Non-Mendelian Inheritance

Mitochondria

Chloroplasts

Examples of non-Mendelian inheritance

Human mtDNA defects

Other forms of non-Mendelian Inheritance:

Infectious cytoplasmic inheritance

Maternal effect

Genomic (parental) imprinting

Extranuclear Genomes:

Mitochondria (animals and plants)

Chloroplasts (plants)

1. Mitochondria and chloroplasts occur outside the nucleus, in the cytoplasm of the cell.

2. Contain genomes (mtDNA/cpDNA) and genes, i.e., extrachromosomal genes, cytoplasmic genes, organelle genes, or extranuclear genes.

3. Inheritance is non-Mendelian (e.g., cytoplasm typically is inherited from the mother).

Origin of mitochondria and chloroplasts:

Both mitochondria and chloroplasts are believed to be derived from:

Endosymbiotic bacteria = free-living prokaryotes that invaded ancestral eukaryotic cells and established a mutually beneficial relationship.

1. Mitochondria - derived from a photosynthetic purple bacterium that entered a eukaryotic cell >billion years ago.

2. Chloroplasts - derived from a photosynthetic cyanobacterium.

Organization of the mtDNA genome:

• mtDNAs occur in all aerobic eukaryotic cells and generate energy for cell function by oxidative phosphorylation (OXPHOS) producing ATP.

• Most mtDNA genomes are circular and supercoiled (linear mtDNAs occur in some protozoa and some fungi).

• In some species %GC is high, allowing easy separation of pure mtDNA from nuclear DNA by gradient centrifugation.

• mtDNAs lack histone-like proteins (like bacteria).

• Copy number is high, multiple genomes per mitochondria and many mitochondria per cell (makes mtDNA easy to isolate and PCR).

• Size of mtDNA varies widely.

• Humans and other vertebrates ~16 kb(all of the mtDNA codes gene products)

• Yeast ~80 kb• Plants ~100 kb to 2

Mb (lots of non-coding mtDNA)

Replication of the mtDNA genome:

• Replication is semi-conservative (like nuclear DNA replication) and uses DNA polymerases specific to the mitochondria.

• Occurs throughout the cell-cycle (not just S phase).

• Control region (non-coding) forms a displacement loop (d-loop) that functions in mtDNA replication.

• Mitochondria (organelle) are not synthesized de novo, but grow and divide like other cells (e.g., mitosis).

Fig. 23.3, mtDNA replication

Contents of the mtDNA genome:

• mtDNA contains genes for:

• tRNAs• rRNAs• cytochrome oxidase, NADH-dehydrogenase, & ATPase subunits.• mtDNA genes occur on both strands.• Functions of all human mtDNA ORFs are assigned.

• Mitochondria’s genetic information also occurs in the nuclear DNA:

• DNA polymerase, replication factors• RNA polymerase, transcription factors• ribosomal proteins, translation factors, aa-tRNA synthetase• Additional cytochrome oxidase, NADH, ATPase subunits.

• Most required mitochondrial (and chloroplast) proteins are coded by nuclear genes in the nuclear genome.

• Copies of the true mtDNA genes can be transposed to the nucleus (a distinct set of genes from above):

numtDNA = nuclear mtDNA

Fig. 23.4, Physical map of the human mtDNA

Transcription of the mtDNA genome:

• mRNAs from the mtDNA are synthesized and translated in the mitochondria.

• Gene products encoded by nuclear genes are transported from the cytoplasm to the mitochondria.

• Mammalian and other vertebrate mtDNAs are transcribed as a single large RNA molecule (polycistronic) and cleaved to produce mRNAs, tRNAs, and rRNAs before they are processed.

• Most mtDNA genes are separated by tRNAs that signal transcription termination.

• In plants and yeast (mtDNA is much larger):

• tRNAs do not separate genes• Gaps between genes are large• Transcription is signaled by non-tRNA sequences • Introns occur (do not occur in animal mtDNA)• Some lack a complete stop codon (3’ end is U or UA; poly (A)

tail completes the stop codon)• Transcription is monocistronic

Translation of the mtDNA genome:

• Mitochondria mRNAs do not have a 5’ cap (yeast and plant mt mRNAs have a leader).

• Specialized mtDNA-specific initiation factors (IFs), elongation factors (EFs), and release factors (RFs) are used for translation.

• AUG is the start codon (binds with fMet-tRNA like bacteria).

• Only plants use the “universal” genetic code. Codes for mammals, birds, and other organisms differ slightly.

• Extended wobble also occurs in tRNA-mRNA base-pairing (22 tRNAs are sufficient rather than 32 tRNA needed for standard wobble).

Useful applications of mtDNA:

• Easy to isolate and PCR (high copy #).

• Most mtDNA is inherited maternally. Can be used to assess maternal population structure (to the exclusion of male-mediated gene flow)

• Because it is “haploid” effective population size of mtDNA is 1/4 that of a nuclear gene.

• As a result, mtDNA substitutions fix rapidly (due to genetic drift) and typically show higher levels of polymorphism and genetic differentiation between populations.

Useful for:

• Maternity analysis• Phylogenetic systematics• Population genetics (and conservation genetics)• Forensics (maternal ID)

Chloroplast genomes (cpDNA):

• Chloroplast organelles are the site of photosynthesis and occur only in green plants and photosynthetic protists,

• Like mtDNA, chloroplast genome is:

• Circular, double-stranded• Lacks structural proteins• %GC content differs

• Chloroplast genome is much larger than animal mtDNA, ~80-600 kb.

• Chloroplast genomes occur in multiple copies and carry lots of non-coding DNA.

• Complete chloroplast sequences have been determined for several organisms (tobacco 155,844 bp; rice 134,525 bp).

cpDNA organization:

• Nuclear genome encodes some chloroplast components, and cpDNA codes the rest, including:

• 2 copies of each chloroplast rRNA (16S, 23S, 4.5s, 5S)• tRNAs (30 in tobacco and rice, 32 in liverwort)• 100 highly conserved ORFs (~60 code for proteins required for

transcription, translation, and photosynthesis).

• Genes are coded on both strands (like mtDNA).

cpDNA translation- similar to prokaryotes:

• Initiation uses fMet-tRNA.

• Chloroplast specific IFs, EFs, and RFs.

• Universal genetic code.

Fig. 23.7

cpDNA of rice

Rules of non-Mendelian inheritance for mtDNA and cpDNA:

• Ratios typical of Mendelian segregation do not occur because meiotic segregation is not involved.

• Reciprocal crosses usually show uniparental inheritance because zygotes typically receive cytoplasm only from the mother.

• Genotype and phenotype of offspring is same as mother.

• Paternal leakage occurs at low levels and usually is transient; mechanisms that degrade paternal mtDNA/cpDNA exist.

• Heteroplasmy (mixture of mtDNA/cpDNA organelles with different DNA substitutions) results in rare cases.

http://bmj-sti.highwire.org/content/77/3/158.full

Examples of non-Mendelian inheritance:

• Variegated-shoot phenotypes in four o’clocks

Fig. 23.8b

Normal chloroplastGreenphotosynthetic

Mutant chloroplastWhitenon-photosynthetic

Mixed chloroplastsWhite/green

Fig. 23.9

Chloroplasts are inherited via the seed cytoplasm

3 types of eggs (female):

NormalMutantMixed

Assumption:

Pollen (male) contributes no information

Examples of non-Mendelian inheritance:

• Mutant [poky] Neurospora possess altered mtDNA cytochrome complements that lead to slow growth.

• [poky] phenotype is inherited with the cytoplasm.

Fig. 23.10, Reciprocal crosses of poky and wild-type Neurospora.

protoperitheca (sexual mating type)

conidia(asexual mating type)

Examples of maternally inherited human mtDNA defects:

• Leber’s hereditary optic neuropathy (LHON), OMIM-535000

• Mid-life adult blindness from optic nerve degeneration.• Mutations in ND1, ND2, ND4, ND5, ND6, cyt b, CO I, CO II, and

ATPase 6 inhibit electron transport chain.

• Kearns-Sayre Syndrome, OMIM-530000

• Paralysis of eye muscles, accumulation of pigment and degeneration of the retina, and heart disease.

• Deletion of mtDNA tRNAs.

• Myoclonic epilepsy & ragged-red fiber disease (MERRF), OMIM-545000

• Spasms and abnormal tissues, accumulation of lactic acid in the blood, and uncoordinated movement.

• Nucleotide substitution in the mtDNA lysine tRNA.

Most individuals with mtDNA disorders possess a mix of normal and mutant mtDNA, therefore severity of diseases varies depending on the level of normal mtDNA.

Exceptions to maternal inheritance:

• Heteroplasmy, mice show paternal DNA present at 1/10,000 the level of maternal DNA.

• Occurs when mtDNA from sperm leak into egg cytoplasm at the time of fertilization.

• In these cases, maternal and paternal mtDNA can recombine!

• Paternal inheritance of chloroplasts commonly occurs in some plants (e.g., gymnosperms).

www.sciencemusings.com/

Maternal effect:

Some maternal phenotypes are produced by the nuclear genome rather than the mtDNA/cpDNA genomes.

• Proteins or mRNA (maternal factors) deposited in the oocyte prior to fertilization; these are important for development.

• Genes for maternal factors occur on nuclear chromosomes; no mtDNA is involved (not epigenetic).

• e.g., shell coiling in the snail Limnaea peregra.

• Determined by a pair of nuclear alleles; D produces dextral (right-handed) coiling, d produces sinistral (left-handed) coiling.

• Shell coiling always is determined by the maternal genotype, not the alleles that the progeny carry or maternal phenotype.

• If coiling were controlled by extranuclear gene (e.g., mtDNA), progeny would always have the same phenotype as mother.

• Cause-female snail deposits products in the egg that regulate orientation of mitotic spindle and direction of cell cleavage.

Fig. 23.17

dextral sinistral

*****dextral ***** *****dextral *****

Maternal effect:

• mRNAs coded by maternal genes (not offspring) are essential for normal structural development and axis orientation.

• Placement of bicoid mRNA determines anterior end of developing Drosophila embryo.

http://scienceblogs.com/pharyngula/2006/06/maternal_effect_genes.php

Genomic (parental) imprinting:

• Expression of genes (or alleles) is determined by whether the gene is inherited from the father or mother.

• Results in expression of single allele (either from father or mother).

• Mechanism is entirely different from maternal effect (e.g., dextral/sinistral coiling of snail shells).

• One allele frequently suppressed by methylation.

• Prader-Willi syndrome, OMIM-176270

• Common in various cancers

Transovarial disease transmission - a type of maternal inheritance:

• Infected cytoplasm infects the egg and is transmitted to offspring.

• Many insect-vectored diseases show transovarial transmission.

• Example - eggs and larvae of mosquitoes infected with West Nile Virus also are infected.

http://gsbs.utmb.edu/microbook/ch056.htm