Mendelian Patterns of Inheritence Flashcards
single gene
a particular genotype at one locus is both necessary and sufficient for the character to be expressed, given an otherwise normal genetic and environmental background
-1.25%
chromosomal disorder
- due to problems at the chromosomal level-deletions, translocations
- 0.4%
multifactorial disorders
- many characters are dependent on a variety of genetic and environmental factors
- 65%, 6% congenital
relatedness
- two individuals that are first degree relatives share half their genes
- second degree= 1/4 genes
- travel down and across pedigrees as long as not a marriage line
mendels first law of segregation
-we are equally related to our siblings as we are to our parents
phenotype
-genotype and environment
allelic (genotypic) heterogeneity
- 2 different mutant alleles at same locus
- same gene, different mutation, same disease
- CFTR-1900+ mutations-all result in CF
locus heterogeneity
- mutations at 2+ loci that produce the same or similar phenotype
- different gene, same phenotype (different mutations)
- retinitis pigmentosa- RP2 on Xp, RP28 on 2p and RP5 on 3q; over 30 RP loci
clinical (phenotypic) heterogeneity
- association of more than one phenotype with mutations at a single locus
- severity of a disease
- different disease from mutations in same gene
- same gene, different mutation, different disease
- multiple endocrine neoplasia II result from different mutations at RET gene 10q11.2
Hirschsprung disease
- absence of ganglionic cells
- severe constipation, intestinal obstruction, massive dilation of colon
- loss of function mutation on RET gene, more often in males
- autosomal dominant
Multiple endocrine neoplasia II (MENII)
- thyroid cancer, pgeochromocytoma (benign adrenal medulla tumor), hyperplasia of parathyroid gland
- autosomal dominant
- mutations are at cysteins at codons 609,618,620 of RET gene
- alter membrane specificity
Variable expression
- different mutations of same gene (genotypic phenotypic heterogeneity)
- can be as mild as normal female or male with no vas deferens to classic CF
modes of inheritence
- autosomal dominant
- autosomal recessive
- X-linked dominant/recessive
- codominant
- mitochondrial
- Y-linked
- sex limited
autosomal dominant
- phenotypically expressed in heterozygotes
- carriers express gene
autosomsal recessive
-trait or gene that is expressed only in homozygotes and compound heterozygotes
codominant
-both alleles are expressed in heterozygous state
dominance and recessive
- properties of characters, not genes
- if product from heterozygote isn’t enough to cross threshold, mutation is dominant
- if product from heterozygote is enough to cross threshold, disease is recessive
deaf and blind
- homozygotes and compound heterozygotes are blind and deaf but heterozygotes are only deaf
- blindness is revessive and deaf is dominant
autosomal dominant inheritance criteria
- most affected individuals will be heterozygotes
- expressed in every generation, but more likely to have reduced penetrence compared to a recessive
- half of the offspring of an affected individual are affected (recurrence risk of 50%)
- affected individuals usually have affected parents
- male to male transmission indicated not likely X-linked
autosomal recessive inheritance criteria
- expect both parents of affected individuals to be carriers
- affected individuals usually have asymptomatic parents
- may appear as sporadic
- often more severe than dominant disorders
- if rare disease, parents more likely to be consanguinous
- recurrence risk is 25%
- affecteds have two mutations-homozygotes or compound heterozygotes
compound heterozygote
- 2 recessive mutations on same gene but arent the same and cause disease
- mom and dad are each carriers for a different CFTR mutation and child results in CF
chance sib is carrier?
- 1st child affected
- 2nd child born and unaffected- 2/3 chance of being a carrier (no chance of having it)
X-linked recessive inheritance
- usually males affected (hemizygous)
- unless an affected male marries a carrier female, or extreme X-inactivation
- all daughters of affected males are carriers
- half the sons of female carriers are affected
- no male to male transmission (pass on y)
- many more affected males than females, mostly males more sever than females (occasionally in extreme x-inactivation results in mildly affected females)
- in genetic lethal diseases, a significant portion of cases are de novo mutations (Haldane’s Rule)
X-linked dominant inheritance
- affected males have normal sons and affected daughters
- twice as many affected females as males in pop
- most affected females will be heterozygous so half their offspring will be affected
- usually more severe or lethal in males
- hypophosphatemic rickets
Y-linked
- apart from male infertility, no/few known y linked diseases
- only males affected, all sons affected
- affected males would have an affected father, all sons affected and no affected daughters
- only about 78 protein coding genes on y
mitochondrial inheritance
- trait appears to be exclusively inherited through females
- all offspring of affected females will probably be affected
- highly mutable compared to nuclear DNA, heteroplasmy (mixed pop of mito) common
- variable expression and can show lack of penetrance
- not inherited from affected males
new mutation
- disease will appear sporadic but will be familial in descendants of affected individuals, but not in earlier generations of other branches of family
- mito have high mutation rate
- estimated that every y chromosome differs by 600 bp from fathers y
- estimated that there are as many as 100-200 new bp changes in each person, and perhaps 1000s of gene conversion events
mosaic
- germline and somatic
- tissue has two or more cell lines of different genotype derived from a single zygote
- mosaicism more common than chimerism
- patchy diseases
- examples in lymphoma and leukemia (PKS)
gonadal mosaicism
-in DMD still significant recurrence rate even if mutation seen in boy is not in mothers blood-mutation is in her germline
chimeric
- derived from cells from 2 different zygotes
- recipient of a bone marrow transplant from donor\
- complete chimerism if all HSCs are from donar
- mixed if donar and recipient HSCs coexist after allotransplantation
- can find a donors XX cell line in the blood of a recipient male
Locus
- position of a gene on a chromosome
- different forms of a gene (alleles) may occupy the locus
Expressivity
The extent to which a genetic defect is expressed, mild to severe but never completely unexpressed
Penetrance
All of none expression of a genetic disease genotype
Polymorphism
-occurrence together in a population of two or more alleles, each at a frequency greater than 1% so that the heterozygous frequency is at least 2%. Alleles with a frequency are called rare genetic variants
-particularly useful in linkage studies when cannot find disease causing mutations
-over 60% of all loci exhibit polymorphisms
Used for: mapping genes to chromosomes, presymptomatic and prenatal diagnosis, carrier detection of heterozygotes
Examples of polymorphisms
- single nucleotide polymorphisms SNPs
- microsattelite, variable number of tandem repeats
Pleiotropy
- multiple phenotypic effects of allele or gene on tissues/systems not ordinarily thought to be related
- reflects the diversity of cell types that use a common molecular pathway for transcriptional regulation
- nearsightedness and malformation of sternum seen in Marfan due to fibrillin gene mutation
Haldane’s Rule
- three rules: x-linked, genetic lethal, neg relevant family history
- boy is 1/3 chance of de novo mutation, 2/3 chance mom is carrier
- gonadal mosaicicm can affect carrier status–can be in germline.
Haldane exceptions
- mutation only in males- no de novo, all moms carriers
- mutation only in females- 1/2 boys will be new mutations and 1/2 mom carriers
