Comparative Endocrinology

• hormones are rarely produced by one tissue/location and rarely have a sing;e target cell/tissue 
• the same hormone does not necessarily bind to the same receptor within different target cells, signal through the same pathway or have the same effect 
• hormones signal to cells, signal to cells through 4 main types of receptors
• -hormones are meant to be transitory signals
• hormone effects are inherently probabilistic in nature and not deterministic
• hormonal control is quite complex because it controls complex physiology and must be robust, reliable and adaptable ( animals change) 
• the factors governing hormone evolution are well known and we assume that factors have bene the same throughout the history of earth
• he laws of chemistry and physics are constant and unchanging
• we can look back through time by looking at existing animals, since the rules governing evolution haven’t changed 
• evolution always surprises us with novel solutions to problems
• found at all levels of hormone action 
• Hormone- any chem compound released by cells into the blood to control the activities of other cells 
• Operation definition- hormones are a subset of the 1000s of chem compounds, lipids, proteins, and peptides released by cells 

  • Released by endocrine cells (secreted in blood) 
  • Target cells have receptors that bind the hormone 
  • Receptor is a discriminator that understands the message carried by hormones 
• *What is a magic act? 

  Signal transduction is mediated by a receptor 
• What have well understood processes of genetic and physiological changes led to? 

  • Speciation
• What do these same evolutionary processes drive?

  The evolution of endocrine systems
• What is evidence that something is a good mutation? Give an example.

  • Offspring have a trait that will make it more successful than without that trait
  • Sickle cell syndrome exists because the mutation in hemoglobin provides protection against malaria, if you have one copy of the gene (haploid), you have a higher resistance to malaria. Problem is when you have 2 copies of the gene, then you have sickle cell anemia
• If we look at 2 sequences, how do we know if they come from the same ancestor/place?

  •  We look to see how similar they are - homology!
• What do we base our understanding of similarities on?

  • essentially a clock, records millions of years of changes in the genetic code
• What is the mutation rate amongst species (dissimilar or similar)? What does a mutation rate act as?

  Mutation rate is relatively similar among species and acts as a molecular clock
• What is an assumption about mutation rate? How many base pairs a year? What is the mutation rate essentially?

  • That it's fairly constant over time
  •  1/10^6 base pairs/year
  • Essentially an error rate!
• Why is the mutation rate fairly constant over time

  Bc if you mutated your genes very easily, you might end up dying before you reproduce! So the people who mutate their genes very rapidly don’t live to give offspring, so those genetic changes are not saved
• How do you measure mutation rate?

  Look at generations of animals and how different their genome is
• Why is error rate important

  Bc you don’t want a perfectly replicated DNA as an animal throughout history bc mutations give rise to change and animals need to change because the environments constantly changing, global warming occurs which causes the environment to change as well, etc., so genome needs to change to adapt
• When an adaptation occurs, and when you change the structure of something in your genome, what are the two possibilities you end up with?

  1. Gain of function mutation
  2. Loss of function mutation

  • I.e. sickle cell syndrome, altered the structure of hemoglobin
• Is a large part of the genome the same?

  Yes! Large part of the genome is repeated. Although it is functional, majority of it does not code for proteins, peptides, and hormones
• What happens when a mutation occurs in a repeated area? 

  What about in the coding region?

  • Repeated area: does not change anything
  • Coding region: does cause change! “Changing the language”, mutations in exons and introns affect gene expression and structure
• What percentage is coding/noncoding?

  Less than 5-10% is coding! Approx. 90% is noncoding
• What is a “conservative change”?

  Example: swap one hydrophobic amino acid for another, you don’t get that much structural change in the protein or peptide! I.e., alanine to glycine or leucine
• What is a “non-conservative change”?

  • Example: change something hydrophobic to hydrophilic
  • Completely changes structure of protein/peptide, i.e. serine to asparagine
• What do transcription factors do?

  Bind lipid soluble metabolic products, dimerize and affect gene transcription
• How do we know that hormones are related?

  Bc the changes within those proteins are subtle
• What do Farnesoid X Receptors do?

   What do they inhibit?

  What sort of feedback loop is this?

  • Bind bile acids, dimerizes and translocates to the nucleus
  • Inhibits the expression of enzymes needed to produce bile acid
• Would this be considered a hormone?

  • Negative feedback loop
  • No, doesn’t follow operational definition (does not rely on blood to carry it from one place to another)
• Are older versions of FxR “more promiscuous”? 

  What is this a consequence of?

  • Yes, able to bind compounds other than bile acids
  • A consequence of normal mutation rate, accumulate enough base pairs so you change the structure of the binding pocket, now other compounds instead of glycolic acid will bind to that pocket, so something new can control bile acid production (example of a gain of function mutation)
• What can the known mutation rate be used to determine? 

  What comparison does this require?

  • When two species have diverged
  • Requires comparison to fossil record (if available) and examination of sequences in extant species
• If two peptides share at least 60% sequence homology, what does this percentage indicate?

  What is a complication of this?

  • ndicates that it likely couldn’t have arisen by chance
  • Precise location of cysteine residues implies homology even if the 50% to 60% homology target is not met. 

   -  Many hormones, such as insulins, have cysteines in specific places, repeated, and distance between them is almost identical, low % this happened by chance! Anchored cysteine residues imply homology
• 2 Sequences with the same structure arose by only a few processes, name 3 of them.

  Speciation, duplication event, horizontal gene transfer
• Define:

  Homologue

  Orthologue

  Paralogues

  • Homologue: Protein or gene are homologous if they share sequence homology bc of a common ancestor
  • Orthologue: Homologous proteins in different species that evolved from a common ancestor through speciation
  • Ex. Ancestors of humans and apes had a globin gene which deviated after speciation into different genes
  • Ex. Histone proteins
  • Paralogues: Sequences are paralogous if created by a gene duplication event. Commonly found in 2 different places in the genome. Not regulated in the same way. Can be genes or large pieces of chromosomes
• Genes separated by speciation are called _____.

  Orthologues