Genetics and genomics

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Genomes

DNA genomes

Linear

Double stranded: Humans

SIngle stranded: Parvovirus

Circular

Double stranded: E. Coli

Single stranded: M13 bacteriophage

RNA genomes

Double stranded: bluetongue virus

Single stranded: retrovirus

 

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Retrovirus structure

  • They have an envelope protein, a reverse transcriptase, and a capsid with RNA
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Small genomes

  • The smallest free living genome is pelagibacter ubique, at 1389 genes
  • The smallest genome is nasuia deltocephalinicola, at 112 kb.
  • Polyomavirus and phi X174  have overlapping genes to pack maximal information into minimal space.
  • Most bacteria have a single chromosome and plasmids.
  • Some have additional replicons (megaplasmids or minichromosomes)
  • Sometimes, the plasmid DNA count is higher than the chromosomal DNA count.
  • Bacterial chromosomes have a single origin of replication, but genes closer to the origin of replication have higher copy numbers. 
  • Resultantly, essential genes are kept near the origin of replication
  • Genes are oriented in the direction of replication to prevent collisions between enzymes
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The minimal genome

  • The minimal genome is the theoretical minimal set of genes required to sustain cellular life. 
  • Genes are divided into essential genes and genes that, while not necessary, give an advantage.
  • An M. Genitalium genome was produced in vitro and introduced into a host cell, marking the genome with tet resistance and lacz.
  • The host cell will eject either the orignal or synthetic genome as it doesn't want to have 2, but due to the markers, the original will be ejected.
  • The lacZ makes the desired colonies appear blue.
  • They called it synthia, and the current iteration has fewer than 500 genes.
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The human genome

  • Has 3200 megabases of DNA
  • The Tetroadon has a similar chromosome number to humans, but the genes are all on different chromosomes
  • Only 1.5% of the genome is translated, and we don't know how much of the genome is transcribed.
  • 95% of human genes have multiple transcripts, which is known as differential splicing.
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Bases

  • DNA contains thymine and not uracil because cytosine can be deaminated to uracil, and the body wouldn't be able to detect it if there was uracil there already.
  • RNA keeps uracil as it costs much less to produce in energy terms than thymine does.
  • 10* of cytosine in DNA is methylated, but only those 5' of guanidine residues (5'  CpG  3')
  • They are rare in the vertebrate genome. 
  • There are 2 types of methylation:
  •                    Maintenance methylation - Methyl groups added to new DNA opposite methyl                                                                       groups on the parent strand.
  •                    De novo methylation - Methyl groups added to the chromosome, repressing gene activity by binding to methyl CpG-binding proteins, which then recruit histone deacetylases.
  • Unmethylated CpG regions are called CpG islands.
  • CpG islands disappear in inactive genes because the inactivation is caused by methylation, which sets up the C to be deaminated to T. Can't happen if CpG isn't methylated.
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Genes can be present in different structures...

1. Repeated gene clusters

  • E.G. The rRNA 5.8S 18S and 28S genes - The cluster is repeated many times identically.
  • It is done for gene products needed in high amount, and can be compared to increased copy number in prokaryotes.

2. Multigene families

  • e.g. Beta globin, which has different varients of the same protein expressed throughout an organisms life time: Embryonic/fetal/adult
  • One of the genes in this example is a pseudogene

3. Pseudogenes

  • A mutation in a gene sequence causes it to be non-functional.
  • Mutations continue to accumulate.
  • Processed pseudogenes are from retroviral RNA that was converted to DNA and then reincorporated back into the genome, forming a gene with no introns or promoters.

4. Gene fragments - incomplete sections of genes

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Interspersed repeated intergenic DNA

  • Repeat units found throught the DNA, seperated by inter-repeat regions.
  • Short ones (SINES), have a frequency of 1.5 million in a genome.
  • Long ones (LINES), have a frequency of 900,000.
  • Long terminal ones (LTRs), have a frequency of 300,000.
  • They are formed by transposable elements that accidentally leave a copy behind when they are transposed to a different part of the genome.
  • They move through the use of an RNA intermediate.
  • A fourth type (f = 300,000) does not use an RNA intermediate: the DNA transposon.
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Tandemly repeated extragenic DNA

  • They can form in microsatellites, minisatellites, or satellites (size order).
  • Microsatellites are caused by replication slippage, where the two strands become misaligned by the DNA polymerase and extra repeats are added or deleted.
  • The length of these repeats is unique to an individual; DNA fingerprinting.
  • In DNA fingerprinting, the allele frequency must be considered.
  • If a match is of a high frequency allele, the match is much less significant than if it was a low frequency allele.
  • If a suspects two alleles are different, the probability must be multiplied by 2.
  • The prosecutor's fallacy confuses the probability that a person will have a matching fingerprint with the probability that they are guilty. 
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Gene expression

  • Transcription of genes involves 5' capping and polyA tailing.
  • Introns are transcribed but not translated. 
  • An example of a gene that undergoes differential splicing is the human slo gene, which produced 500 different transcripts.
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Splicing

  • All introns are preceded by a 5' splice site and succeeded by a 3' splice site, which itself is preceded by a polypyrimidine tract.

1. A cut made at the 5' end branches and bonds with an A in the middle of the intron through hydroxyl attack.

2. A bond forms between the 5' and 3' splice site.

3. The intron is debranched and degraded.

  • Small nuclear RNAs (SnRNA) play an important role as part of the spliceosome complex.
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Introns

  • Different types of introns, such as the GU-AG introns, work in different places.
  • Two hypotheses exist for the fate of introns:
  •                            Early hypothesis - introns are ancient and are being lost
  •                            Late hypothesis - introns are recent and are accumulating (more evidence                                                                for this). 
  • Introns can actually contain genes, which are translated before splicing.
  • Twintrons are introns within introns, and are spliced separatley, with the internal intron going first.
  • Examples of introns in genes:
  •            Insulin - has 2 introns that take up 70% of the gene.
  •            Dystrophin - Has 78 introns that take up 98% of the gene. 
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Small nucleolar RNAs

  • E.G. snoRNA
  • It is used to modify rRNAs, such as through methylation.
  • It can also do pan-editing, which is where an extra nucleotide is added through the snoRNA acting as a guide RNA.
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Micro RNA

  • aka miRNA
  • These are bits of RNA that bind to the untranslated region between the stop codon and the polyA tail.
  •              It stops translation, suppressing gene expression through causing the removal of the                 polyA tail.

1. miRNA made as a long molecule.

2. It folds up into stem loops.

3. An enzyme called Drosha cuts it into miRNA precursor.

4. These are cut by a dicer, which produces the miRNA

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Short interfering RNA

  • aka siRNA

1. Double stranded viral RNA is cut by dicer nuclease.

2. The siRNA fragments that result, once they have been made into a single strand, attach to the viral mRNA

3. This causes incorporation into the RISC complex.

4. Argonaute cuts the mRNA opposite to where the siRNA has bound.

  • This is called RNA interference (RNAi).
  • The double stranded RNA can actuallty be made by transcribing the gene in both directions, therefore artificially triggering RNAi.
  • It is about 20bp long, and is important for research as you can use it to knockdown a gene to see its function,
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