11 M

11.1 Manhattan Plot

This article is adapted Wikipedia, the free encyclopedia:https://en.wikipedia.org/wiki/Manhattan_plot

A Manhattan plot is a type of scatter plot commonly used in genome-wide association studies (GWAS) to display significant SNPs (single nucleotide polymorphisms). The data being plotted has some unique features because

  1. All values are non-negative
  2. Most values are low
  3. Researchers are interested in only the highest values, which indicate SNPs which are near parts of a genome of potential biological importance.
## Load packages and data
#install.packages("qqman")
library(qqman)
data(gwasResults)

# ## Investigate results
# dim(gwasResults)
# names(gwasResults)
# 
# 
# ## Distributio of P values
# #hist(gwasResults$P)
# 
# # Make Manhattan plot
# manhattan(gwasResults)

manhattan(gwasResults,
          annotatePval = 0.005, 
          main = "Manhattan Plot", 
          ylab = "Significance",
          annotateTop = TRUE)

Manhattan plots get their name from the similarity of such a plot to the Manhattan skyline: a profile of skyscrapers towering above the lower level “buildings” which vary around a lower height.

11.1.1 GWAS

In GWAS Manhattan plots, genomic coordinates are displayed along the X-axis, with each dot on the Manhattan plot signifies a SNP. The Y-axis represents the strength statistical significance of the SNP-phenotype association. The different colors of each block usually show the extent of each chromosome.

11.2 Talking Glossary: Microarray

https://www.genome.gov/genetics-glossary/Microarray-Technology

Microarray technology is a developing technology used to study the expression of many genes at once. It involves placing thousands of gene sequences in known locations on a glass slide called a gene chip. A sample containing DNA or RNA is placed in contact with the gene chip. Complementary base pairing between the sample and the gene sequences on the chip produces light that is measured. Areas on the chip producing light identify genes that are expressed in the sample.

Image: https://www.genome.gov/sites/default/files/tg/en/illustration/microarray_technology.jpg

Audio: https://www.genome.gov/sites/default/files/tg/en/narration/microarray_technology.mp3

Microarrays are a technology that basically miniaturize processes that have been used in molecular genetics laboratories for years. They allow detection of DNA or RNA molecules by hybridizing or sticking to target DNA molecules or RNA molecules on a glass slide, with detection of that adherent DNA or RNA molecule by various labels or dyes that allow them to be seen under a microscope.

Leslie G. Biesecker, M.D.

11.3 Talking Glossary: Missense Mutation (1.25 min)

https://www.genome.gov/genetics-glossary/Missense-Mutation

Abstract: “A missense mutation is when the change of a single base pair causes the substitution of a different amino acid in the resulting protein. This amino acid substitution may have no effect, or it may render the protein nonfunctional.”

Image: https://www.genome.gov/sites/default/files/tg/en/illustration/missense_mutation.jpg

Audio: https://www.genome.gov/sites/default/files/tg/en/narration/missense_mutation.mp3

Transcript: “A missense mutation is a mistake in the DNA which results in the wrong amino acid being incorporated into a protein because of change, that single DNA sequence change, results in a different amino acid codon which the ribosome recognizes. Changes in amino acid can be very important in the function of a protein. But sometimes they make no difference at all, or very little difference. Sometimes missense mutations cause amino acids to be incorporated, which make the protein more effective in doing its job. More frequently, it causes the protein to be less effective in doing its job. But this is really the grist of evolution, when missense mutations happen, and therefore small changes, frequently small changes in proteins, happen, and it happens to be that it improves the function of a protein. That will sometimes give the organism that has it a competitive advantage over its colleagues and be maintained in the population.”

Christopher P. Austin, M.D.

11.4 Talking Glossary: Mitochondrial DNA (1.5 min)

https://www.genome.gov/genetics-glossary/Mitochondrial-DNA

Abstract: “Mitochondrial DNA is the small circular chromosome found inside mitochondria. The mitochondria are organelles found in cells that are the sites of energy production. The mitochondria, and thus mitochondrial DNA, are passed [almost always - but there are exceptions!] from mother to offspring.”

Note: Mitochondrial DNA is frequently used in population genetics and phylogenetics. Its almost always (like 99.999999% of the time) inherited maternally which has useful properties when constructing phylogenies and tracing the history of populations.

Image: https://www.genome.gov/sites/default/files/tg/en/illustration/mitochondrial_dna.jpg Mitochondria and mitochondrial genome.

Audio: https://www.genome.gov/sites/default/files/tg/en/narration/mitochondrial_dna.mp3

Animation: https://youtu.be/TiqTAfHhOCo

Transcript: “Inside the mitochondrion is a certain type of DNA. That’s different in a way from the DNA that’s in the nucleus. This DNA is small and circular. It has only 16,500 or so base pairs in it. And it encodes different proteins that are specific for the mitochondrial. Now, remember those pathways that are within the mitochondrion for producing energy. Some of the enzymes in those pathways, and some of the proteins that are needed to function in those pathways, are produced by the mitochondrial DNA. The mitochondrial DNA is critically important for many of the pathways that produce energy within the mitochondria. And if there’s a defect in some of those mitochondrial DNA bases, that is to say a mutation, you will have a mitochondrial disease, which will involve the inability to produce sufficient energy in things like the muscle and the brain, and the kidney. Mitochondrial DNA, unlike nuclear DNA, is inherited from the mother [almost always - but there are exceptions!], while nuclear DNA is inherited from both parents. So this is very helpful sometimes in determining how a person has a certain disorder in the family. Sometimes a disease will be inherited through the mother’s line, as opposed to both parents. You can tell from a pedigree or a group of family history whether or not this is a mitochondrial disease because of that.”

William Gahl, M.D., Ph.D.

11.5 Talking Glossary: Mutagen (0.5 min)

Abstract: “A mutagen is a chemical or physical phenomenon, such as ionizing radiation, that promotes errors in DNA replication. Exposure to a mutagen can produce DNA mutations that cause or contribute to diseases such as cancer.”

Audio: https://www.genome.gov/sites/default/files/tg/en/narration/mutagen.mp3

Transcript: “A mutagen is a chemical or physical agent that has the ability to change our genetic code in a harmful way. The change in the genetic code is called a mutation, and throughout our lifetime we actually accumulate many mutations within our cells. And our body has the ability to recognize and repair these mutations. However, if some of these mutations escape repair, they can cause a normal cell to be transformed to become a tumor cell. Therefore, mutations are actually associated with the development of cancer.”

Daphne W. Bell, Ph.D. Photo: https://i.irp.nih.gov/pi/0012727407.jpg

11.6 Talking Glossary: Mutation (0.5 min)

Abstract: “A mutation is a change in a DNA sequence. Mutations can result from DNA copying mistakes made during cell division, exposure to ionizing radiation, exposure to chemicals called mutagens, or infection by viruses. Germ line mutations occur in the eggs and sperm and can be passed on to offspring, while somatic mutations occur in body cells and are not passed on.”

Audio: https://www.genome.gov/sites/default/files/tg/en/narration/mutation.mp3

Image: Sequence-scale mutations (“micro”) versus chromosome-scale mutations (“macro”) https://www.genome.gov/sites/default/files/tg/en/illustration/mutation.jpg

Transcript: “Mutation has been the source of many Hollywood movies, but it’s really a simple process of a mistake made in a DNA sequence as it’s being copied. Some of that’s just the background noise that DNA copying is not perfect, and we should be glad of that or evolution couldn’t operate. But mutation can also be induced by things like radiation or carcinogens in a way that can increase the risk of cancers or birth defects. But it’s pretty simple; it’s basically an induced misspelling of the DNA sequence. That’s a mutation”

Francis S. Collins, M.D., Ph.D.