genetics in medicine

BIOL429

modern medical genetics

application of genetic principles to medical practice

medical genetics main aspects

patient symptoms, familial history, molecular basis of disease

gene (genetics definition)

something that encodes a specific trait containing 2 alleles, one from each parent

gene (molecular definition)

unit that encodes a specific protein, carries out gene function, forms outward manifestation of trait

heredity

transmission of trait from parent to offspring

single gene disorder

arise from mutation of one gene that can be tracked through families. phenotype is determined by genetics

multifactorial gene disorder

more than one gene is affected, environmental factors contribute to disease phenotype

chromosomal disorders

part of chromosome is lost or gained, they rearrange or translate, spontaneous and not inherited

mitochondrial disorders

caused by mutations in mitochondrial DNA, inherited maternally, easily tracked

infectious diseases

disease that can be contagious, virus, bacteria, can be treated

non-infections diseases

genetic disorders, cannot be transmitted, are inherited

model system

lower organism used for biological study because functions at the cellular level are very similar to humans

mutation

accidental change in gene sequence, can be inherited

allele

variant of gene that has a different nitrogenous base sequence

gene pool

all alleles in a given population for specific gene

Gregor Mendel

determined how traits are inherited using pea plants.

Mendel’s 3 laws

law of segregation, law of independent assortment, concept of dominant

Archibald Garrod

first scientist to study human genetic disease

what did Garrod study

Alkaptoonuria, inborn error in metabolism caused by consanguinity

Thomas hunt

first to discover X-linked inheritance

main concerns of modern medical genetics

transmission of traits, molecular mechanisms that lead to trait expression, disruption of molecular mechanisms that cause disease, genetic counsiling

importance of genetic counsiling

risk and prognosis and treatments available

molecular basis of gene expression

DNA→RNA→Protein

four levels which DNA info is used

molecular, cellular, tissue, organismal

how to genes differ from one another

by the number and order of nitrogenous bases

what effects do mutations have

can lead to changes in phenotype, or disease but most have no affect

how has pediatric mortality changed over last century

has increases 16.5%→50% due to vaccines and treatment for infectious diseases

gene expression

expression of gene that causes phenotype

transcription

using DNA template to produce RNA

Translation

using RNA to protuce protein

nucleotide

building block of RNA and DNA

Nitrogenous bases

parts of DNA and RNA, A C G T U

phosphate groups

bound to 5’ carbon by ester linkage, usually 3 p-groups bound

phosphodiester bond

what bonds nucleotides together

DNA Strand

double stranded helix that is antiparallel, includes base pairings

DNA strand direction

5’→3’

DNA double helix

right handed clockwise turn, very close together 10.5 BP per turn

B-type DNA double helix

predominant confirmation, composed of major and minor grooves

major groove

wide and of moderate depth

minor groove

narrow and of moderate depth

promoter

drives and controls transcription of gene

5’ UTR

5’ mRNA regulation, starts translation, untranslated region

3’ UTR

3’ mRNA regulation, stabilizes mRNA, untranslated region

ORF

open reading frame, part of mRNA that is translated

molecular pathology

takes genotypes and understands how they are expressed on molecular level. determined how phenotypes are affected

loss-of-function allele

mutation that leads to non-functional protein

gain-of-function allele

mutation that leads to over functional protein

dominant negative allele

only one copy is mutated but phenotype is caused by loss of function

null allele

nonfunctional DNA sequence that results in no gene product

coding strand

Watson strand, similar sequence to pre-mRNA

noncoding strand

Crick strand, template for transcription

components of nucleotide

5 carbon sugar, Phosphate groups, nitrogenous bases

how nucleotides are polymerized

phosphodiester bonds formed between phosphate group of 1 nucleotide and 5 carbon sugar of another

purines

G+A

pyridines

T+C

how to nitrogenous bases bind to 5-carbon sugar

bound to 1’ carbon by N-glycosidic linkage

RNA polymerase 2

enzyme that transcribes mRNA

three units in mRNA

5’ UTR, ORF, 3’ UTR

RNA produced by transcription in Eukaryotes

mRNA, rRNA and tRNA

processing of mRNA

5’ capping, splicing of introns, 3’ AAA tail

pre-mRNA splicing

removing of introns and exons come togetehr

diversity of alternative splicing

sometimes coding exons are spliced alongside the introns which causes a variety of different RNA to be formed which causes protein diversity.

codon

sequence of three nucleotides that form genetic codes

start codon

AUG, starts translation

stop codon

UAA, stops translation

b-confirmation of DNA

forms in dilute salt concentration, major and minor groove, 10.5 BP per turn, clockwise twist

where to sequence specific DNA proteins bind

they bind on the major groove

A-T H bond acceptors and donors

ADAM

G-C H bond acceptors

AADH

alpha helix

parallel beta sheets

antiparallel beta sheets

unstructured turns

COOH-COOH bond or NH2-COOH bond between beta sheets

pedigree

chart of family

autosome

relating to any of the chromosomes

autosomal dominant

only one copy of gene needed to inherit disease

autosomal recessive

2 copies of gene needed to have disease

x-linked dominant

1 copy of gene on x-chromosome needed to have disease

x-linked recessive

all x chromosomes contain allele for diease

y-linked

copy of disease allele on y chromosome

mitochondrial inheritance

inherited from mother, very rare

penetrance

individuals that have a genotype for disease but do not show it

expressitivity

rate at which phenotype of disease is expressed

age-related penetrance

patient seems healthy but symptoms dont appear until later in life

first degree relatives

parents, siblings, offspring

second degree relatives

grandparents, grandchildren, aunts, uncles, nieces, nephews, half-siblings

third degree relatives

first cousins

proband

affected individual in pedigree

consultand

unaffected individual in pedigree

normal distrubution

±2 std dev from mean, more than likely individual is healthy

quantitative trait

trait that can be measured

qualitative trait

whether or not phenotype appears

autosomal dominant pedigree

both sexes have equal frequency, affected individual=affected parent

autosomal recessive pedigree

both sexes have equal frequency, skips generations, both parents have to be heterozygous for offspring to have diease

x-linked dominant pedigree

both sexes affected, doest skip generations, affected father=all daughters will be affected

x-linked recessive pedigree

males affected more often than females, skips generations, mothers must be carriers for male to be affected, affected dad+carrier mom=affected daughter

y-linked pedigree

only males will be affected, doesnt skip generations

problems of age-related penetrance and single gene disorders

disease phenotype not expressed until older, has time to reproduce offspring before knowing disease exists

male lethality in x-linked disorders

males often die before birth

mosaisism

phenotype is only shown in certain areas