8: genetics and inheritance

allele

copy of a gene

mendelian genetics

based on inheritance of chromosomes and genes following meiosis and fertilization

what mutation typically causes defects and affects multiple organ systems

chromosome

what mutation depends on type and location of change and may be conditional

single gene mutation

epigenetic change

• chemical modifications of DNA that affect expression without altering sequence

• typically DNA methylation

• can permanently change gene expression

• can be inherited by daughter cells

what are the mendelian phenotypic patterns of inheritance

• autosomal

• sex-linked

• recessive

• dominant

• monogenic

non-mendelian phenotypic pattern of inheritance

• imprinting (epigenetic)

• mitochondrial

other phenotypic patterns of inheritance

• anticipation

• syndromic

• sporadic/spontaneous

• digenic/multigenic

autosomal inheritance

based on variation of single genes on regular chromosomes

sex-linked inheritance

based on variation of single genes on sex-determining chromosomes

cytoplasmic inheritance

based on variation of single genes on organelle’s chromosomes

what are ways a protein loses function

• mutation on the active site

• mRNA or protein is unstable

• protein is not made or does no accumulate

recessive mutation

if presence of normal allele totally compensates for reduction in functional gene product

semi-dominant mutation

if normal allele only partially compensates

gain of function mutations

• often dominant

• presence of normal allele cannot overcome abnormal function of mutant protein

• presence of mutant allele may interfere w/ normal function

• present of mutant may have new, undesirable functions

what are some examples of recessive diseases of the eye/retina

• Leber’s Congenital Amaurosis

• Retinitis Pigmentosa

• Usher’s syndrome

• Congenital Stationary Night Blindness

• Bardet-Biedel Syndrome

where are recessive diseases more often found

small, isolated communities such as small islands, ethnic groups with little outside communication, religious communities

why are recessive mutations more often found in isolated communities

• higher probability of incestual relationships

• higher prob that individual gets mutant copy from both parents

why are some recessive mutations present at unusually high frequencies in general population

• typically bc being heterozygous for mutant confers some selective advantage

• ex. heterozygotes for sickle cell are resistant to malaria

dominant mutation

• mutant masks function of normal allele

• may add deleterious function that is fully expressed

• heterozygotes and homozygotes for mutated allele show same phenotype

semi-dominant mutation

• heterozygotes have intermediate phenotype that is less severe than homozygotes

• haplo-sufficient

co-dominant

both alleles are fully expressed

pedigree features for autosomal dominant disease

• disease phenotype present in every generation

• both males and females affected

• affected individuals have 1 affected parent

• 2 unaffected parents means all children are unaffected

pedigree features for autosomal recessive disease w/o consanguineous relationship

• parents and children of disease person not affected

• diseased person may have siblings w/ disease but usually less than 1 in 4

pedigree features for autosomal recessive disease w/consanguineous relationship

• diseased person has one or more siblings affected

• no one in previous generation affected

examples of dominant diseases w/ocular involvement

• some forms of retinitis pigmentosa

• axenfeld-rieger syndrome

• blepharoptosis

• fuchs endothelial corneal dystrophy

• familial exudative vitroretinopathy

• vitroretinochoroidopathy

semi-dominant diseases with ocular involvement

• aniridia

• marfan’s syndrome

features of x-linked recessive disease

• mutation on X chromosome

• most often seen in males

• generation skipping pattern in pedigree

• affected males have unaffected sons and daughters

• 100% of daughters are carriers

• affected female must have father with disease and heterozygous carrier in mother

mosaicism

• patches of cells with different phenotypes and/or genotypes

• common w/X-linked genes

what causes mosaicism in female carriers

x-inactivation

why does x-inactivation occur

cells must maintain same level of transcription from X chromosome genes in males and females

X-inactivation methods

• random inactivation (lyonization) in females

• during development, one X in female cells is inactivated

• forms barr bodies (highly methylated)

disease w/ trinucleotide repeat expansion

• manifests once number of trinucleotide repeat units reaches ‘disease size’ on one allele

• inheritance pattern: dominant or x-linked with ‘anticipation’ (premutation in one generation anticipates expansion to disease size in future generation)

sperm mitochondria

• highly specialized

• does not enter oocyte at fertilization

oocytes mitochondria

• many mitochondria in cytoplasm

• fertilized egg and embryo gets all mitochondria from oocyte

typical pedigree for mitochondrial inheritance

• mutations in mitochondrial genes on autosomes typically have autosomal recessive inheritance

• mutations in mitochondrial genes on X chromosome follow X-linked inheritance

mitochondrial diseases affecting the eye

• cataract

• retinopthy

• optic atrophy

• cortical visual loss

• ptosis

• opthalmoplegia