congenital cardiac abnormalities

--GAIN OF FUNTION MUTATION

approximately 50 genes

genes encode for proteins involved in gonadal and genital development

47, XXY or 48, XXXY

or mosaic 46, XY/47, XXY

tall and thing; hypogonadism; infertile

[image]

45X, 46Xi

or mosaid 45X/46XX or 45X/46i

shorter stature; webbed neck; infertile

LOSS OF FUNCTION MUTATION

[image]

nondisjunction during mitotic division

presence in individual or tissue of 2 or more cell lines

differ in genetic composition, but are derived from same zygote

*all women express mosaicism with sex chromosomes

derived from two zygotes

both zygotes are normal but genetically distinct

*exchange of material between heterozygotic twins

loss of chromatin

clinical variation based on type and number of genes deleted

maintenance of total chromosome number

partial deletion of 5p

multiple congenital anomalies: microcephaly, round face, hypertelorism

mental retardation; cat-like cry; mewing

partial deletion of 4p

"greek warrior" helmet; retardation; seizures

[image]

velocardiofacial syndrome

*DeGeorge Syndrome

deletion of 22q11.2

*microdeletion*

low-set ears; micrognathia

thymic hypoplasia; parathyroid hypoplasia

[image]

microdeletion of 11p13

Wilm's tumor

Aniridia (absense of iris)

Genitourinary abnormalities

Retardation

reciprocal exchange of fragments between 2 non-homologous chromosomes

--total # of chromosomes remains 46

--carrier is phenotypically normal

philadelphia chromosome (9 & 22)

fatigue, malaise, weight loss

abdominal fullness

bleeding episode

translocation between 2 ACROCENTRIC chromosomes

loss of short arms

reduction of total chromosomes to 45

no consequence to this*

genomic imprinting: maternal 15q imprinted

deletion of paternal 15q11-q13

uniparental disomy: 2 maternal chr. 15s

no paternal chromosome 15

genomic imprinting: paternal 15q imprinted

deletion of maternal 15q11-13

uniparental disomy: 2 paternal chr. 15s

no maternal chr. 15

**high-energy; always smiling and laughing

profound retardation

phenomenon that results in some genes being active only when paternally inherited; others active only when maternally inherited

**methyl group add/sub.

cell inherits a "determinant" that causes it to differentiate along a particular path

--mRNA edcoding transcription facts

--originates from the egg

--may be unequally inherited in daughter cells

*encoded for homeodomain proteins which are major regulatory transcription factors in embryogenesis

-spacial pattern control and partitioning

-axial skeleton and limb formation

-development of the CNS

-development of GI and urogenital tracts

*4 clusters (39 genes)

*direct correlation between cluster position and spatial expression

HOXD13 MUTATION

insertion of an additional digit between 3rd and 4th fingers and 4th and 5th toes; webbing

[image]

HOXA13 MUTATION

shortening of the 1st and 5th digit, hypospadias in males and bicornuate uterus in femals

**some cases of autism and mental retardation have been associated with HOX mutations

occr in clusters (9 genes)

important in development of nervous system, vertebral column, and eyes

MUTATION IN PAX3

eyes wide apart; front white blaze of hair; congenital deafness; limb abnormalities

-anteroposterior patterning, regionalization of brain, limb outgrowth, growth and differentiation

-tyrosine kinase receptors activate MAP kinase signal transduction pathways

craniosynostosis syndrome

mutation in FGF receptor (FGFR2)

premature fusion of cranial structure

hand and foot abnormalities

binds to receptor patched (PTCH), requires smoothened

CNS development, limb outgrowth, L/R axis determination

mutations in SHH can cause holoprosencephaly and limb abnormalities

mutations in PTCH can cause gorlin syndrome

occurs from beginning!

examples: cleft lip, neural tube defects

pits in lower lip, cleft lip, and/or cleft palate

AUTOSOMAL DOMINANT MUTATION IN TRANSCRIPTION FACTOR IRF6

starts out fine, then BAM! external factor disrupts process

examples: amniotic bands compromising limb or digit development, bowel atresia due to vascular accidents

**asymmetric malformations

abnormal mechanical force that distorts an otherwise normal structure

exampless: talipes (club foot) and dislocation of hip

different (twin individuals) sharing the same trait

(discordant if not)

type I

type II

MODY

neonatal

gestational

"insulin-dependent"; auto immune destruction of B-cells in pancreatic islets that produce insulin

major loci: HLA, INS VNTR (insulin repeats)

12-20 minor susceptibility loci

only some are insulin-dependent

no major predisposing loci

many positive variants in minor loci

additive effect of environment and multiple minor susceptibility loci

autosomal dominant

mutations in glucokinase genes

mild hyperglycemia

**transcription factors needed for proper B-cell development

transient form: overexpression of paternally-inherited gene 6q24

permanent form: caused by mutations in KCNJ11 or ABCC8, which are ATP-sensitive potassium channels in B-cells (constitutively open, no insulin release)

results from atherosclerosis

multifactorial:

high cholesterol, lack of exercise, smoking

high LDL/low HDL

major loci: LDLR, MEF2A

defects in neuronal ion channels:

K+

NA+

Cl-

nicotinic ACh receptor/CA2+

most common form of dementia

amyloid plaques

neurofibrillary tangles

loss of cholinergic neurons

Single gene mutations: APP, PRESENILIN

Susceptibility genes: APOE, LRP, a2-macroglobulin

most common psychotic disorder

mood swings/depression

genetic component in approx. 60% of cases DRD4

(dopamine D4 receptor gene)

DRD4.4 - most common

DRD4.2 - assoc. with unipolar depression

DRD4.7 - assoc. with ADHD and schizophrenia

121 million worldwide/4th leading cause of disease burden

short form/allele 5-HTT (serotonin transporter)