G-Non-mendelian inheritance

lecture

principles of mendelian inheritance

law of segregation : the 2 alleles are placed in different gametes

law of independent assortment : inheritance of one gene does not affect another

law of dominance : when 2 diff alleles are present only one is expressed = dominant

define mosaicism

=presence of 2 or more cell populations with diff genotypes in an individual whe has developed from a single zygote (happens post zygote)

variant can occur in a single cell and divide to produce cells different from the og zygote

dev stage/timing influences phenotype, distribution and likelyhood of transmission

benign variant

• removed by repair/apoptosis

• expression is not relevant to the tissue function

• small proportion (not manifested)

pathogenic variant

• occur earlier in dev

• greater proportion of affected cells

• = impact on phenotype

variants that occur later in adulthood can transfer cells with malignant potential = cancer

germline mosaicism

all or a portion of the individuals gamets harbor the variant for a condition but not somatic cells

if only germline → typically unaffected with disorder

pts blood and other tissue = normal

variatn transmittable to offspring → not mosaic

only suspected when 2 or more affected, non-mosaic children are born

commonly seen with autosomal dominant and X-linked disorders

define chimerism

organism whose cells are derived from 2 or more zygotes

recipients of tissue or organ transplants are artificial chimeras

can result in male and female organs, 2 blood types, subtle variations in form…

define genetic anticipation

=disorders that increase in severity or have earlier age of onset in successive generations

in some disorders, the sex of the transmitting parent can influence the severity/age of onset

cause

• dynamic type of abnormal variant can arise = unstable repeat expansion

• tandemly repeating untis of 3 or more nucs in or around a gene increase beyond normal range

• larger # repeats = higher likelyhood of expansion

• unstable in meiosis and mitosis

trinucleotide repeat expansion

tend to grow progressively longer due to slippage during DNA replication

replicating strand detaches and reataches at a different spot causing a loop = expansion

can also occur during DNA repair, transcription and other processes

define genomic imprinting

both maternal and paternal genes are required for normal fetal mammalian dev

some genes are turned on or off depending on which parent they came from to control their expression (epigenetics likr DNA methylation and modification of histones)

inherit only 1 working copy in imprinted genes

imprints are established in the germline (in oogenesis or spermatogenesis

imprints are maintained during embryonic dev and into adulthood

but reased in primordial germ cells before new imprints are set

uniparental disomy

inheritance/presence of both homologous chroms of a pair from one parent and none from the other

rare because it generally requires 2 independent events to happen

• nondisjunction in meiosis i or ii to form abn gametes

• after fertilization rescue or monosomy or trisomy

  • trisomy rescue = got 2 crhoms from parent 1 and 1 from parent 2. the homologue from parent 2 is removed to have disomy but both chroms are from same parent

  • monosomy rescue = the monosomic chrom is duplicated to have 2 copies but → both from same parent

nost UPD cases will have no affect

but if theres an imprinted gene involved → phenotype

define X chromosome inactivation (XCI)

happens early in female embryonic dev

random in each somatic cell (paternal or maternal)

super condensed structure in interphase → barr body

non-random XCI happens when theres a structural abn to keep one full copy of X and the rest silenced

highly variable penetrance of X-linked traits in females due to skewed inactivation of parental Xs

X-linked recessive conditions affect males much more commonly

fmales are either carriers or need both copies to be affected

rarely XCI can skew to express variant X -→manifesting heterozygote

define mitochondrial inheritance

mtDNA is ds and circular floating in mitochondrias

sperm mitochondria are generally eliminated from embryo so only maternal inheritance

replicative segregation

• mtDNA replicate and sort randomly among newly synthesized mito during mitosis and meiosis

• new mitos distributed randomly between daughter cells

homoplasmy = cell contains only normal or only variant mtDAN

heteroplasmy = cell contains a mixture of normal and variant mtDNA

mitochondrial disease

• can result in severe disease

• can be inherited or de novo

• affects many different tissues and involves many organ systems

• only manifests when critical threshold exceeded

• variantion in presentation and severity between individuals (including siblings